Wolbachia

Wolbachia is a genus of intracellular bacteria that infects mainly arthropod species, including a high proportion of insects, and also some nematodes. It is one of the most common parasitic microbes and is possibly the most common reproductive parasite in the biosphere. Its interactions with its hosts are often complex, and in some cases have evolved to be mutualistic rather than parasitic. Some host species cannot reproduce, or even survive, without "Wolbachia" colonisation. One study concluded that more than 16% of neotropical insect species carry bacteria of this genus, and as many as 25 to 70% of all insect species are estimated to be potential hosts. 
History.
The genus was first identified in 1924 by Marshall Hertig and Simeon Burt Wolbach in the common house mosquito. They described it as "a somewhat pleomorphic, rodlike, Gram-negative, intracellular organism [that] apparently infects only the ovaries and testes". Hertig formally described the species in 1936, and proposed both the generic and specific names: "Wolbachia pipientis". Research on "Wolbachia" intensified after 1971, when Janice Yen and A. Ralph Barr of UCLA discovered that "Culex" mosquito eggs were killed by a cytoplasmic incompatibility when the sperm of "Wolbachia"-infected males fertilized infection-free eggs. The genus "Wolbachia" is of considerable interest today due to its ubiquitous distribution, its many different evolutionary interactions, and its potential use as a biocontrol agent.
Phylogenetic studies have shown that "Wolbachia persica" (now "Francisella persica") was closely related to species in the genus "Francisella" and that "Wolbachia melophagi" (now "Bartonella melophagi") was closely related to species in the genus "Bartonella", leading to a transfer of these species to these respective genera. Furthermore, unlike "Wolbachia", which need a host cell to multiply, "F. persica" and "B. melophagi" can be cultured on agar plates.
Method of sexual differentiation in hosts.
These bacteria can infect many different types of organs, but are most notable for the infections of the testes and ovaries of their hosts. "Wolbachia" species are ubiquitous in mature eggs, but not mature sperm. Only infected females, therefore, pass the infection on to their offspring. "Wolbachia" bacteria maximize their spread by significantly altering the reproductive capabilities of their hosts, with four different phenotypes:
Effects of sexual differentiation in hosts.
Several host species, such as those within the genus "Trichogramma", are so dependent on sexual differentiation of "Wolbachia" that they are unable to reproduce effectively without the bacteria in their bodies, and some might even be unable to survive uninfected.
One study on infected woodlice showed the broods of infected organisms had a higher proportion of females than their uninfected counterparts.
"Wolbachia", especially "Wolbachia"-caused cytoplasmic incompatibility, may be important in promoting speciation. Wolbachia strains that distort the sex ratio may alter their host's pattern of sexual selection in nature, and also engender strong selection to prevent their action, leading to some of the fastest examples of natural selection in natural populations.
The male killing and feminization effects of "Wolbachia" infections can also lead to speciation in their hosts. For example, populations of the pill woodlouse, "Armadillidium vulgare" which are exposed to the feminizing effects of "Wolbachia", have been known to lose their female-determining chromosome. In these cases, only the presence of "Wolbachia" can cause an individual to develop into a female. Cryptic species of ground wētā ("Hemiandrus maculifrons" complex) are host to different lineages of "Wolbachia" which might explain their speciation without ecological or geographical separation.
Fitness advantages by "Wolbachia" infections.
"Wolbachia" infection has been linked to viral resistance in "Drosophila melanogaster", "Drosophila simulans", and mosquito species. Flies, including mosquitoes, infected with the bacteria are more resistant to RNA viruses such as Drosophila C virus, norovirus, flock house virus, cricket paralysis virus, chikungunya virus, and West Nile virus.
In the common house mosquito, higher levels of "Wolbachia" were correlated with more insecticide resistance.
In leafminers of the species "Phyllonorycter blancardella", "Wolbachia" bacteria help their hosts produce green islands on yellowing tree leaves, that is, small areas of leaf remaining fresh, allowing the hosts to continue feeding while growing to their adult forms. Larvae treated with tetracycline, which kills "Wolbachia", lose this ability and subsequently only 13% emerge successfully as adult moths.
"Muscidifurax uniraptor, a" parasitoid wasp, also benefits from hosting "Wolbachia" bacteria.
In the parasitic filarial nematode species responsible for elephantiasis, such as "Brugia malayi" and "Wuchereria bancrofti", "Wolbachia" has become an obligate endosymbiont and provides the host with chemicals necessary for its reproduction and survival. Elimination of the Wolbachia symbionts through antibiotic treatment therefore prevents reproduction of the nematode, and eventually results in its premature death.
Some "Wolbachia" species that infect arthropods also provide some metabolic provisioning to their hosts. In "Drosophila melanogaster", "Wolbachia" is found to mediate iron metabolism under nutritional stress and in "Cimex lectularius", the "Wolbachia" strain "cCle" helps the host to synthesize B vitamins.
Some "Wolbachia" strains have increased their prevalence by increasing their hosts' fecundity. "Wolbachia" strains captured from 1988 in southern California still induce a fecundity deficit, but nowadays the fecundity deficit is replaced with a fecundity advantage such that infected "Drosophila simulans" produces more offspring than the uninfected ones.
Life-history consequences of "Wolbachia" infection.
"Wolbachia" often manipulates host reproduction and life-history in a way that favours its own propagation. In the Pharaoh ant, "Wolbachia" infection correlates with increased colony-level production of reproductives (i.e., greater reproductive investment), and earlier onset of reproductive production (i.e., shorter life-cycle). Infected colonies also seem to grow more rapidly. There is substantial evidence that the presence of "Wolbachia" that induce parthenogenesis have put pressure on species to reproduce primarily or entirely this way.
Additionally, "Wolbachia" has been seen to decrease the lifespan of "Aedes aegypti", carriers of mosquito-borne diseases, and it decreases their efficacy of pathogen transmission because older mosquitoes are more likely to have become carriers of one of those diseases. This has been exploited as a method for pest control.
Genomics.
The first "Wolbachia" genome to be determined was that of one that infects "D. melanogaster" fruit flies. This genome was sequenced at The Institute for Genomic Research in a collaboration between Jonathan Eisen and Scott O'Neill. The second "Wolbachia" genome to be determined was one that infects "Brugia malayi" nematodes. Genome sequencing projects for several other "Wolbachia" strains are in progress. A nearly complete copy of the "Wolbachia" genome sequence was found within the genome sequence of the fruit fly "Drosophila ananassae" and large segments were found in seven other "Drosophila" species.
In an application of DNA barcoding to the identification of species of "Protocalliphora" flies, several distinct morphospecies had identical cytochrome c oxidase I gene sequences, most likely through horizontal gene transfer (HGT) by "Wolbachia" species as they jump across host species. As a result, "Wolbachia" can cause misleading results in molecular cladistical analyses. It is estimated that between 20 and 50 percent of insect species have evidence of HGT from "Wolbachia"—passing from microbes to animal (i.e. insects).
Horizontal gene transfer.
"Wolbachia" species also harbor a bacteriophage called bacteriophage WO or phage WO. Comparative sequence analyses of bacteriophage WO offer some of the most compelling examples of large-scale horizontal gene transfer between "Wolbachia" coinfections in the same host. It is the first bacteriophage implicated in frequent lateral transfer between the genomes of bacterial endosymbionts. Gene transfer by bacteriophages could drive significant evolutionary change in the genomes of intracellular bacteria that were previously considered highly stable or prone to loss of genes over time.
Small RNA.
The small non-coding RNAs WsnRNA-46 and WsnRNA-59 in "Wolbachia" were detected in "Aedes aegypti" mosquitoes and "Drosophila melanogaster". The small RNAs (sRNAs) may regulate bacterial and host genes. Highly conserved intragenic region sRNA called ncrwmel02 was also identified in "Wolbachia pipientis." It is expressed in four different strains in a regulated pattern that differs according to the sex of the host and the tissue localisation. This suggested that the sRNA may play important roles in the biology of "Wolbachia."
Relation to human-related infections.
Disease vector.
Outside of insects, "Wolbachia" infects a variety of isopod species, spiders, mites, and many species of filarial nematodes (a type of parasitic worm), including those causing onchocerciasis (river blindness) and elephantiasis in humans, as well as heartworms in dogs. Not only are these disease-causing filarial worms infected with "Wolbachia", but "Wolbachia" also seems to play an inordinate role in these diseases. 
A large part of the pathogenicity of filarial nematodes is due to host immune response toward their "Wolbachia". Elimination of "Wolbachia" from filarial nematodes generally results in either death or sterility of the nematode. Consequently, current strategies for control of filarial nematode diseases include elimination of their symbiotic "Wolbachia" via the simple doxycycline antibiotic, rather than directly killing the nematode with far more toxic antinematode medications.
Disease prevention.
Naturally existing strains of "Wolbachia" have been shown to be a route for vector control strategies because of their presence in arthropod populations, such as mosquitoes. Due to the unique traits of "Wolbachia" that cause cytoplasmic incompatibility, some strains are useful to humans as a promoter of genetic drive within an insect population. "Wolbachia"-infected females are able to produce offspring with uninfected and infected males; however, uninfected females are only able to produce viable offspring with uninfected males. This gives infected females a reproductive advantage that is greater the higher the frequency of "Wolbachia" in the population. Computational models predict that introducing "Wolbachia" strains into natural populations will reduce pathogen transmission and reduce overall disease burden. An example includes a life-shortening "Wolbachia" that can be used to control dengue virus and malaria by eliminating the older insects that contain more parasites. Promoting the survival and reproduction of younger insects lessens selection pressure for evolution of resistance.
In addition, some "Wolbachia" strains are able to directly reduce viral replication inside the insect. For dengue they include wAllbB and wMelPop with "Aedes aegypti", wMel with "Aedes albopictus". and "Aedes aegypti". A trial in an Australian city with 187,000 inhabitants plagued by dengue had no cases in four years, following introduction of mosquitoes infected with "Wolbachia". Earlier trials in much smaller areas had been carried out, but the effect in a larger area had not been tested. There did not appear to be any environmental ill-effects. The cost was A$15 per inhabitant, but it was hoped that it could be reduced to US$1 in poorer countries. The "strongest evidence yet" to support the "Wolbachia" technique was found in its first randomized controlled trial, conducted between 2016 and 2020 in Yogyakarta, an Indonesian city of about 400,000 inhabitants. In August 2020, the trial's Indonesian lead scientist Adi Utarini announced that the trial showed a 77% reduction in dengue cases compared to the control areas.
"Wolbachia" has also been identified to inhibit replication of chikungunya virus (CHIKV) in "A. aegypti". The Wmel strain of "Wolbachia pipientis" significantly reduced infection and dissemination rates of CHIKV in mosquitoes, compared to "Wolbachia" uninfected controls and the same phenomenon was observed in yellow fever virus infection converting this bacterium in an excellent promise for YFV and CHIKV suppression.
"Wolbachia" also inhibits the secretion of West Nile virus (WNV) in cell line Aag2 derived from "A. aegypti" cells. The mechanism is somewhat novel, as the bacteria actually enhances the production of viral genomic RNA in the cell line "Wolbachia". Also, the antiviral effect in intrathoracically infected mosquitoes depends on the strain of "Wolbachia", and the replication of the virus in orally fed mosquitoes was completely inhibited in wMelPop strain of "Wolbachia".
"Wolbachia" infection can also increase mosquito resistance to malaria, as shown in "Anopheles stephensi" where the "w"AlbB strain of "Wolbachia" hindered the lifecycle of "Plasmodium falciparum".
However, "Wolbachia" infections can enhance pathogen transmission. "Wolbachia" has enhanced multiple arboviruses in "Culex tarsalis" mosquitoes. In another study, West Nile Virus (WNV) infection rate was significantly higher in "Wolbachia"-infected mosquitoes compared to controls.
"Wolbachia" may induce reactive oxygen species-dependent activation of the Toll (gene family) pathway, which is essential for activation of antimicrobial peptides, defensins, and cecropins that help to inhibit virus proliferation. Conversely, certain strains actually dampen the pathway, leading to higher replication of viruses. One example is with strain wAlbB in "Culex tarsalis", where infected mosquitoes actually carried the west nile virus (WNV) more frequently. This is because wAlbB inhibits REL1, an activator of the antiviral Toll immune pathway. As a result, careful studies of the "Wolbachia" strain and ecological consequences must be done before releasing artificially-infected mosquitoes in the environment.
Deployments.
In 2016 it was proposed to combat the spread of the Zika virus by breeding and releasing mosquitoes that have intentionally been infected with an appropriate strain of "Wolbachia". A contemporary study has shown that Wolbachia has the ability to block the spread of Zika virus in mosquitoes in Brazil.
In October 2016, it was announced that US$18 million in funding was being allocated for the use of "Wolbachia"-infected mosquitoes to fight Zika and dengue viruses. Deployment is slated for early 2017 in Colombia and Brazil.
In July 2017, Verily, the life sciences arm of Google's parent company Alphabet Inc., announced a plan to release about 20 million Wolbachia-infected "Aedes aegypti" mosquitoes in Fresno, California, in an attempt to combat the Zika virus. Singapore's National Environment Agency has teamed up with Verily to come up with an advanced, more efficient way to release male Wolbachia mosquitoes for Phase 2 of its study to suppress the urban "Aedes aegypti" mosquito population and fight dengue.
In November 3, 2017, the US Environmental Protection Agency (EPA) registered Mosquito Mate, Inc. to release Wolbachia-infected mosquitoes in 20 US states and the District of Columbia.
Effect on the sex-differentiation enzyme aromatase.
The enzyme aromatase is found to mediate sex-change in many species of fish. "Wolbachia" can affect the activity of aromatase in developing fish embryos.