the inflammasomes are a group of cytosolic protein complexes that function as a molecular platform for caspase-1-dependent proteolytic maturation and secretion of interleukin ( il)-1 and il-18 ( 1 - 4 ) . of the members of the nucleotide binding oligomerization domain ( nod)-like receptor ( nlr ) inflammasomes , the nucleotide - binding domain and leucine - rich repeat protein 3 ( nlrp3 ) inflammasome is the most extensively studied . activation of the nlrp3 inflammasome in response to diverse pathogenic and endogenous stimuli leads to the assembly of protein components of the complex : the cytoplasmic innate receptor nlrp3 , the adaptor apoptosis - associated speck - like protein containing a card ( asc ) , and the effector caspase-1 ( 1 , 4 , 5 ) . the nlrp3 inflammasome is activated by two steps : a priming step is required to induce expression of both nlrp3 and pro - il-1 ; and a second step triggers assembly of the nlrp3 inflammasome after exposure to microbial toxins and ionophores or endogenous danger molecules ( 6 , 7 ) . in addition , the nlrp3 inflammasome is activated during infection of macrophages with various bacterial , viral , and fungal pathogens and is required for host immune defense to these pathogenic infections ( 6 - 8 ) . the potent inflammatory activities of il-1 and il-18 by inflammasome activation are pathogenic in nlrp3-associated autoinflammatory disorders ( 5 , 9 ) . nlrp3 inflammasome activation can lead to excessive inflammatory responses and cell death , which is potentially hazardous to host defense during a variety of bacterial infections , while numerous bacteria and their components can activate or modulate nlrp3 inflammasome activation . in this review , we will examine how the nlrp3 inflammasome is activated and contributes to host defense during diverse bacterial infections . we will further discuss current knowledge of the strategies by which various pathogenic bacterial virulence factors modulate the nlrp3 inflammasome . the innate immune system rapidly recognizes and provides an immediate host defense response to microbial and endogenous stimuli . the germ - line encoded pattern recognition receptors ( prrs ) specific subsets of prrs , nod - like receptor ( nlr ) and the pyhin protein families , detect molecular patterns in the cytosol and activate the formation of supramolecular complexes , termed inflammasomes . the nlrp3 inflammasome , the best - characterized family member of inflammasomes , is a multi - protein complex composed of nlrp3 , asc , and caspase-1 ( 1 - 4 ) . the protein structure of nlrp3 contains an n - terminal pyrin domain ( pyd ) , a central nacht ( naip , ciita , het - e , and tp1 ) , and a c - terminal leucine - rich region ( 4 ) . a recent study with high resolution structure analysis showed that nlrp3 has a specific disulfide bond between cys-8 and cys-108 that may participate in regulation of nlrp3 activity by reactive oxygen species ( 10 ) . after sensing signals , the three components - nlrp3 , asc , and pro - caspase-1-assemble to form a typical multimeric inflammasome complex , which results in activation of caspase-1 , leading to processing of pro - il-1 and pro - il-18 to their mature , biologically active , forms ( 3 - 5 ) . during this activation , the adaptor protein asc , which contains an n - terminal pyd and a c - terminal caspase activation and recruitment domain ( card ) , plays an important role in assembly of the nlrp3 inflammasome through its interaction with nlrp3 via a homotypic pyd interaction . recent studies have reported that the asc pyd domain is also required for its self - association , as well as interaction with nlrp3 ( 11 ) . the first signal mediates transcriptional activation of pro - il-1 and nlrp3 through recognition of ligands for toll - like receptors ( tlrs ) , il-1 receptor , and tumor necrosis factor ( tnf ) receptor . the second signal leads to inflammasome oligomerization and activation , thereby causing maturation and secretion of il-1 and il-18 . the second signal may include a variety of pathogen - associated molecular pattern molecules ( pamps ) or damage - associated molecular patterns ( damps ) ( 2 , 6 , 9 , 12 ) . several important second signals have been reported ; i.e. , plasma membrane disruption for bacterial toxins and atp ; internalization of particulate activators by phagocytosis ( 1 ) ; k efflux and pore formation by extracellular atp or bacterial toxins ( 13 ) ; or lysosomal destabilization with release of protease cathepsin b into the cytoplasm by particulate activators including silica , alum , fibrillar amyloid- protein , or uric acid crystals ( 1 ) . a recent study has shown that liposomes trigger activation of the nlrp3 inflammasome through mitochondrial reactive oxygen species and calcium influx via the transient receptor potential melastatin 2 channel ( 14 ) . during infection , bacterial pathogen escape from the lysosome after phagocytosis is an important signal inducing nlrp3 inflammasome activation ( 15 ) . however , activation of the nlrp3 inflammasome appears to be dependent on various cell types and stimuli . for example , the nlrp3 inflammasome can be spontaneously activated by primary stimulation of human monocytes , during which stimulation of certain pamp and damp signals provide sufficient signals to trigger mature il-1 secretion ( 16 ) . the general concepts of nlrp3 inflammasome activation and the two - signal model are shown in fig . 1 . emerging evidence has also revealed involvement of other mechanisms / signaling molecules , beyond the core machinery of the inflammasome complex , in inflammasome activation . a recent study showed that double - stranded rna - dependent protein kinase ( pkr , also known as eif2ak2 ) plays an important role in inflammasome activation through physical interaction with several inflammasome components , including nlrp3 ( 17 ) . another study showed that guanylate binding protein ( gbp ) 5 , a member of the interferon ( ifn)-inducible gbp family , can physically interact with the pyrin domain of nlrp3 and contributes to oligomerization of the nlrp3 inflammasome complex ( 18 ) . to activate nlrp3 inflammasome , it was suggested that the adaptor asc on mitochondria should be moved to nlrp3 on the endoplasmic reticulum ( 19 , 20 ) . a recent study proposed a spatial assembly model of microtubule - driven approximation between asc and nlrp3 , which depends on a low intracellular concentration of nad+ and sirt2-dependent deacetylation of microtubules ( 20 ) . the nlrp3 inflammasome - activating signals trigger the recruitment of nlrp3 to mitochondria , and this is dependent on mitochondrial antiviral signaling protein ( mavs ) ( 21 ) , the mitochondrial outer membrane protein that was originally reported as a signaling adaptor leading the production of type 1 interferon ( ifn ) ( 22 , 23 ) . in addition , voltage - dependent anion channels ( vdac ) is essential for nlrp3 inflammasome activation through the uptake of ca into the mitochondria from mams ( 19 ) . the current model of nlrp3 inflammasome activation and its assembly we discuss several bacterial pathogens and their products that induce nlrp3 inflammasomes in vitro and in vivo ( fig . earlier studies showed that gram - positive staphylococcus aureus or listeria monocytogenes , but not salmonella typhimurium or francisella tularensis , require nlrp3 inflammasome activation ( 24 ) . in addition , shigella flexneri can cause nlrp3-dependent necrosis ; i.e. , pyronecrosis , in macrophages ; however , this necrotic death is not caspase-1 and il-1 dependent ( 25 ) . other gram - negative enteropathogens , such as enterohemorrhagic escherichia coli ( ehec ) and citrobacter rodentium , induce nlrp3 inflammasome activation in bone marrow - derived macrophages in a toll - il-1 receptor ( tir)-domain - containing adapter - inducing interferon- ( trif)-dependent pathway . interestingly , trif plays an essential role in the activation of caspase-11 in nlrp3 inflammasome activation during gram - negative bacterial infection ( 26 ) . gram - negative diplococcic neisseria gonorrhoeae infection promotes nlrp3 inflammasome activation through activation of cathepsin b and leads to nlrp3-dependent monocytic cell death ( 27 ) . although mycobacterium tuberculosis ( mtb ) resists inflammasome activation ( 28 ) , the atypical mycobacterium mycobacterium abscessus can induce the maturation and secretion of il-1 in human monocyte - derived macrophages ( 29 ) . however , there are controversial results in mtb - induced nlrp3 inflammasome activation . in human monocytes / macrophages , the m. tuberculosis protein esat-6 was reported to stimulate nlrp3 inflammasome by disrupting cell membranes and allowing of ag85 to access cytosol ( 30 ) . moreover , recent studies have shown that murine microglia primed with conditioned media from cultures of macrophages infected with mtb induce caspase-1 activation and il-1 secretion after mtb stimulation in a nlrp3- and asc - dependent manner , suggesting a role for microglialeukocyte interactions in the pathogenesis of tuberculous meningitis ( 31 ) . interestingly , a recent study has shown that orientia tsutsugamushi , a pathogen causing scrub typhus , induces asc inflammasome activation to secrete il-1 in macrophages ; however , this was not dependent on nlrp3 , nlrp4 or aim2 ( 32 ) . chlamydia pneumoniae , a common respiratory pathogen in atypical pneumonia , induces maturation and secretion of il-1 in unprimed bone marrow - derived macrophages during productive infection . c. pneumoniae - dependent caspase-1 activation and il-1 maturation were dependent on nlrp3/asc ( 33 ) . in addition , a variety of bacterial components induce nlrp3 inflammasome activation through diverse mechanisms . several bacterial toxins ; e.g. , nigericin ( streptomyces hygroscopicus ) , valinomycin ( several streptomyces strain ) , maitotoxin ( gambierdiscus toxicus ) , aerolysin ( aeromonas hydrophila ) and listeriolysin o ( l. monocytogenes ) , trigger the nlrp3 inflammasome pathway through pore formation and plasma membrane disruption , as mentioned above ( 24 , 34 ) . the -hemolysin of group b streptococci , a frequent life - threatening systemic inflammation and meningitis , can induce secretion of il-1 , as well as pro - il-1 synthesis , in bone marrow - derived dendritic cells . interestingly , the production of il-1 and pro - il-1 can be efficiently blocked by bafilomycin treatment , suggesting that group b streptococci - induced inflammasome activation is dependent on bacterial internalization and phagosomal acidification ( 35 ) . in addition , the pneumolysin virulence factor of s. pneumoniae can induce the nlrp3 inflammasome , leading to enhanced secretion of cytokines , including il-17a and ifn- ( 36 ) . recent studies have also reported that the s. aureus virulence factors - , - , and -hemolysin can activate the nlrp3 inflammasome during s. aureus pneumonia , although pulmonary injury induced by live s. aureus is not dependent on il-1 signaling ( 37 ) . moreover , s. aureus pore - forming toxin pvl activates the nlrp3 inflammasome and subsequent pyronecrosis ( 38 ) . a recent study showed that td92 , a surface protein of treponema denticola , one of the major periodontopathogens , can induce nlrp3 inflammasome activation in macrophages through a direct interaction with the host cell membrane integrin 51 ( 39 ) . moreover , the cholera toxin b of vibrio cholerae can induce non - canonical nlrp3 inflammasome activation in a caspase-11-dependent manner ( 40 ) . the effector yopj of yersinia pestis , the causative agent of plague , also leads to activation of the nlrp3/asc / capsase-1 inflammasome in macrophages through a mechanism dependent on k efflux ( 41 ) . bacterial mrna released from the lysosome can be sensed by nlrp3 inflammasome in the cytosol through detection of a special class of viability - associated pamps ( 42 ) . the lipooligosaccharide structure of n. gonorrhoeae potently activates the nlrp3 signaling system , suggesting that the lipooligosaccharide structure is involved in the pathogenesis of gonococcal infections ( 27 ) . accumulated knowledge of bacterial pathogens , their components , and the nlrp3 inflammasome activation will evoke a new avenue for understanding the pathogenesis , and/or developing potential strategies to treat , bacterial infections . extensive research has revealed that nlrp3 inflammasome activation contributes to host defense against numerous bacterial infections . mice lacking nlrp3 , asc , or caspase-1 were more susceptible to group b streptococcal infection than wild - type mice , suggesting a critical role for the nlrp3 inflammasome in successful anti - streptococcal responses ( 35 ) . streptococcal pneumolysin - induced nlrp3 inflammasome activation contributes to protective immunity through induction of il-17a and ifn- secretion against respiratory infection with s. pneumoniae ( 36 ) . using a murine model of melioidosis , previous studies showed that the inflammasome components asc , caspase-1 , and nlrp3 are critical for host defense against lung infection with burkholderia pseudomallei through synthesis and secretion of il-1 ( 43 ) . in addition , mice lacking the inflammasome components nlrp3 , nlrc4 , and caspase-1 exhibited increased susceptibility to citrobacter rodentium infection , which is similar to human infection with enteropathogenic and enterohemorrhagic e. coli ( 44 ) . in addition , il-1- and il-18-null mice also had increased bacterial burdens and showed an exacerbated pattern of histopathology ( 44 ) . moreover , mice lacking both nlrp3 and nlrp4 are highly susceptible to s. typhimurium infection , suggesting the redundant roles of the two nlrs in host innate defense against salmonella infection ( 45 ) . however , a recent study has shown that caspase-11-not nlrp3 , nlrc4 , or asc - is critical for host defense and enhanced clearance of bacteria using a s. typhimurium mutant strain ( sifa ) , which can aberrantly enter the host cell cytosol ( 46 ) . during chronic infections caused by mtb , inflammasome activation and generation of il-1 although aim2 inflammasomes appear to be protective against mtb infection ( 47 ) , nlrp3 inflammasome activation is associated with the immunopathology of tuberculosis , rather than host defense against mtb infection ( 48 , 49 ) . in mycobacterium kansasii infection , nlrp3 inflammasome activation and secreted il-1 derived from caspase-1 activation play an important role in host defense and restriction of intracellular m. kansasii ( 50 ) . moreover , gbp5-deficient mice are defective in caspase-1 cleavage and maturation of il-1/il-18 in vitro and impaired host defense against listerial infection in vivo ( 18 ) . in this context , a recent study demonstrated that a network of immune cell populations spatially organized in lymph nodes can efficiently interact with lymphatic sinus - lining sentinel macrophages , and respond rapidly to inflammasome - induced il-18 produced by these phagocytes , leading to lymphoid cell ifn- secretion , which limits systemic spread of the pathogens ( 51 ) . thus , inflammasome activation is important for a local and acute innate immune response to limit deep invasion of the lymph nodes by pathogenic bacteria ( 51 ) . although the inflammasome activation plays a key role in limiting the spread of an invading pathogen , it can be deleterious due to tissue damage associated with chronic inflammatory responses . when inflammasome activation functions improperly or is uncontrolled , chronic inflammation may develop into various immune disorders , including crohn 's disease , ulcerative colitis , or arthritis ( 52 ) . il-1 and il-18 are potent proinflammatory cytokines that are required for host defense against diverse infections , and simultaneously are involved in various inflammatory pathologies . in addition to processing il-1 , inflammasome activation often results in the caspase-1-mediated pyroptotic form of cell death , which leads to bacterial exposure , efficient uptake , and killing by neutrophils ( 53 ) . however , repeated rounds of pyroptosis can lead to severe inflammatory changes and significant damage to host tissues , particularly in the absence of downstream killing by neutrophils ( 53 ) . trif signaling is essential for nlrp3 inflammasome activation by several gram - negative bacteria , and in detrimental inflammation associated with enteric infections ( 26 ) . earlier studies showed that il-1 secreted by epithelial cells after chlamydia trachomatis infection is associated with tissue damage to the fallopian tube , potentially leading to infertility ( 54 ) . it was also reported that c. trachomatis infection of human monocytes triggers secretion of il-1 through nlrp3 inflammasome activation , which induces an inflammatory response to this pathogen ( 55 ) . in genital infection with chlamydia muridarum , mice lacking nlrp3 , nlrc4 , and asc showed no reduction in oviduct pathology compared with control mice , suggesting a limited role for the inflammasome pathway during genital chlamydial infection ( 56 ) . in helicobacter pylori infection , il-1 is primarily proinflammatory , whereas il-18 counteracts the inflammatory responses induced by il-1 and th17 ( 57 ) . interestingly , two caspase-1 substrates act together to achieve balanced control of helicobacter infection and avoid excessive gastric pathology ( 57 ) . the gram - negative spirochete , borrelia burgdorferi , a pathogen of chronic lyme disease - associated arthritis , activates the inflammasome in a manner dependent on asc and caspase-1 , but not nlrp3 ( 58 , 59 ) . in addition , il-1 is a major pathogenic mediator of lyme arthritis and is not required for control of lyme borreliosis in murine models ( 59 , 60 ) . activation of the nlrc4 inflammasome by the flagella of pseudomonas aeruginosa is deleterious to bacterial clearance in acute pneumonia and associated with increased cell death ( 61 ) . in corneal infection with p. aeruginosa , caspase-1 deficiency leads to inhibition of cytokine and chemokine production , and reduced infiltration of polymorphonuclear leukocytes , suppressing corneal damage and inflammation ( 62 ) . these studies suggest that targeting the inflammasome limits the pathological responses during p. aeruginosa infection . in mycobacterium marinum infection , the esx-1 ( type vii ) secretion system , a major virulence determinant , promotes nlrp3 and the asc - dependent inflammasome . however , nlrp3 inflammasome activation by m. marinum is responsible for host - detrimental effects without restricting bacterial growth ( 48 ) . similarly , the esx-1 secretion system and esat-6 proteins induce nlrp3 inflammasome activation , which leads to necrotic death of thp-1 human macrophages via a syk tyrosine kinase ( 63 ) . in vivo , an mtb aerosol infection study indicated that neither nlrp3 nor casp-1 null mice show any differences in pulmonary bacterial burden or long - term survival , when compared with wild - type mice ( 64 ) . however , asc appears to be important in host protection against chronic mtb infection because asc - deficient mice exhibit reduced survival and defective granuloma formation ( 64 ) . moreover , killed mtb , the immunostimulatory component in complete freund 's adjuvant , promotes experimental autoimmune encephalomyelitis through activation of the inflammasome complex in dendritic cells and increased il-17 production by cd4 and  t cells ( 65 ) . these findings suggest that modulation of inflammasome activation may prevent tissue damage and host death in response to a variety of bacterial infections . bacteria use diverse strategies to hijack or manipulate inflammasome activation in host cells ( 66 ) . earlier studies indicated that p. aeruginosa exos , a type iii effector protein , negatively regulates caspase-1-dependent il-1 maturation through a mechanism dependent on its adp ribosyltransferase activity ( 67 ) . in addition , yersinia yope and yopt prevent the activation of caspase-1 through inhibitory effects on rac1 ( 68 ) . the yersinia type iii secreted effector protein , yopk , can inhibit inflammasome activation through interaction with the t3ss translocon ( 69 ) . detection of the yersinia type iii secretion system ( t3ss ) by nlrp3 and nlrc4 induces the assembly of inflammasomes , and promotes bacterial clearance ( 69 ) ; yopk - mediated inhibition of inflammasome activation may have detrimental effects on host defense . in addition , legionella pneumophila can manipulate asc levels to modulate inflammasome and nf-b pathway activation , thus evading immune evasion and promoting growth ( 70 ) . when asc was over - expressed in cells to maintain constant levels of protein during infection , caspase-1 activation and restriction of legionella growth resulted ( 70 ) . the zinc metalloprotease zmp1 of mtb is involved in the prevention of inflammasome activation by mtb . zmp1-deleted mtb enhances the secretion of il-1 through inflammasome activation , which plays a role in mtb phagosomal maturation and enhancement of mycobacterial clearance in murine aerosol - infection models ( 28 ) . the francisella tularensis ripa protein inhibits secretion of il-1 , il-18 , and tnf- by macrophages to escape from host immunity , and an f. tularensis ripa - deletion mutant ( lvsripa ) induced higher levels of inflammatory cytokines in animals ( 71 ) . collectively , these data demonstrate that a class of bacterial components modulates inflammasome recognition and assembly to evade the host immune system and promote bacterial survival within host cells / tissues . nlrp3 inflammasome activation is crucial for recognition of cytosolic pathogenic microbes and allows the host to induce an appropriate protective innate immune response . a two - signal theory of triggering nlrp3 inflammasome assembly and activation has been proposed . however , evidence of activation or regulation of the inflammasome complex by other mechanisms / molecules has accumulated . interestingly , many bacteria and their products can manipulate and/or activate the nlrp3 inflammasome complex . future studies will identify additional host molecules or bacterial components that activate the inflammasome pathway . it is clear that nlrp3 inflammasome activation contributes to host defense during a variety of bacterial infections . however , chronic inflammation accompanied by dysregulated inflammasome activation during persistent infection may result in detrimental effects and immunopathologies . in addition , many pathogenic bacteria subvert the nlrp3 inflammasome pathways , often through inhibition of , or interaction with , the inflammasome core machinery by virulence factors . in future research , additional virulence factors and mechanisms by which successful microbial pathogens modulate host inflammasome pathways will be clarified . current knowledge of inflammasome activation or regulation by pathogens or their components must be expanded using appropriate genetic and/or animal models . understanding how pathogens subvert host inflammasome signaling pathways will contribute to development of interventions to control bacterial infection and provide protective innate immunity to the host .