Malaria is an infectious disease and a serious public health problem in the world, with 3.3 billion people in endemic areas in 100 countries and about 200 million new cases each year, resulting in almost 1 million deaths in 2018. Although studies look for strategies to eradicate malaria, it is necessary to know more about its pathophysiology to understand the underlying mechanisms involved, particularly the redox balance, to guarantee success in combating this disease. In this review, we addressed the involvement of oxidative stress in malaria and the potential benefits of antioxidant supplementation as an adjuvant antimalarial therapy. Malaria is an infectious disease and a serious public health problem, with 3.3 billion exposed people in endemic regions at risk of contracting the disease in 85 countries. According to the latest World Malaria Report from the World Health Organization (WHO), in 2020, there were an estimated 241 million cases of malaria and 627,000 malaria deaths worldwide. Compared to the year 2019, there was an increase of about 14 million new cases and 69,000 more deaths. About 47,000 of these additional deaths were related to disruptions in the provision of malaria prevention, diagnosis, and treatment during the COVID-19 pandemic [In the Americas, about 138 million people live in areas at risk of malaria, with 765,000 cases of the disease being reported . VenezuePlasmodium reported to infect humans, however, the deadliest form of the disease, cerebral malaria, is associated with Plasmodium falciparum infection, although there are reports describing severe manifestations, and even deaths, caused by Plasmodium vivax [To date, there are six species of um vivax . The maium vivax . Plasmodium resistance to drugs is growing worldwide, especially in endemic areas. In addition to quinine and chloroquine [oroquine , resistaoroquine , atovacooroquine , mefloquoroquine , and to oroquine ,10. In tInfection by the parasite triggers oxidative stress that consists of the host’s redox imbalance due to the high production of reactive oxygen and nitrogen species (ROS/RNS), to the detriment of the host’s endogenous antioxidant defenses. The production of these oxidizing compounds occurs through the degradation of hemoglobin by the parasite, which uses it as a source of amino acids for its nutrition, as well as through the host’s immune response, which produces ROS/RNS inside the phagocytes, a process called respiratory burst, alongside the involvement of ischemia-reperfusion syndrome (SIR) .The increase in oxidative stress in malaria is responsible for systemic and tissue oxidative damage, affecting organs such as lungs and brain. This redox imbalance has been related to the most serious manifestations, such as cerebral malaria, and, depending on the lesions in the brain parenchyma, it can lead to physical and cognitive impairments .To combat oxidative changes, the host organism has an antioxidant defense system that uses enzymes and small antioxidant molecules to fight free radicals produced by the infection . HoweverSupplementation with antioxidants represents a promising therapeutic alternative in malaria, which would prevent or reduce the oxidative damage generated by the parasite and by antimalarials. Based on this idea, several studies have demonstrated the beneficial role of antioxidant supplementation in fighting the infection and restoring redox balance. The supplementation with vitamins A ,19,20,21Agaricus sylvaticus [Supplementation with other substances is also reported, such as N-acetylcysteine (NAC) ,27, minelvaticus .In addition, it has been reported that vitamin A and zinc supplementation in pregnant women prevents placental malaria . AdditioThus, this review aims to demonstrate the role of oxidative stress in malaria, emphasizing the benefit of antioxidant supplementation as a complementary therapy to drug treatment.Oxidative stress in malaria is involved in various stages of infection and, depending on the stage of the disease, can be both harmful and beneficial during plasmodial infection ,35,36. IP. falciparum malaria.In a similar study, Nsiah et al.  identifiP. berghei infection, suggesting them as mediators of the increase in the conductance of pulmonary endothelial fluid.Complications in severe malaria are systemic, with impairment to the pulmonary and central nervous system. Pulmonary manifestations such as cough with or without sputum and dyspnea have been described . AnotherP. berghei infection in mice has been associated with brain damage, with long-term physical and cognitive dysfunction [Cerebral malaria is a fatal complication, and oxidative stress in the central nervous system is related to the development and worsening of the disease . Studiesfunction . The parfunction . These cfunction .In addition to the involvement of these key organs, the role of oxidative stress in the myocardial wall and in the high pulmonary pressure in children with severe malaria has also been demonstrated, and it is caused by intravascular hemolysis and a decrease in nitric oxide (NO) production, with a consequent cardiopulmonary effect . AdditioAccording to Percário et al. , the indP. falciparum present impaired oxidative burst due to increased plasma heme, resulting in cerebral vasculopathy [In the initial stage of infection, neutrophils are one of the first defense cells. When activated, they can destroy malaria parasites through various mechanisms, mainly through the production of ROS/RNS through oxidative stress . The neuulopathy . Additioulopathy ,52,53,542O2), but the regulation of these factors is still unclear. According to Borges et al. [2O2 production in those animals.The proinflammatory response is associated with the severity of cerebral malaria, with an increase in nitric oxide (NO) and hydrogen peroxide , and the ROS/RNS generated by this enzyme increase the secretion of cytokines induced by the parasite and the surface expression of CD80 in DC. Therefore, oxidative stress during infection contributes to the inflammatory response, with an increase in CD4+ T cells and DC [+ T cells by DC give rise to subsets of helper T cells (Th), including Th1, Th2, or Th17, leading to the production of IFN-γ, interleukin-4 (IL-4), or IL-17, respectively [During the inflammatory process of the disease, oxidative stress influences the maturation and function of dendritic cells (DC) in response to infection by s and DC ,51. It iectively .This suggests that the severity of infection and inflammatory cytokine production correlate with plasma XO levels in patients with malaria. In a study conducted by Ty et al. , the ROS2O2 through the Fenton (or Haber–Weiss) reaction, oxidizing the iron and producing highly toxic free radicals, such as the hydroxyl radical (OH•) and superoxide (O2●--) [2●-, generating in this reaction even more H2O2 and OH• [Malarial infection results in a high production of ROS/RNS, which are harmful to both the host and the parasite. Initially, the parasite inside the erythrocyte degrades hemoglobin to use its amino acids for its nutrition, and the rapid growth of the parasite in the host cell is not only dependent on nutritional absorption but also on the redox balance . The iro (O2●--) ,59. In t and OH• .P. falciparum lipocalin (PfLCN) expressed during the parasite intra-erythrocyte development. It is located in the parasitophoric and digestive vacuoles, neutralizing the cellular damage caused by oxidative stress during the reproduction of Plasmodium sp. in erythrocytes.The oxidative stress generated at the erythrocytic level affects both the parasite and the host cell through oxidative changes triggered mainly by the lipid peroxidation of red blood cells ,62. HoweMoreover, due to the high density of parasitized erythrocytes in the pulmonary and cerebral microvasculature obstructing blood flow, ischemia and reperfusion syndrome occurs, producing hypoxia in these tissues, which is probably responsible for pulmonary and brain lesions. Since free radicals and inflammatory components are generated in this syndrome, the damage is accentuated ,64,65.Plasmodium. Accordingly, a recent study found that the absence of NADPH-oxidase expression, an important enzyme in the synthesis of free radicals by macrophages, caused no differences in the progression of parasitemia in knockout mice for any of the Plasmodium species tested . These findings led the authors to believe that free radical production increased as a result of infection and not from the respiratory burst of phagocytes, possibly due to production by the parasite itself [Besides host ROS/RNS production in response to infection, the parasite itself is capable of producing free radicals, which in turn interfere with the biochemistry of red blood cells and may promote or facilitate the internalization of the parasite in hepatocytes and red blood cells (RBC). Despite scarce exploration in the scientific literature, aerobic membrane transport mechanisms are a major source of ROS/RNS generation in e itself . AnotherAnother factor that generates oxidative stress during plasmodial infection is the treatment itself, as antimalarial drugs are pro-oxidant sources ,68. An eIn a study by Giovanella et al. , in whicPlasmodium-rich histidine-II and III proteins, generating an accumulation of toxic ferriprotoporphyrin IX, with consequent oxidative stress [Artemisinin and its derivatives also display antimalarial activity by inducing ROS/RNS production, which oxidizes proteins and lipids within infected erythrocytes . Furthere stress ,76. Artee stress .●, O2●-, NO, lipid peroxide radical (LOO•), H2O2, and singlet oxygen (*O2) [Biological systems produce, through fundamental chemical processes for cell maintenance, unstable and highly reactive molecules that can cause oxidative damage. These molecules, called free radicals or ROS/RNS, are produced continuously by the cells and are involved in energy production, growth regulation, cell signaling, endothelial pressure control, and the phagocytosis of pathogens ,79. Amonen (*O2) ,81,82.Notwithstanding the harmful effects of ROS/RNS, their production can also occur from endogenous sources, for example, NADPH, myeloperoxidase (MPO), phagocytosis , and exoPlasmodium via oxidative stress during the erythrocytic phase [During malaria infection, ROS/RNS are involved in the destruction of ic phase . Howeveric phase . The stiic phase . On the ic phase .2●− from NAPH oxidase (NOX), acting on O2, which is later converted into H2O2 and OH●. The NOX enzyme is found in the cytoplasm and phagosome membranes of neutrophils, producing ROS/RNS that diffuse through the membrane, destroying extracellular phagocyted and intracellular parasites via oxidative stress [Defense cells such as neutrophils can destroy the parasite through respiratory explosion, initially producing a high amount of Oe stress .One of the main ROS/RNS involved during malaria infection is NO, which is synthesized from the amino acid L-arginine, through the action of nitric oxide synthase (NOS). Three isoforms of NOS are characterized, according to tissue location, two constitutive forms (cNOS) and one inducible (iNOS). Constitutive forms include neuronal NOS or NOS-I, expressed in neuron cells during neurotransmission, and endothelial NOS or NOS-III, produced in endothelial cells to promote vasodilation. The inducible form (iNOS or NOS-II) is activated by inflammatory cells producing large amounts of NO in a short time ,95.The role of NO in malaria is still unclear, but some researchers suggest that cerebral malaria is related to high NO production to promote parasite death ,96,97,98●-, inducing oxidative stress, or indirectly by increasing the immunological response via cytokine stimulation and increased ROS/RNS [Indeed, NO can act in two main ways to control malaria, directly through the parasiticidal action of peroxynitrite generated by the reaction of NO with O2 ROS/RNS .Moreover, many authors believe that NO and carbon monoxide (CO) display a protective effect against cerebral malaria, as they inhibit severe forms of the disease. This effect is related to three main mechanisms, which are the expression of erythroid-related nuclear transcription factor 2 (NRF-2), the induction of HO-1, and the production of CO via heme catabolism by HO-1.+ and the activation of CD8+ T lymphocytes, through a mechanism related to HO-1 and CO [In addition, the protective effect of NO on this disease is related to the inhibition of CD41 and CO . Additio1 and CO . In a si1 and CO , the preP. vivax and P. falciparum malaria. These authors concluded that the iNOS polymorphism acts in the regulation of NO expression, and genotyping increases the risk of developing the disease, since there was a reduction in total antioxidant capacity and ROS during infection [However, there are researchers who believe that NOS polymorphisms do not prevent the onset of cerebral malaria. To them, this conclusion was reached from the evaluation of the genetic regulation of NO synthesis, through the levels of oxidative stress and polymorphisms of iNOS in nfection .P. falciparum malaria compromised the microvasculature and resulted in greater consumption of O2 in the tissues. In addition, the reduced bioavailability of arginine and NO result in endothelial dysfunction in P. vivax malaria, causing microvascular injury [Nevertheless, there are studies that suggest that the reduction of NO bioavailability is related to the worsening of malaria, such as the study by Yeo et al. , in whicr injury .The dysfunction of NOS is also related to the reduction of NO bioavailability in malaria, as in Ong et al. , who assP. falciparum-generated hemozoin, from the digestion of hemoglobin in infected red blood cells and released into the bloodstream, accumulates in leukocytes, and high levels are related to the severity of the disease. Studies have shown the low bioavailability of L-arginine and NO in P. falciparum malaria and positively correlated it with hemozoin levels [P. falciparum-induced hemozoin reduced the bioavailability of the amino acid L-arginine to iNOS, with a consequent reduction in NO synthesis in macrophages. Moreover, monocyte polarization during P. falciparum malaria infection reduced the NO bioavailability and increased the severity of the disease in children [Another factor related to the reduction of NO is that n levels ,108. In n levels , P. falcchildren .P. berghei-induced cerebral malaria in mice and observed that sildenafil (a phosphodiesterase-5 inhibitor) reduced the level of NO required to prevent cerebral malaria, while L-arginine and tetrahydrobiopterin increased NO bioavailability but did not increase the survival rate of infected animals.Other authors support the idea that the reduction of NO bioavailability to a certain level in malaria by exogenous inhibitory substances used in the treatment provides a protective role against the worsening of the disease. This fact was identified by Martins et al. , who evaP. berghei. On the other hand, when NO synthesis is inhibited by Nω-nitro-L-arginine methyl ester (L-NAME), there is an increase in animal mortality, with a consequent reduction in parasitemia in P. berghei-infected mice, suggesting that the physiological effects of NO outweigh its pro-oxidant role in experimental malaria [According to Moreira et al. , the inh malaria .P. gallinaceum increased chickens’ survival, but there was an increase in parasitemia. Nevertheless, aminoguanidine was able to reduce thrombocytopenia, anemia, and inflammation by reducing hemozoin in the liver and spleen of infected animals [In a similar study, the inhibition of NO synthesis by aminoguanidine in avian malaria caused by  animals .P. falciparum malaria, identified that there is a reduction in arginine levels in both children and adults. It has been described that the reduction of liver activity by asymmetric dimethylarginine inhibits NO synthesis in severe malaria [Weinberg et al. , by inhi malaria . Based oIn this sense, to increase the bioavailability of NO in malaria, some researchers have suggested that supplementation ,116 or iP. yoelii in mice reduced parasitemia and prolonged the survival rate of infected animals. In addition, there is an increase in activated CD4+ and CD36+ T cells and macrophages during the first stages of infection, followed by an increase in IFN-γ, TNF-α, and NO in spleen cells.In a study by Zhu et al. , supplemIn addition to supplementation, the inhalation of NO gas improves clinical features in children with severe malaria who are undergoing standard antimalarial treatment, since this suggestion is based on NO acting on the modulation of endothelial activation, and supplementation with L-arginine is effective against cerebral malaria in animals and improves endothelial function . A studyP. falciparum has been reported [Notwithstanding, other studies suggest that arginine therapy is controversial because the parasite has highly active arginase and can cause hypoarginemia in the host, impairing the bioavailability of NO ,121,122.reported .Any substance that, when present in low concentration compared to an oxidizable substrate, can prevent or delay the oxidation of the substrate is considered an antioxidant. Antioxidants are mainly involved in preventing, blocking, or quenching ROS/RNS and, consequently, oxidative stress, as well as other parameters of cell damage ,126. EndPlasmodium destroys red blood cells, leading to the production of large amounts of free radicals. In addition, neutrophils and macrophages are recognized for producing O2●− radicals and H2O2, which are essential for defense against phagocytes or invasive parasites. Therefore, antioxidants are necessary to regulate the reactions that release ROS/RNS.During the infectious process of malaria, The main enzymatic antioxidants that constitute an important line of defense for the body include SOD, catalase (CAT), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), and peroxiredoxins Prx; . These aP. falciparum malaria.There is enough evidence that antioxidants contribute to the balance between pro- and antioxidant status related to anemia development and clinical features of malaria infection ,128. In 2O2, reducing it to water [2O2 and lipid peroxides (ROOR) into less harmful molecules, such as H2O, alcohol, and O2 [CAT is a tetrameric hemoprotein present in liver cells and erythrocytes in high concentrations. It undergoes divalent oxidation and alternating reduction in its active site in the presence of Hto water . Like CA, and O2 . The thi, and O2 .2O2 due to the decrease in CAT and GSH-Px activities in patients with malaria can inactivate SOD activity, which catalyzes the conversion of O2•− into H2O2. In a study by Babalola et al. [P. falciparum malaria, but the start of antimalarial treatment resulted in an increase in the activity of GSH, SOD, CAT, and GSH-Px.However, the accumulation of Ha et al. , reduceda et al.  found a a et al. , with a 2+) to ferric iron (Fe3+), preventing a Fenton reaction and the consequent production of OH● radicals.In parallel, Ezzi et al.  demonstrP. vivax malaria. These patients displayed decreased thioredoxin reductase (TrxR) activity, which catalyzes the disulfide reduction of the protein binding site using NADPH, being essential for the maintenance of the redox balance. NO, derived from parasite–host interactions, is involved in the regulation of TrxR expression, which can lead to decreased levels of this enzyme in patients with P. vivax malaria [P. falciparum infection, the GSH system reduces Trx, which is the substrate for TrxR [Previously, a clinical study conducted by Fabbri et al.  showed a malaria . Moreovefor TrxR . On the for TrxR .The other line of defense consists of antioxidants and cofactors with low molecular weight in the diet, including flavonoids, alpha-tocopherol (vitamin E), ascorbic acid (vitamin C), carotenoids, lipoic acid, selenium, copper, iron, zinc, GSH, and coenzyme Q, among several others ,138. TheP. falciparum malaria; however, there was a reduction in ascorbate levels in both cases [P. falciparum malaria [The levels of non-enzymatic antioxidants and the total antioxidant status (TAS) in patients with malaria and dengue were evaluated, and an increase in GSH levels was observed in dengue and th cases . In anot malaria .Dietary antioxidants were linked to the modulation of host susceptibility or resistance to infectious pathogens. Several pieces of evidence relate micronutrient deficiencies to malaria incidence, especially in endemic areas ,141. MalMicronutrients are antioxidants that play a vital role in fighting anemia and other adverse effects of malaria infection. However, a reduction in total antioxidant capacity is associated with the severity of malaria: the more severe the malaria, the lower the total antioxidant capacity .Plasmodium sp. [In assessing the impact of malaria on the total antioxidant status of children, studies have found a strong and negative correlation between parasitemia and total antioxidant levels. In this sense, Cu, Fe, vitamin C, albumin, and β-carotene, which have been reported to have a modulating effect on malaria pathogenesis, were considered deficient in children infected with dium sp. ,145. TheMalaria appears to interfere with children’s nutritional status, with a marked reduction in the speed of linear growth and the impairment of other indices associated with chronic malnutrition. According to Alexandre et al. , childreA study by Sakwe et al.  also demPlasmodium were low, and that the more severe the infection, the lower the levels of these antioxidants [In this sense, vitamin A is essential for normal immune function and can influence the antibody response and cell-mediated immunity against different infectious diseases ,149. A soxidants . Recent oxidants ,152.Plasmodium to neutralize oxidative damage associated with malaria infection. Thus, adequate medical and nutritional management must be ensured to prevent the adverse effects of malaria infection [The low levels of antioxidants observed in these studies may result from the greater use of plasma host antioxidants by nfection .To improve the host’s antioxidant and immunological response against malaria, recent studies have demonstrated the potential benefits of supplementation with antioxidant compounds from plants, mushrooms, vitamins, and drugs, which would act by modulating the host’s response, strengthening the endogenous antioxidant defense against oxidative stress or acting indirectly towards parasite destruction.Terminalia albida [Terminalia avicennioides, rich in gallic acid [Acacia nilotica, which displayed in vitro schizonticidal activity against P. falciparum [Artemisia annua L combined with artemisinin [Dacryodes edulis and Ficus exasperata [Momordica charantia, Bixa orellana, Allamanda cathartica, Ficus exasperata; Cymbopogon citratus [Dissotis rotundifolia [Trichilia heudelotii, Polyalthia longifolia, and Markhamia tomentosa [Some promising plants tested displayed high antimalarial and/or antioxidant activity, such as the stem bark of a albida , which ilic acid ; extractlciparum ; flavonoemisinin ,158; flaasperata ; phenolicitratus , Dissotindifolia , Trichilomentosa . It has omentosa ,164.Aspidosperma nitidum, an Amazonian medicinal plant, reduced parasitemia by 80% on the 5th day of P. berghei-infection in mice; however, this reduction was not sustained until the 8th day of infection. In addition, the antiplasmodial activity of the ethanolic extract of A. nitidum was identified in vitro against a chloroquine-resistant P. falciparum clone. In a similar study conducted with a plant of the Amazon region, Vale et al. [Eleutherine plicata, and this effect was associated with the cytochrome bc 1 complex, according to a molecular modeling study. Such in vitro antimalarial action of quinones isolated from medicinal plants has already been reported as possible candidates for new antimalarials [Brandão et al.  identifie et al.  identifialarials ,168.Agaricus sylvaticus in P. berghei-infected mice, concluded that both supplements reduced parasitemia during infection and increased the total antioxidant capacity of animals, with A. sylvaticus being more effective in reducing oxidative damage. Notwithstanding, both represent important adjuvant treatment strategies in malaria. Nevertheless, in another study, NAC was unable to protect pregnant P. chabaudi-infected mice [Another therapeutic alternative with possible antimalarial action tested is supplementation with commercial drugs that contain antioxidants in their formulation, such as L-glutathione, NAC, melatonin, fenozyme, deferoxamine, or folate. Among the studied drugs, one that displayed very promising results was NAC, a drug widely used as a mucolytic agent and that has become the target of studies as an antioxidant supplement for adjuvant therapy for malaria, as it is an exogenous precursor of GSH, one of the main components of the antioxidant defense system ,169,170.ted mice .Plasmodium falciparum, essential for the synchronization of the parasite [Regarding the action of melatonin, an endogenous hormone synthesized and released by the pineal gland, studies suggest that it can perform important functions in the pathophysiology of malaria . In factparasite ,173,174.Melatonin has also been described as capable of modulating genes that are coupled to aerobic respiration and ATP production, including S-adenosylmethionine decarboxylase/ornithine decarboxylase, glutamine synthesis, and the synthesis of the alpha subunit of succinyl-CoA and acyl-CoA, favoring the metabolic pathways of the replication of the parasite .Plasmodium-infected animals [Additionally, it has been demonstrated that melatonin is a powerful antioxidant, capable of direct and indirect elimination of ROS/RNS and that it easily crosses the blood–brain barrier, conferring protection to brain cells and providing increased survival to  animals ,178,179.Plasmodium berghei ANKA, as well as clinical changes and neurocognitive dysfunction, resulting in protection against changes induced by experimental cerebral malaria. Thus, the neuroprotection of melatonin may be associated with its antioxidant effect that attenuates oxidative stress and the inflammatory process, which are marked features of cerebral malaria [In this sense, Ataide et al.  showed t malaria ,182.Another antioxidant with beneficial effects is fenozyme, a mimetic nanoenzyme of catalase. In the study by Zhao et al. , the admPlasmodium [Another molecule that plays a key role in brain function, energy metabolism, and neurotransmission is iron , which iasmodium . Clinicaasmodium ,187. It asmodium . Plasmodium falciparum strains. According to the authors, the combination of iron chelator antioxidants and antimalarial agents is a promising strategy for the prevention of cognitive damage in patients with severe malaria.In a recent study, Tiwari et al. , reporteAccording to Dey et al. , deferoxNotwithstanding, it is noteworthy that malaria and malnutrition often coexist, and evidence suggests that malnutrition has a detrimental effect on malaria immunity, especially in pregnant women and children, so that supplementation with nutrients, including iron and folic acid, can help in the development of malaria immunity and reduce malaria susceptibility in high-risk groups ,192.Prado et al. , in a raOn the other hand, in a prospective cohort study that included 636 mothers and only children of 828 pregnant women who received daily iron and folic acid supplements throughout pregnancy, Mireku et al.  observedPlasmodium depends on the availability of iron.In fact, iron supplementation does not seem to be completely safe, especially in endemic environments, and may increase susceptibility to malaria ,196. In Plasmodium infection, iron deficiency, or anemia, compared to folic acid supplements isolated in the pregnant or non-pregnant cohort. According to the authors, iron supplementation, as routinely given to populations in a hazardous area, is not useful and is potentially harmful.Moreover, a double-blind, randomized, and controlled study of non-inferiority in rural Burkina Faso, Gies et al. , in an aNevertheless, several antioxidants are promising as adjuvant therapy of malaria. In a study by Penna-Coutinho and Aguiar , an antiAmong the studies of antioxidants tested in malaria, the most studied to date are vitamins, which can reduce or prevent oxidative damage generated by antimalarials or triggered by the presence of the parasite in the host.Vitamins are responsible for optimizing molecular performance and cellular protection against oxidizing agents, and the intake of these micronutrients is essential for the proper functioning of the immune system. Supplementation with antioxidants for malaria patients represents a complementary alternative to drug treatment, since vitamins promote a better balance between pro-and anti-inflammatory cytokines, which is essential for malaria control ,202,203.Vitamin supplementation as an adjuvant to antimalarial therapy is addressed in several studies, both in isolated form and in vitamin complexes, with promising results. Olofin et al.  investigPhyllanthus amarus seed, chloroquine, and artesunate with vitamins A, B, C, and E, pointed to a greater antioxidant capacity and parasiticidal effect of P. amarus when combined with vitamins A, B, or E. In addition, there was an increase in the antimalarial activity of drugs combined with vitamins A, B, or E. In this study, supplementation with vitamin C did not show good results.Ojesele et al. ,205, whoP. berghei-infected mice, and found that the supplement improved hematological parameters; however, neither mortality nor parasitemia were significantly reduced.Few studies have been conducted evaluating the role of vitamin C alone. Despite its known antioxidant capacity, vitamin C supplementation has not displayed relevant results in the treatment of malaria, such as those presented by Ekeh et al. , who evaP. yoelii in mice, observed that administering vitamin C  increased the immune response during the early stages of malaria infection, regardless of dose. In addition to vitamin C, vitamin A and vitamin D have been studied alone as adjuvants for malaria therapy.In contrast, Qin et al. , when evPlasmodium parasitemia. Hamzah et al. [P. berghei. The results showed a prophylactic function of retinol, with the reduction of parasitemia due to the increase of retinol stock within tissues.Another important vitamin in antioxidant defense is vitamin A, which acts in modulating innate and adaptive immune responses and protecting cells against the deleterious effects of oxidative stress ,141. In h et al.  evaluateVitamin A supplementation was also evaluated in a murine model of cerebral malaria; however, although no difference was observed in the conditions associated with cerebral malaria, mortality was reduced during adjuvant treatment with this vitamin .Following the principle of the high antioxidant power of vitamin A, several studies associated this vitamin with Zn to enhance cellular protection against oxidative stress generated during malaria infection. Zeba et al. , throughAdditionally, Owusu-Agyei et al.  evaluateP. yoelii or P. berghei, observing a reduction in parasitemia. Nevertheless, the mortality rate was not significantly altered in animals infected with P. yoelii, while, in those infected with P. berghei, the treatment reduced parasitemia and delayed the outcome of cerebral malaria. These data corroborate the effectiveness of vitamin A as an adjuvant supplement in the treatment of malaria, in addition to positively influencing the reduction of mortality.In a more recent study, Chen et al.  investigAnother vitamin studied for its antioxidant properties is vitamin D, a fat-soluble vitamin synthesized in the skin after exposure to solar ultraviolet radiation or provided by the diet. In addition to its traditionally known roles in the regulation of bone metabolism and calcium–phosphorus homeostasis, vitamin D is able to act through several mechanisms, including protein expression or the modulation of oxidative stress, inflammation, and cellular metabolism . NeverthP. berghei in susceptible mice. The authors suggested the protective effect of vitamin D occurred through the inhibition of a strong proinflammatory response from the host (IFN-γ and TNF-α), mediated directly by its action on Th1 cells, as well as indirectly through the inhibition of innate immunity. In addition, treatment with vitamin D expanded the regulatory T cells (Tregs) and inhibited the differentiation, maturation, and functioning of DC, which altogether resulted in the increased expression of IL10.He et al. , showed The antimalarial activity in knockout mice for the vitamin D3 receptor (VDR) and its 22-oxacalcitriol analog (22-OCT), which causes less hypercalcemia than vitamin D3, is related to the direct and indirect action of VDR, resulting in a reduction of IFN-γ with a consequent increase in the survival of infected animals .P. berghei and conferred protection against cerebral malaria. In addition, the integrity of the blood–brain barrier was restored. Recently, Wu et al. [In the study by Dwivedi et al. , the comu et al.  also verP. berghei-infection. In the same year, Ibrahim et al. [P. berghei, showing an antagonistic effect of vitamin E when combined with the medication [P. falciparum synthesizes vitamin E for its own antioxidant defense as a protection against ROS generated by antimalarial treatment, but when vitamin E biosynthesis is inhibited in the parasite by succinic acid, there is an increase in ROS levels, causing the death of the parasite [Another fat-soluble vitamin tested is vitamin E. However, few studies have shown beneficial effects from supplementing this vitamin in the treatment of malaria. In a study developed by Ibrahim et al. , the intm et al.  found thdication . It has parasite .Studies showed that a reduction of vitamin E has a beneficial and protective effect on malaria and that this effect is related to the inhibition of the transfer protein α-tocopherol (α-TTP), which regulates the levels of this vitamin. However, vitamin E deficiency in the diet impairs the integrity of the erythrocyte membrane that is susceptible to ROS/RNS aggression ,214,215.The parasite is sensitive to in vitro and in vivo oxidative stress induced by antimalarials, such as artemisinin , chloroqAccording to WHO recommendations, artemisinin is the main drug that can be combined with other antimalarials, such as artemether-lumefantrine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, artesunate-sulfadoxine-pyrimethamine, artesunate-pyronaridine, and artesunate-mefloquine. Artemisinin is identified by the presence of the endoperoxide group in its structure, which is responsible for its antimalarial activity , for it To reduce the damage caused by ROS/RNS as a consequence of infection and antimalarial treatment, supplementation with antioxidants has been suggested. However, according to Isah and Ibrahim , the rolP. berghei compared to artemisinin monotherapy. In a similar study, it was identified that the combined therapy between chloroquine and NAC results in a synergistic effect, generating a reduction of parasitemia and MDA levels in P. berghei-infected mice [Regarding NAC, the study by Fitri et al.  sought tted mice .Plasmodium only to some extent [Mckoy et al. , when eve extent . Thus, ve extent . Plasmodium berghei. However, in a study conducted by Iyawe and Onigbinde , who souA. sylvaticus).The involvement of oxidative stress in malaria is complex and progresses with changes in the host’s pro-oxidant and antioxidant balance. The main sources of antioxidant defenses involved in malaria are: (1) host enzyme antioxidants ; (2) host non-enzymatic antioxidants ; (3) non-enzymatic antioxidants from the host’s metal chelation system ; (4) exogenous antioxidants of dietary origin or drugs (flavonoids, phenolic compounds, minerals, NAC, and the mushroom The studies presented in this revision showed that supplementation, mainly with vitamins A and D, is advantageous. This provides a potential and beneficial strategy for the prophylactic application of vitamins and the prevention of malaria.Notwithstanding, supplementation with antioxidants from different sources would act in the prevention and control of oxidative changes generated by the parasite during infection, with a consequent increase in the total antioxidant capacity and a reduction of cellular damage to the host, constituting a complementary therapy to antimalarial treatment. However, further studies are needed to corroborate this hypothesis.


Ethiopia is a Sub-Saharan African country with a high annual malaria case count, owing to the majority of the country's geography favoring vector rearing. As part of the country's prevention-based health policy, substantial efforts have been made to control and prevent malaria transmission. The objective of this study was to determine the prevalence of malaria and the associated factors in the community of Mizan-Aman and its catchment. P value of <0.05.  From September to October 2021, a community-based cross-sectional survey was undertaken among the communities of Mizan-Aman town and its catchment area in Southwest Ethiopia. A pretested structured questionnaire was used to collect sociodemographic data, as well as a capillary blood sample from each study participant. Epi-data manager (v4.0.2.101) was used to enter the data and analyzed by SPSS version 25.0. A statistical significance was set at a  The study comprised a total of 412 people, of which 87 (21.1%) tested positive for malaria parasites, with a greater prevalence reported among those aged 25 to 34 years (5.8%). Individuals who lived near stagnant water were more likely to become infected with the malaria parasite  compared to those who lived further away, in warm climates, and those who did not use insecticide-treated bed nets were more susceptible to malaria parasite infection  compared to those who did use ITN and With ; participants with a history of antimalarial medication appear to have a protective function against malaria infection, respectively. Plasmodium falciparum accounting for the vast majority of cases. The overall malaria prevalence in this study was 87 (21.1%), demonstrating that malaria remains a significant concern to the populations in the study area, with  Malaria is a serious public health issue that continues to cause illness and death. According to data from 85 malaria endemic countries, the worldwide malaria burden increased from 227 million cases in 2019 to 241 million cases in 2020, with the majority of the rise coming from countries in the African Region [Due to service disruptions during the coronavirus pandemic, these regions were responsible for about 95% of malaria cases, with 14 million more cases and 47 000 more deaths reported worldwide than the previous year . MalariaAs one of these countries, Ethiopia is plagued by malaria, which poses a serious threat to the country's health and economy. The disease's distribution pattern varies by climate, rainfall patterns, and altitude across the country .Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, and Plasmodium ovale are the four most frequent species that cause human malaria, as well as a fifth parasitic species, Plasmodium Knowles, a monkey parasite [Plasmodium vivax is responsible for the great majority of malaria infections, owing to its widespread distribution [P. vivax. Plasmodium falciparum continues to infect people in tropical and subtropical areas, and it is the most common cause of a fatal type of malaria [parasite . Plasmodribution . The onl malaria .Anopheles mosquito, which is the principal vector. Anopheles arabiensis is the primary vector, with secondary vectors such as Anopheles phronesis, Anopheles funestus, and Anopheles nili [Malaria is spread by the les nili .Plasmodium species begins with a bite from a malaria-infected female Anopheles mosquito as the insect collects its blood meal. The number and variety of mosquitoes present in a specific region, as well as the temperature, determine the risk of infection [Human infection with nfection . Three cnfection . Malarianfection , 13. Malnfection . There anfection .Malaria epidemics are widespread in highland or highland fringe areas in Ethiopia, primarily 1,000 to 2,000 meters above sea level . ChangesMalaria remains a major public health problem despite significant successes and advances in improving people's health and lowering the disease's burden. It is one of the top ten major causes of sickness and mortality in a wide range of people, including children under the age of five and adults . MalariaEthiopia is still among the countries known for having very high malaria burden and in particular the study area (Mizan-Aman town community and its surrounding) was suffering a lot from this disease which is affecting health of the people living in that area as evidenced by the deaths of people in this area including children and pregnant women which consequently results in reduced working capacity and other day-to-day activities of the community as general. So, this study could help to provide additional insight for the country's government to strengthen prevention and control strategies to reduce and cease the health impact of the disease.The study was conducted at Mizan-Aman town and its catchment area from September to October 2021, which is found in the Benchi-Sheko zone, SNNPR region, Southwest Ethiopia.A community-based cross-sectional study was conducted among Mizan-Aman town communities and its catchment area in Southwest Ethiopia. The study's source population was the Mizan-Aman town and its catchment area. The study populations were people who lived in selected households that were available during the data collection period and were chosen by a lottery system from each house in the research area. The study included participants with and without fever who had not used antimalarial medications or antibiotics in the previous month and were willing to participate and voluntarily supply blood samples.n = minimum sample size, P = estimation prevalence rate of malaria 50%, d = margin of error (5%), and (Zα/2))2 = the standard normal variable.The sample size was calculated using a single population proportion formula, and the following assumptions were considered 95% confidence interval; the estimated prevalence rate/proportion of malaria was taken as 50% since no similar study in the region. Based on those considerations, the sample size is calculated using the following formula:After adding 10% for possible nonresponse, the final sample size became 384 + 384(0.1) = 422.Study participants who fulfilled the eligibility criteria were recruited by a systematic random sampling technique considering the population density and proximity of the households to each other. All individuals with and without signs and symptoms of malaria and available during the study period were included. One study subject from each of the selected households was selected randomly to participate in the study. If the selected study participants were an infant/child, guardian/caregiver, or parents, they were interviewed instead. Individuals who were on antimalarial drug treatment, antibiotics therapy within the past 30 days before recruitment, and unable to provide blood samples were excluded.μL (capillary blood from the fingertip), taken by finger prick, and both thick and thin films were prepared according to the standard operating procedures.The data were collected using structured questionnaires modified from previous research  that incMedical laboratory workers collected data after receiving a two-day instruction on the study's goals and how to gain informed consent from the study participants. For data collection, three medical laboratory technologists were recruited, as well as two supervisors to help with the operations.Giemsa was used as it is the standard stain used for staining of blood films for malaria diagnosis, and blood films microscopy was done since it remains a basic technique and the gold standard for the diagnosis of malaria in resource limited settings. Details of the test procedure and principle are shown at the end of the manuscript (Appendix).The data collectors described the data gathering techniques, technologies used, and how to tackle ethical considerations. Before the start of the main study, a pretest was conducted with 5% of the sample size at Tepi town, which is 50 kilometers away from the study area. Data collectors received two days of training on how to collect data. During data collection, the questionnaire was translated into the respondent's native language. The supervisors and the investigators kept a close eye on the data collection process to ensure that everything was done correctly.To detect malaria parasites, the blood films were stained with a 10% Giemsa working solution and examined microscopically using a 100X oil immersion objective, and a thin blood film was prepared according to the SOPs. Epi-data manager (v4.0.2.101) was used to enter the data, and SPSS version 25.0 was used to analyze it. To see if there was a link between the outcome variable and the risk factors, researchers used descriptive statistics and bivariate and multivariable logistic regression.A large number of 412 people who took part in the study were infected with malaria parasites. Malaria was recorded in people of all ages; however, the infection rate was highest in people aged 25 to 34. Malaria parasite prevalence was high among low-income persons, possibly due to people's inability to afford mosquito bed nets. The survey included people from various occupations, with housewives and students contributing disproportionately greater numbers of malaria cases. .Plasmodium falciparum and Plasmodium vivax being the two species that were found  were infected with malaria parasites, with re found .Data was collected from 412 study participants to look into the role of various risk factors in malaria prevalence. As a result, more than three-quarters of them lacked access to insecticide-treated bed nets (ITNs), which contributes to the bulk of malaria cases in our study. Furthermore, nearly two-thirds of those polled said that their home was not sprayed with insecticide chemicals. Individuals who live near stagnant water and in hotter climates were found to be more susceptible to malaria infection .Despite significant financial investments and efforts made both locally and globally to reduce malaria transmission, the disease continues to be the most serious threat to people's health in Sub-Saharan Africa, particularly Ethiopia. This study had recruited a total of four-hundred twenty-two participants; however, only 412 of them with complete data (interviews and blood samples) were included in the analysis, resulting in a none-response rate of (2.4%). The study included two hundred one male and two hundred eleven female participants, and having a low income seems to contribute the most to malaria prevalence in this study (18.7%). Moreover, a quarter of the study, participants were students, who were the second most category after housewives in terms of contribution to malaria positivity rate compared to other occupations in this study.Plasmodium falciparum (10.7%) having the highest prevalence, followed by Plasmodium vivax (9.2%). A study from Butajira, Ethiopia's south-central region, found a Plasmodium falciparum prevalence of 12.4%, which was similar to the current study [). This could be related to the projected decreased exposure and accessibility to the medium of communication in rural communities compared to metropolitan dwellers (9.7%). Malaria cases were found to be more prevalent in warmer/“Kolla” climate conditions (74%), followed by ten (2.4%) and three (0.7%) for medium/Woina Dega and colder/Dega climate conditions, respectively. Although the study participants agreed that “the use of ITNs is a powerful vector control tool for preventing malaria transmission and thus reducing the prevalence of the disease elsewhere in the country where malaria is endemic,” only 20.4 percent of them had ITNs in their homes, and ITN ownership by itself is not a guarantee for its use, as evidenced by the finding that more than three-quarters of the study participants (82.5%) did not utilize a bed net  of the study participants had malaria parasites, with nt study . The prent study . Malaria bed net .In this study, it was discovered that the use of ITNs differs significantly from a study from Kenya, which found that approximately (92.11%) of households use mosquito bed nets, and malaria prevalence is lower among households that use mosquito bed nets (8.05%) than those who do not use mosquito nets (23.11%) .Plasmodium infection . People who now have access to ITNs have also been found to be more susceptible to malaria parasite infection . Using an ITN and having a history of antimalarial medication, on the other hand, appears to protect against malaria infection  and , respectively.The use of ITNs is considered one of the parasite's protective mechanisms; nonetheless, the frequency of malaria among individuals who did not use ITNs (17.5%) was significantly greater than among those who did. More than three-quarters of the study participants said that they did not have an ITN in their home, which is evidenced by the high malaria infection observed among those ITN nonusers. Sixty-two (15.0%) participants whose blood film examination revealed the presence of malaria parasites responded that there was stagnant water nearby their home, as indicated by the high rates of malaria infection among nonusers of ITNs. Sixty-two (15.0%) of those whose blood film tests confirmed the presence of malaria parasites said that there was stagnant water near their residence. People who lived near stagnant water were nearly nine times more likely to contract malaria , while those who lived in hot climates were four times more likely to contract ) [The malaria prevalence found in this study  was lower than other studies conducted in different parts of the world, such as various areas of Nigeria, 64.9%, 227/350), , , ), India 22-26, 36.6%), Malaysia  [/350, (51) , 33, [17) , 35, and.6%, Mala) , South E) , 40, andThe finding of this study could be better given that the testing was done using advanced molecular techniques like polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) which have higher detection capacity compared to light microscopy.Plasmodium falciparum being the most common species. Malaria was more common in people between the ages of 25 and 34. (5.8%). Providing health education that enhances people's knowledge of the disease and changing community ITN usage behaviors may assist to stem the spread of the disease.The overall malaria prevalence in the research was 87 (21.1%), indicating that malaria remains a serious public health concern in the area, with


Some studies have suggested the importance of vitamin D [25(OH)D] in malaria clinical practice. The prevalence of 25(OH)D deficiency in the Amazon population is not well known, and there are few studies in patients with malaria. This study aimed to evaluate 25(OH)D serum levels in patients with malaria and determine their relationships with epidemiological, clinical, laboratory, and parasitemia data.t-test), non-parametric tests (Mann-Whitney U), and Spearman’s correlation  were used according to the nature of the distribution of the variables. For the qualitative variables, Pearson's chi-square test, Fisher's exact test, and the G test were used. Spearman's correlation was used to compare the results of the 25(OH)D levels and blood counts performed among patients and the control group.  An analytical cross-sectional study of 123 patients with malaria and 122 individuals without malaria was performed in Itaituba, Pará, Brazil, from January 2018 to October 2019, by evaluating sociodemographic, clinical-epidemiological, parasitological, and laboratory data and adopting a 5% significance level. Parametric tests , and platelet levels had an inverse correlation with parasitemia (Plasmodium vivax). 25(OH)D deficiency was evidenced in Itaituba, in the state of Pará, which is an endemic area of malaria in the Amazon region.  Malaria patients residing in a mining area had 25(OH)D serum levels that were significantly lower than those in the control group residing in the mining area, though both were within normal levels. Red blood cell counts had an inverse correlation with parasitemia ( There has been a global reduction in the estimated number of malaria cases: 231 million in 2017 to 218 million in 2018et al.Cusick Plasmodium, parasitemia, and the degree of immunity-In malaria, hematological exams must be evaluated and interpreted according to patients’ clinical manifestations and by taking into consideration the type of In the Amazonian population, the infectious disease with the greatest impact is malariaA cross-sectional analytical study of patients with a positive diagnosis for malaria (thick blood smear) was conducted in Itaituba, a municipality located in the southwest region of the state of Pará (PA), in the Amazon region of BrazilPatients with suspected malaria who sought help from the Malaria Diagnostic Service located at the Itaituba Municipal Hospital were invited to participate in the study. The study was approved by the Ethics and Research Committee (Comitê de Ética e Pesquisa - CEP) of the Tropical Medicine Nucleus (NMT) of the Federal University of Pará (UFPA) and the Evandro Chagas Institute (IEC). Each patient signed an informed consent form upon acceptance to the study and in accordance with the principles of Declaration of Helsinki, 1964, as revised in 1975, 1983, 1989, 1996, and 2000. The participants were divided into two groups: individuals with a positive thick blood smear test for malaria, and individuals with a negative thick blood smear test for malaria (control). All thick blood smears were read twice: once by a microscopist from the Malaria Diagnostic Service of the Hospital Municipal de Itaituba, PA, and then by a microscopist (blinded to the first thick blood smear diagnosis) from the Laboratory of Clinical Trials in Malaria of the IEC in Ananindeua, PA.Plasmodium, and living in the city of Itaituba, Pará. For the controls, the same criteria were adopted, but only those with a negative diagnosis for malaria (thick blood smear) and who were asymptomatic were included .The inclusion criteria for the cases were as follows: individuals of both sexes, aged 19 to 59 years, with a positive thick blood smear test for any species of Those who were receiving supplementation of 25(OH)D, calcium, anticonvulsants, corticosteroids, heparin, isoniazid, antihistamine, cholestyramine, or rifampicin were excluded from both groups, as were individuals with alterations in their renal function tests (urea and creatinine), those with chronic renal failure, those with severe malaria , and pregnant women. et al.For the sample calculation, the values for 25(OH)D deficiency and prevalence in individuals with and without malaria  were based on the study by Cusick Plasmodium species, parasitemia, clinical symptoms, history of infection, time for current illness to develop, and time since last malaria episode) as dependent variables.In this study, 25(OH)D deficiency was established as a dependent variable, whereas the patients’ sociodemographic data  were established as independent variables for the malaria group and the control group. 25(OH)D deficiency was established as an independent variable when related to the malaria variables  was used to acquire the EDTA blood count , at the Itaituba Municipal Hospital in Pará. The remaining 7 mL was centrifuged to obtain serum, followed by preparation in aliquots for storage (-20ºC) and performing the 25(OH)D examinations The normal serum levels adopted for the laboratory parameters included:Blood counts Red blood cells: 3.80-6.50 million/mm³; hemoglobin: 11.5-17.0 g/dL; hematocrit: 37-54%Leukocytes: 4,000-10,000/mm³Platelets: 150,000-500,000/mm³ 25(OH)D level: >20 ng/mLA clinical score measured the presence and intensity of the signs and symptoms, such as fever, chills, headache, sweating, coughing, dyspnea, abdominal pain, diarrhea, nausea, vomiting, anorexia, oliguria, choluria, arthralgia, myalgia, backache, dizziness, and prostration. Its intensity was graded from 0 to 3 points as follows: 0=absent, 1=mild (somewhat bothersome), 2=moderate , and 3=intense (quite bothersome and prevents activities form being performed). Microsoft Office Excel (2007) spreadsheet. Descriptive and analytical statistics were extracted using Epi Info 3.5.2 (2010), BioEstat 5.0 (2007), and SPSS Statistics 17.0 (2010). A Data Collection Protocol was developed to record the participants’ information, which was completed by the members of the study team and later presented (double entry) in a t-test), non-parametric tests (Mann-Whitney U (MW)), and Spearman’s correlation  were used according to the nature of the distribution of the variables. To interpret the magnitude of the correlation coefficients, the following values were used: rs=0.10-0.30 (weak), rs=0.40-0.6 (moderate), and rs=0.70-1 (strong)The normality of the quantitative variables D level, and blood count) was evaluated via the D’Agostino-Pearson test (K samples). Parametric tests (Student's Spearman's correlation was used to compare the 25(OH)D level and blood count results among patients and the control group. All study participants had access to the results of the laboratory tests. Individuals with altered exams received referrals and guidance to medical care at the Family Health Strategy Center in Itaituba, Pará.This study was approved by the CEP of the NMT at the UFPA (CEP decision no. 2.420.183 on 06/12/2017); and the CEP of the IEC in Ananindeua, Pará (CEP decision no. 2.974.069 on 22/10/2018). All participants signed the informed consent form .p<0.001, t-test). The cases caused by Plasmodium vivax  predominated, followed by Plasmodium falciparum . Among malaria patients, 18.7% (23 of 123) were experiencing their first episode of malaria. Most  reported previous episodes of malaria . The median  time since the first symptom in the current illness was 4±5 days. The median time since the last malarial infection was 3±15.5 months (median±IQR).There were 245 individuals included in this study , which was conducted between January 2018 and October 2019 in the municipality of Itaituba, Pará, Brazil. The malaria triad  occurred in 55.3% (68 out of 123) of the patients. The most frequent and most intense clinical symptoms were headache, back pain, fever, inappetence, chills, arthralgia, myalgia, asthenia, abdominal pain, sweating, and dizziness, which, taken together, culminated in an intensity clinical score between 4 and 44 points (14±10.5 points).P. vivax  or P. falciparum . A history of previous malaria infection  had no influence on the parasitemia caused by P. vivax  or P. falciparum . The mean value for the P. vivax parasitemia  in the patients who reported the malaria triad was different from those who did not report it . Likewise, the median value of the P. falciparum parasitemia  in the patients who reported the malaria triad was not significant in relation to those who did not report it . There was no difference between the median values of parasitemia for either P. vivax malaria and low 25(OH)D levels  compared to patients with P. vivax malaria and normal 25(OH)D levels . In the patients with P. falciparum malaria and low 25(OH)D levels, the mean value of parasitemia  was not statistically different compared to patients with P. falciparum and normal 25(OH)D levels . There was also no correlation between clinical scores and P. vivax or P. falciparum parasitemia .There was no difference in the parasitemia means of the patients with p=0.11, t-test). Low serum 25(OH)D levels were seen in 28.5% (35 out of 123) of the patients with malaria and in 24.6% (30 of 122) of the control group, with no significant difference . The serum concentrations of 25(OH)D were within normal levels (>20 ng/mL) in the malaria and control groups, with mean values of 32.3±11.9 ng/mL and 34.7±11.5 ng/mL, respectively, and with no significant difference among the groups , however, both values were within the reference range. In terms of the plasmodial species involved , there was no statistical difference between the frequency of low serum levels of 25(OH)D in individuals infected with P. vivax malaria (29.2% (33 out of 113)) compared to individuals infected with P. falciparum malaria (20% (2 out of 10)). The patients with malaria residing in the mining area had a mean 25(OH)D value (32.2 ng/mL) that was significantly lower than the controls residing in the mining area  than patients with a prior history of malaria . A history of malaria showed no statistical difference in relation to the serum levels of red blood cells .s=-0.258 and p=0.004; Spearman's correlation). The time for the current illness to develop (days) was not correlated with the serum levels of red blood cells or hemoglobin .The time (days) for the current illness to develop showed an inverse correlation  with the serum levels of platelets  between the cell counts from men with malaria (4.99±0.56 million/mm3) and from the men in the control group (5.01±0.62 million/mm3). Among the women, the mean number of red blood cells in the group with malaria (4.52±0.54 million/mm3) and in the control group (4.36±0.47 million/mm3) also showed no statistical difference . However, when stratifying by diagnosis, the men in the malaria group had a mean number of red blood cells (4.99±0.56 million/mm3) that was significantly higher in than the women . The same occurred in the control group, in which the median value for the number of red blood cells among men (5.01±0.90 million/mm3) was significantly higher than of the women .In this series, the mean number of red blood cells was significantly higher in the group with malaria than in the control group. However, when the serum levels of red blood cells were stratified by sex, there was no statistical difference . Among the patients with P. vivax malaria, there was an inverse correlation  between parasitemia and platelets: the greater the parasitemia, the lower the platelet serum levels . In the patients with P. vivax) and with the period of time since the onset of the disease. In addition, red blood cells showed a significant inverse correlation with parasitemia . Patients with primary malaria infection had significant leukopenia.This study evaluated the serum levels of 25(OH)D in patients with malaria and its relationship with epidemiological, clinical, laboratory and parasitemia parameters at the Malaria Diagnostic Service, which is located in the Municipal Hospital of Itaituba, Pará, Brazil. Low serum levels of 25(OH)D were identified among individuals with malaria (28.5%) and without malaria (24.6%), but without statistical difference. However, serum platelet levels showed a significant inverse correlation with parasitemia ; this is similar to the results reported (71.9%) by Lopes ,et al.Regarding education, most of the patients with malaria had little education: 66.7% had only elementary education, which is in accordance with other Brazilian studies,In the group with malaria, the mean age was 33.7±9.9 years; this is a range that includes the economically active age group of the population and is a result that is similar to that reported by other authorsP. vivax,,In Brazil, the main species causing malaria is ,The prevalence of low serum levels of 25(OH)D were similar in both groups: 28.5% in the patients with malaria and 24.6% in the control group. However, the patients with malaria who resided in the mining area had lower 25(OH)D levels than patients in the control group that also resided in the mining region, although the levels in both groups were within the normal range. The association between low serum levels of 25(OH)D and malarial infection has been verified in the results of authors highlighting the role of 25(OH)D in experimental malariaIn a study of 60 children (aged 18 months to 12 years) in Uganda, Africa, in which 40 had severe malaria  and 20 did not have malaria, a high percentage of 25(OH)D insufficiency (<30 ng/mL) was found in both groups , with significantly reduced levels of 25(OH)D in those with severe malaria. Although the authors emphasized that their results were preliminary due to the need for a larger sample size of children in order to analyze the relationship between 25(OH)D levels and malaria severity, upon using a logistic regression model, the authors concluded that for each 1 ng/mL increase in 25(OH)D plasma levels, the chance of having severe malaria declined by 9%Plasmodium species (91.9% P. vivax), and the type of malarial infection . The lack of association between low serum levels of 25(OH)D and malaria determined in this study compared to the results above may be due to the age range of the participants (adults), the predominance of the et al.Plasmodium infectionsIn this series, there was no correlation between parasitemia and a patient’s clinical score, nor between parasitemia and presence of the malaria triad , which is similar to the results by Silva P. falciparum malaria had an inverse correlation between parasitemia and serum levels of red blood cells; this is in contrast to the patients infected with P. vivax, who did not demonstrate such a correlation. It is known that both species of Plasmodium can cause hemolysisP. falciparum is the more virulent species, invading red blood cells of all ages, whereas P. vivax preferentially infects the reticulocytes (the young forms of erythrocytes)Our patients with ,,According to the results of other studies, primary malaria infection was associated with a decrease in serum levels of leukocyteset al.P. vivax malaria than in controls. However, our study differs from others studies that have observed a decrease in red blood cell, hemoglobin, and hematocrit values in patients with malaria. Additionally, anemia is common in patients with severe P. vivax malaria,,In the malaria group, the mean red blood cell count was significantly higher than that in the control group. The time for the current illness to develop, time since last infection, and history of malaria were not associated with serum levels of red blood cells and hemoglobin. These results agree with those by Costa P. vivax malaria, it was observed that the greater the parasitemia and the time for the disease to develop, the lower the serum levels of platelets. Thrombocytopenia is a common pathogenic phenomenon in patients with malaria,P. vivax malaria,P. vivax malaria are not well defined, it is believed that they may be related to coagulation disorders, antibody-mediated platelet destruction, platelet aggregation, oxidative stress, platelet sequestration in the spleen, and alterations in the bone marrow,In patients with The limitations presented in this study are related to its cross-sectional and analytical experimental design, which could not establish a cause-and-effect relationship between the analyzed factors and low serum levels of 25(OH)D based on nutritional status and nutrient consumption.P. vivax) and the time for the disease to develop. The serum levels of red blood cells had a significant inverse correlation with parasitemia . Compared to the patients with a prior history of malaria, the patients with their first infection had significant reductions in their serum levels of leukocytes.It can be concluded that in Itaituba, which is in the state of Pará, which is in the Amazon region, the prevalence of low serum levels of 25(OH)D were similar in the group with malaria (28.5%) and the control group (24.6%). However, the patients with malaria that resided in the mining area had lower 25(OH)D levels than those in the control group that resided in the mining area. The serum levels of platelets had a significant inverse correlation with parasitemia (


This study, therefore, sought to investigate the clinical performance of microscopy and RDT assuming highly sensitive varATS qPCR as gold standard.The World Health Organization recommends parasitological confirmation of all suspected malaria cases by microscopy or rapid diagnostic tests (RDTs) before treatment. These conventional tools are widely used for point-of-care diagnosis in spite of their poor sensitivity at low parasite density. Previous studies in Ghana have compared microscopy and RDT using standard 18S rRNA PCR as reference with varying outcomes. However, how these conventional tools compare with ultrasensitive varATS qPCR. The sensitivity, specificity, and predictive values were assessed using varATS qPCR as gold standard.1040 suspected malaria patients were recruited from two primary health care centers in the Ashanti Region of Ghana and tested for malaria by microscopy, RDT, and varATS qPCR respectively. Using varATS qPCR as the standard, RDT was more sensitive (55.7% vs 39.3%), equally specific (98.2% vs 98.3%), and reported higher positive (95.7% vs 94.5%) and negative predictive values (75.3% vs 69.0%) than microscopy. Consequently, RDT recorded better diagnostic agreement (kappa = 0.571) with varATS qPCR than microscopy (kappa = 0.409) for clinical detection of malaria.Parasite prevalence was 17.5%, 24.5%, and 42.1% by microscopy, RDT, and Plasmodium falciparum malaria in the study. However, both tests missed over 40% of infections that were detected by varATS qPCR. Novel tools are needed to ensure prompt diagnosis of all clinical malaria cases.RDT outperformed microscopy for the diagnosis of The online version contains supplementary material available at 10.1186/s12936-023-04506-5. Malaria remains a major public health concern, particularly in sub–Saharan Africa where > 93% of global malaria cases and deaths occur annually . MalariaPlasmodium species [In line with World Health Organization (WHO) policy of test before treatment, the National Malaria Control Programme in Ghana promotes the usage of microscopy or rapid diagnostic tests (RDTs) for routine malaria diagnosis . Microsc species . Additio species . The lim species  though t species . Microsc species .hrp2 gene deletions, thus leading to false negatives [hrp2/hrp3 gene deletions in clinical malaria cases exceeds 5% [The advent of rapid diagnostic tests and its adoption in Ghana has led to a significant reduction in presumptive diagnosis across the country . RDTs pregatives , 16. Theceeds 5% .Nucleic acid amplification tests (NAATs) provide by far the highest sensitivity and specificity for malaria diagnosis. Commonly used NAATs include Polymerase Chain Reaction (PCR) and Loop-mediated Isothermal Amplification (LAMP) that detect parasite DNA in blood . The limvar gene family of P. falciparum has been developed and proven to be 10 times more sensitive than conventional 18S rRNA PCR [var gene family is mostly located in sub telomeric regions where it encodes P. falciparum erythrocyte membrane protein 1 (PfEMP1) [var genes have been identified in the genome of 3D7 culture strain. var genes possess intracellular acidic terminal sequences (ATS) with domains which are well-conserved. The limit of detection of varATS qPCR has been reported as 0.03 parasites/μl of blood [Several diagnostic accuracy studies in Africa and Asia have compared microscopy and RDT using conventional or nested 18S rRNA PCR as reference , 21–24. rRNA PCR . The mul(PfEMP1) . About 5of blood , 27.varATS qPCR assay. This study provides baseline information on how the commonly used malaria tests in Ghana perform against varATS qPCR. As Ghana set ambitious targets from malaria control to elimination [varATS qPCR as gold standard. The study also aimed to shed light on the burden of missed and submicroscopic infections among clinical malaria patients in Ghana.Whiles most studies in Ghana have compared microscopy and RDTs using conventional PCR methods as reference , 28, 29,mination , active o50’N and longitude 1o29’W). About 47% of the inhabitants live in rural areas and 67% are involved in agriculture. The mean annual rainfall ranges between 855 mm and 1500 mm with a daily warm to hot temperature at about 27 °C [The study was conducted at two primary health centers in the Ashanti Region of Ghana Fig. , namely ut 27 °C .Fig. 1A o42’N and longitude1o45’W. Mankranso has a wet semi-equatorial climate with a mean monthly temperature between 26 °C–28 °C with two major rainfall patterns in the district [Mankranso Government Hospital is located at Mankranso, the capital of the Ahafo Ano South West District (formerly Ahafo Ano South District) in the Ashanti Region of Ghana. According to the 2010 Population and Housing Census, about 90% of the total population live in rural areas. Approximately 81.7% percent of indigenous households in Mankranso are engaged in crop farming whiles others are actively involved in poultry farming. The district is located at latitude 6district .This was a cross-sectional hospital-based study conducted between January and June 2021. Sampling was done three days per week between the hours of 9 a.m. and 3 p.m. each day. Inclusion criteria for the study were suspected malaria patients  of all ages and gender. Written informed consent was obtained from all participants who were ≥ 18 years old. Parental or guardian consent was obtained for all those who were below 18 years old. Unsuspected malaria patients and participants who could not provide informed consent were excluded from the study.β = 0.20) as previously described [The sample size was pre-calculated as the minimum number of samples required to attain 95% sensitivity and specificity assuming a 5% margin of error at 95% confidence level . Afterwards, 2 ml of venous blood was collected from participants into EDTA tubes. RDT was immediately performed for all participants and blood smears (thick and thin) were prepared for microscopic diagnosis. 1 ml aliquots were also taken for diagnosis by qPCR and transported in cold boxes to the Vector-Borne Infectious Diseases laboratory at Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana, for storage and further analysis.The CareStart™ Malaria Pf (HRP2) Ag RDT  kit was chosen for the present study since it passed WHO-recommended criteria for routine diagnosis . BrieflyDuplicate thick and thin blood films were prepared for each participant on clean, well-labelled, frosted glass slides. Briefly, 2µL and 6µL of whole blood were pipetted to prepare thin and thick films respectively on the slide as previously described . The thiP. falciparum var acidic terminal sequence (varATS) multi-copy gene assay. The reaction mixture was made of 1.28μL of PCR water, 6μL of 1 × Perfect tough PCR MasterMix, 0.48μL of 10uM forward and reverse primers, 0.24μL of 10uM probe, and 4μL eluted DNA. The forward, reverse, and probe sequence used have been previously described [℃ for 30 s. Amplification of the target gene was done at 45 cycles. Parasite density was estimated using a standard curve of purified parasite genomic DNA (gDNA) quantified by droplet digital PCR of a tenfold dilution of 3D7 parasite culture . The limit of detection of qPCR was < 0.1 parasites/µL blood.DNA was extracted from 200 µL whole blood using the Macherey–Nagel NucleoMag extraction kit and eluted in 100 µL buffer. qPCR was done on a ThermoFisher QuantStudio 3 instrument in a total volume of 12 µL, including 4µL eluted DNA, corresponding to 8 µL blood using the highly sensitive escribed . CyclingData from the questionnaire and laboratory results were coded and entered using Microsoft Excel 2016. The data was analyzed using GraphPad Prism 9.0  at 95% confidence level and a significance at p < 0.05. 2 × 2 contingency tables were drawn after which sensitivity, specificity, positive predictive value, and negative predictive values were calculated. Descriptive statistics were performed for socio-demographic features which were represented as frequencies and percentages. Mean or median was used to summarize quantitative data. Parasite density across the age groups was computed using ANOVA (geometric mean) and post-hoc analysis using Tukey’s multiple comparison test. The agreement between different diagnostic tests was calculated using the Kappa (κ) measure of inter-rater agreement. Briefly, κ < 0.20 indicated poor agreement, 0.21–0.40 fair, 0.41–0.60 moderate, 0.61–0.80 good, 0.81–0.99 very good and 1.00 indicate perfect agreement [Of the 1,040 participants recruited for the study, 458 (44.0%) were obtained from Mankranso Government Hospital (MGH) with the remaining 582 (56.0%) from Agona Government Hospital (AGH). All data is presented for both sites combined. Participants' age ranged between 3 weeks and 96 years with a median age of 22 years (IQR = 7 – 36 years). Majority of the study populace fell within the 15–30 age group (34.9%), followed closely by the > 30 (32.4%), < 5 (20.3%), and 5–14 (12.4%) age groups in descending order. Females were more than twice (70.7%) the number of males involved in the study (29.3%). Studentship/apprenticeship was the predominant occupation (33.0%) of the participants whereas civil servants (6.1%) were the least represented in the study  infections whereas microscopy could detect only 172 (39.3%) true positives. Similar false positive rates were recorded in RDT, 11 (1.8%) and microscopy, 10 (1.7%) , whiles RDT reported similar PPV (95.7% vs 94.5%) but higher NPV (75.3% vs 69.0%) than microscopy. Ultimately, RDT showed “moderate” agreement with qPCR (κ = 0.571), whereas microscopy showed “fair” (κ = 0.409) agreement , low (100–999 parasites/µl), moderate (1000–4999 parasites/µl), high , and hyper  as previously described . InteresAll three different tests detected high positivity rate among the 5–14 age group, with values that were distinctly higher than the other age groups  in parasite density estimation was observed across the age groups. The geometric mean parasite density in the 5–14 age group (1246p/μl) was sevenfold higher than in children < 5 years (166.8p/μl), and 100-fold higher than that of adults > 30 years (12.4p/μl). The 15–30 age group had a geometric mean parasite density of 84.3p/μl. Figure Prompt and accurate diagnosis of malaria is the fundamental first step to effectively identify, treat and interrupt disease transmission . An excevarATS qPCR as reference in a clinical setting. Most P. falciparum strains possess relatively fewer 18S ribosomal subunits (5–8 copies/genome) [var gene family which has approximately 59–60 copies/genome [varATS qPCR therefore has a very low limit of detection (~ 0.03–0.15 parasites/µL) and has been proven to be tenfold more sensitive than traditional 18S rRNA PCR methods [In Ghana, like most African countries, microscopy and RDTs are commonly used for routine malaria diagnosis in healthcare centers. Whilst extensive studies have compared microscopy and RDT based on standard 18S rRNA PCR results, this study is the first in Ghana to make comparisons using /genome)  than thes/genome , 46. var methods . It is i methods .varATS offer superior sensitivity compared to single copy genes [Comparisons between microscopy, RDT, and PCR need to consider vastly different limits of detection of qPCR. Extraction from whole blood results in better sensitivity compared to dried blood spots . The corpy genes . As a revarATS qPCR-positive infections [varATS qPCR-positive infections than RDT (12%) [The present study revealed that microscopy missed almost two-thirds (60.7%) of infections, whereas RDT missed nearly half (44.3%) of qPCR-positive (438) cases. This corroborates a previous study where microscopy missed 169 (57%) out of 295 fections . A similDT (12%) . hrp2 gene deletions, this does not seem to be crucial in Ghana currently [False negatives are of huge concern since failure to treat diseased persons may lead to continued disease transmission, increased morbidity and mortality . Though urrently , 51. It urrently , 53. In urrently  whereas urrently . Meanwhiurrently . Also, rurrently , 58. Suburrently , 60 howeurrently . This maP. falciparum species [P. falciparum species. In the present study, there was a single case of P. ovale microscopy-positive infection that was missed by varATS qPCR and the HRP-2 based RDT, both of which are specific for P. falciparum infections.Contrary to the high false negative rates observed in the study, both microscopy (10) and RDT (11) reported fewer false positives. The false positive HRP2-based RDT results may be due to persistent circulation of HRP2 antigens (up to two weeks) after parasite clearance , 62, 63. species  and morpvarATS qPCR than microscopy (κ = 0.409). This finding corroborates a community-based study in Nigeria [varATS qPCR than microscopy. The study in Nigeria also reported microscopy to be more specific than RDT (99.5% vs 97%), albeit a marginal difference was observed in the present study [From the study, RDT was more sensitive, equally specific, and was a better predictor of malaria than microscopy Tables  and 4. C Nigeria  where RDnt study . The relnt study .Analysis of diagnostic performance across age groups revealed that sensitivity and specificity were influenced by parasite density Figs.  and 5. HThe generally high PPV (> 93%) but low NPV (< 76%) from this study indicate that a positive RDT or microscopy test is a good predictor of malaria however, a negative test may not necessarily indicate no infection , 67, henvarATS qPCR. There is, therefore, a need to adopt measures to improve microscopy and RDT performance via refresher training and development of quality-assured RDTs. The authors recommend further studies to investigate the role of submicroscopic infections in clinical malaria outcomes and also critically assess its contribution to disease transmission in Ghana. As Ghana sets up a cross-parliamentary caucus to accelerate malaria elimination, submicroscopic infections missed at the hospital should be considered an important bottleneck to overcome.This study found RDT to be more sensitive and accurate than microscopy for the detection of clinical malaria in Ghana. Nevertheless, both tests missed substantial submicroscopic infections which were detected by Additional file 1. Diagnostic agreement and performance between both experts.


Plasmodium falciparum infection. Albeit many issues concerning the inflammatory responses remain unresolved and need further investigations, current knowledge of the underlying molecular mechanisms is highlighted. Furthermore, and in the light of significant limitations in preventative diagnosis and treatment of cerebral malaria, this review mainly discusses our understanding of immune mechanisms in the light of the most recent research findings. Remarkably, the newly proposed CD8+ T cell-driven pathophysiological aspects within the central nervous system are summarized, giving first rational insights into encouraging studies with immune-modulating adjunctive therapies that protect from symptomatic cerebral participation of Plasmodium falciparum infection.This review focuses on current clinical and immunological aspects of cerebral malaria induced by  Plasmodium falciparum (Pf). However, P. vivax infections also can cause CM  to eliminate malaria worldwide and malaria cases and death have been reduced within the last ten years, in 2021, this progress was impeded as the COVID-19 pandemic disrupted malaria services and diagnosis. The immense number of malaria cases in 2021 (241 million cases) and the distressing number of deaths (627 000) revealed how fragile medical services are. Especially in the African region, where 96% of all malaria deaths occurred, 80% were children under five, significantly more effort is needed to reverse the last year’s trend for 2022  is characterized by unarousable coma not attributable to other neuro-pathologies combined with  therapy . Childre therapy . 14-25%  therapy , 9. As tArtemisinins, which have the fastest parasite clearing time of all anti-malarial drugs, have become the drugs of the moment, and artesunate is the first-line therapy for treating severe and cerebral malaria in both children and adults  should be followed .Pf malaria. Although not widely available, respiratory support and artificial ventilation are crucial  of the MosquirixTM  vaccine showed protection from severe and cerebral malaria in 32.2% of children aged 5-17 months . TherefoPlasmodium species. Considering this, it is no surprise that both parasite and host have undergone genetic alterations for successful coexistence. On the host side, protective variations include sickle-cell anaemia  associated with 33% protection against severe malaria (DDC (L-DOPA decarboxylase) gene is associated with cerebral malaria susceptibility . Many genetic polymorphisms related to malaria are relevant for red blood cell (RBC) biology, like variants of the  malaria , or vari malaria . Howevertibility . DDC is subtypes . SNPs ne malaria , 23. Strseverity . Both gechildren . Polymorchildren .ADORA2A and GRK5 genes were associated with virulence and infectivity of the malaria parasite  molecules on the surface of iRBCs are responsible for most parasite-host cell interactions.Magnetic resonance imaging has achieved vital progress in elucidating cerebral malaria pathology in children suffering from cerebral manifestations. It has become evident that brain swelling and brain stem herniation lead to respiratory arrest and death . Furthervia interaction with specific adhesion molecules. PfEMP1 is encoded by the var gene family with approximately 60 members  might activate brain endothelial cells , being the principal protector of endothelium homeostasis, have been reported in children with  malaria . However malaria . Another malaria . This peUnder hypoxic conditions, after vasoconstriction due to sequestration of iRBCs, vascular endothelial growth factor-A (VEGF-A) is released by endothelial cells . VEGF-A Many of these peptides from endothelial activation have been suggested as possible biomarkers to predict the fatal outcome of CM. However, currently, there is no test available to confirm the diagnosis of cerebral manifestations prior to the appearance of clinical symptoms.The blood-brain barrier (BBB) comprises brain endothelial cells connected by tight junctions formed by transmembrane proteins occludin, claudin and zonula occludens protein-1 (ZO-1). Endothelial cells are in contact with surrounding pericytes and astrocytes situated in the perivascular space. Together, these cells provide a highly functional barrier between the blood and the brain interstitial fluid. In cerebral malaria, an impaired barrier function allows leakage of plasma proteins and fluids into the perivascular space causing vasogenic oedema and brain swelling . One reaNumerous studies showed that serum levels of the pro-inflammatory cytokine TNF-α were higher in CM than in severe forms of malaria in children and adults . NeverthLikewise, IFN-γ is released from immune cells like CD4+ and CD8+ T cells, natural killer cells and γδ-T cells during malaria infection. IFN-γ is a potent activator of macrophages, increasing their phagocytosis activity, vital in the early control of parasite growth. On the other side, IFN-γ induces brain endothelium activation and an increase of adhesion molecules . HoweverBesides promoting the expression of adhesion molecules in the brain vasculature, IFN-γ is active in up-regulating CXCL10 released from endothelial cells . ConfirmFrom murine cerebral malaria research, we know that T cells play a crucial role in the experimental cerebral malaria (ECM) model, and functional studies using neutralizing antibodies or T cell-deficient mice have demonstrated a significant role of CD8+ T cells in inducing brain damage . HoweverPf infected RBCs and are therefore unable to add to clearance of blood-stage infections. Instead, CD8+ T cells are suspected to be the main drivers for cerebral pathology in humans and experimental mouse models (via their major histocompatibility complex class I (MHCI) (CD8+ T cells recognize pathogens through major histocompatibility complex I molecules (MHCI) on the surface of antigen-presenting cells or infected cells and contribute, therefore, to clearance and immunity against intracellular pathogens. However, as erythrocytes lack MHCI receptors, CD8+ T cells do not recognize e models , 69. OneI (MHCI) , 71. In Plasmodium berghei ANKA (PbA). In this mouse model, RBCs bearing asexual forms of the parasite are injected intraperitoneal (106 infected RBCs) or intravenously (104 infected RBCs). As asexual forms do not enter hepatocytes, the liver stage of the disease is circumvented, and the blood stage is visible in blood smears after approximately three days. Mice show signs of neurological symptoms such as ataxia, convulsions or paralysis starting from day four and die between days 6-8. Mice that do not develop cerebral manifestations die from hyper-parasitemia and anaemia at later time points (day 14 to 21)  is studied with C57BL/6 mice infected with 4 to 21) . Similar4 to 21) . In addi4 to 21) . The mos4 to 21)  due to t4 to 21) , 76. Sev species , 78. Twoot known –81.PbA showed resistance against cerebral manifestations of malaria. The identified genes can serve as potential therapeutic targets. Many of the involved genes discussed hereafter encode proteins that function in leukocyte migration to the brain and modulate T-cell effector functions. However, the limitations of the experimental murine model for translational research will also be discussed in the following passage.In experimental malaria models, multiple pathways have been classified as essential for developing CM. After the deletion of specific genes, several knockout mice infected with + IFN-γR2flox/flox) did not prevent cerebral symptoms and early death (Cytokines such as interferon-gamma (IFNγ) and its receptors (IFNγR) seem crucial for CM development. In mouse models, IFNγR2 knockout proved protective against CM, whereas specific knockout on T cells  deficient mice were resistant to CM pathology and maintained BBB integrity during infection with PbA . AccordiPbA .Instead, Lymphotoxin alpha (LTα), which binds the same receptors as TNFα (TNFR1 and TNFR2), might be a more specific target and control late-stage inflammation to prevent neurological complications. LTα knockout animals and LIGHT-lymphotoxin beta receptor (LTβR) deficient mice were protected from CM , and LTβHowever, the translational potential of TNFα and LTα for human CM is questionable, as, similar to IFNγ, TNFα and its receptors are associated with gaining immunity against malaria .PbA infected mice by reducing parasitemia by stimulation of Th2 CD4+ T cells and the phagocytic system. However, IL-4 treatment was only effective as a preventive strategy, whereas starting therapy on day five after infection did not abrogate CM fatality (Interleukins (IL) are other cytokine family members playing a role in cerebral malaria complications. For instance, prophylactic treatment with IL-4 increased survival time in fatality . Howeverfatality . In humafatality , probablInterleukin-12 receptor beta2 (IL-12Rβ2) deficient mice are protected against cerebral complications, whereas IL-12-p40 deficient mice show similar susceptibility as wild-type animals , suggestThe Interleukin-33 receptor (ST2) is expressed on brain endothelial cells, and ST2 knockout mice are protected from CM due to less cytotoxic CD8+ T in the brain microvasculature .-/- mice are protected from brain pathologies  is a membrane protein found on the surface of ECs and has been described as essential for cytoadherence of iRBCs in ECM, although survival of CD36 knockout mice was not improved . In huma-/- mice are protected from fatal ECM by decreased infiltration of perforin-positive CD8+ T cells to the brain. The results suggest that CXCR3 is necessary for the migration of CD8+ cells to the brain  is the dominant apolipoprotein in the brain, and ApoEncidence . WhetherProtein kinase C-theta (PKC-theta) deficient mice do not show neurologic symptoms typical for CM, such as abrogated cerebral microcirculation or brain ischemia. Interestingly, recruitment and activation of CD8+ T cells were reduced in the brain of resistant mice . FurtherSumming up the latest research data from mouse and human CM studies, the importance of lymphocyte sequestration in the brain vasculature has achieved objective evidence. Although substantial progress has been made in elucidating the cause of death in CM, specific treatment is still missing, and solutions are not within sight. For this reason, research regarding targets, which are drugable in the human setting, is urgently needed, and focus should be concentrated on the development of adjunctive therapies for treating and preventing the potentially fatal evolution into CM.KA-S wrote the manuscript, performed literature research and prepared the table and figure. PL reviewed the manuscript and added an essential part due to his expertise in malaria research and neurology. ES reviewed the manuscript and added essential parts due to his expertise in malaria research and neurology. GB revised the manuscript and added an essential part due to his expertise in T cell biology. All authors contributed to the article and approved the submitted version.This study was supported by the Austrian Science Fund TAI80-B to KA-S.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.