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Virulence

Volume 3, 2012 - Issue 3
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Review

The role of inflammasome modulation in virulence

Christopher R. Lupfer Department of Immunology; St. Jude Children’s Research Hospital; Memphis, TN USA
&
Thirumala-Devi Kanneganti Department of Immunology; St. Jude Children’s Research Hospital; Memphis, TN USACorrespondencethirumala-devi.kanneganti@stjude.org
Pages 262-270
Published online: 01 May 2012

Review

The role of inflammasome modulation in virulence

Abstract

Pathogens frequently exist in an immunological balancing act with their host. Pathogens must not only replicate within a host but also transmit effectively between hosts to perpetuate their species. On the other hand, the host seeks to maintain homeostasis by clearing pathogens. The inflammasome is a multi-protein complex that can induce cell death and processes IL-1β and additional proinflammatory substrates. In this review we discuss the pathogen specific modulation of inflammasome activation and the role this plays in virulence and disease pathology.

Introduction

Host-pathogen interactions are essential for modulation of immunity. As the host evolves the ability to defend itself from invasion, the pathogen must adapt. Some pathogen adaptations lead to enhancement or suppression of the host immune system, often with severe pathological consequences or even death. Innate immunity to infection is the first line of host defense and is initiated by a group of diverse pattern recognition receptors (PRR) that recognize proteins, sugars or nucleic acid structures present only in pathogens and not the host. One such innate immune pathway, the inflammasome, has been studied extensively in recent years and yet our understanding of the full range of inflammasome sensors, activators and repressors continues to grow. As inflammasome signaling is important for both innate and adaptive immunity, a more detailed understanding of how the inflammasome is perturbed by pathogen-derived proteins will facilitate the design or implementation of new therapeutic treatments or vaccine adjuvants that modulate these same pathways.

The inflammasome is a large molecular complex consisting of caspase-1, ASC (apoptosis-associated speck-like protein containing a CARD), and an upstream activator such as an NLR (nucleotide-binding domain and leucine-rich repeat containing) or PYHIN (pyrin and HIN domain containing) family member. Bioinformatics studies have discovered 22 NLR genes in the human genome and 34 NLR genes in the mouse genome.Citation1-Citation3 The NLRs NLRP1, NLRP3 and NLRC4 and the PYHIN family member AIM2 have been shown to assemble inflammasomes in response to a range of ligands of microbial, environmental or endogenous origin. The role of inflammasomes is to process interleukin-1β (IL-1β) and IL-18 from their immature pro-forms into active forms that are released from the cells. Caspase-1 activation also leads to a form of cell death known as pyroptosis, which is important for the clearance of several intracellular pathogens.Citation4-Citation6 Recently, the caspase-1 related inflammatory protease caspase-11 was shown to play a significant role in inflammasome signaling and is essential for caspase-1 processing and IL-1β production by E. coli, C. rodentium and V. cholerae.Citation7

In general, inflammasome activation and subsequent pyroptosis or release of proinflammatory substrates is required for efficient clearance of pathogens. In addition to its role in pathogen clearance, inflammasome activation can also lead to inflammatory pathology, which is detrimental to the host but may play a role in facilitating dissemination of the pathogen. Modulation of inflammasome activation is therefore an integral part of virulence. In this review, we discuss the mechanisms by which the host recognizes and activates the inflammasome in response to invading pathogens. In addition, we discuss the pathogen encoded activators and inhibitors of inflammasomes which regulate their virulence.

Inflammasome Activation

A wide variety of microbial, environmental and endogenous ligands have been shown to trigger inflammasome complex formation. AIM2 is activated by cytosolic dsDNA derived from a wide variety of pathogens in the cytosol of infected immune cells.Citation8-Citation12 The NLRP1b inflammasome responds to B. anthracis lethal toxin in the cytosol, and mutations in the Nlrp1b gene were shown to alter anthrax lethal toxin-induced macrophage cell death responses.Citation5,Citation13 Notably, NLRP1b inflammasome-induced macrophage cell death confers resistance to infection with B. anthracis spores in vivo, demonstrating the importance of pyroptosis for host defense.Citation5 Although AIM2 and NLRP1b are activated by single ligands, the molecular mechanisms leading to activation of the NLRC4 and NLRP3 inflammasomes by specific stimuli are less clear.

NLRP3 is the best-studied sensor of the NLR family and is activated by a wide range of pathogens or endogenous/exogenous danger or damage causing agents. The exact mechanism by which NLRP3 is activated by such a diverse range of agents is still under investigation but activation of NLRP3 is generally thought to comprise a two-step process involving priming with Toll-like receptor (TLR) or NLR ligands, which activate NFκB and enhance the expression level of pro-IL-1β and NLRP3.Citation14 Subsequent exposure to microbial pore-forming toxins and ionophores such as listeriolysin O,Citation15 streptolysin O,Citation16 α-hemolysin,Citation17 nigericin or maitotoxin then fully activate the NLRP3 inflammasome.Citation18,Citation19 The NLRP3 inflammasome also responds indirectly to invading pathogens by monitoring potassium egress from the cell, through phagosomal destabilization following phagocytosis of large particles (especially crystalline particles) or through the generation of mitochondrial reactive oxygen species (ROS).Citation19,Citation20 It should be noted that many bacterial, viral and fungal pathogens are capable of providing both the priming and activation signals for the NLRP3 inflammasome.Citation19,Citation20

The NLRC4 inflammasome detects bacterial flagellin from Legionella and the PrgJ family of proteins that comprise the basal body rod component of bacterial type III secretion systems (TTSS) of Salmonella, Pseudomonas and Shigella species.Citation18,Citation21-Citation23 In addition to the secretion of IL-1β and IL-18, the Nlrc4 inflammasome also induces pyroptotic cell death in order to clear flagellin-expressing bacteria such as L. pneumophila and B. thailandensis.Citation4 One ongoing question is how NLRC4 can recognize multiple bacterial ligands. Two independent groups recently published that NAIP (NLR family, apoptosis inhibitory protein) family members NAIP5 and NAIP6 specifically recognize flagellin and that NAIP2 recognizes TTSS rod components. These NAIPs then bind NLRC4 to induce inflammasome activation.Citation23-Citation26 It should be noted, however, that several earlier studies reported that NAIP5 was dispensableCitation27 or only partially requiredCitation28 for NLRC4 inflammasome activation. These differences may be due to partial redundancy between NAIP5 and NAIP6 or may indicate that low levels of NAIP5 are sufficient for NLRC4 activation, as the A/J mouse strain containing mutations in NAIP5 is not completely deficient for NAIP5 protein.Citation29 It was also recently shown that NAIP5 may only be required in response to certain pathogens or that only the C-terminal portion of flagellin activates NAIP5, whereas the N terminus of flagellin utilizes another pathway.Citation25

Finally, as pathogens are continuously evolving and evading detection, it is important to note the overlap that exists between different inflammasomes and pathogen detection. As an example of redundancy in the host, the NLRP3 inflammasome also contributes to host defense during systemic S. Typhimurium infection when flagellin expression is inhibited and NLRC4 can no longer be activated.Citation4,Citation30 In the case of S. pneumoniae, AIM2 is the predominant sensor, but NLRP3 is also capable of inflammasome activation.Citation31 These findings highlight the complexity of the relationship between the host and the pathogen.

Inflammasome Induced Pathology

Although the role of inflammation is to clear or limit the spread of an invading pathogen, there is frequently collateral damage associated with the somewhat nonspecific nature of the innate immune response. Inflammasome activation leads to the proinflammatory pyroptotic form of cell death, which kills the infected cell but leads to tissue damage and inflammation.Citation4 Furthermore, IL-1β and IL-18 release participate in the recruitment of macrophages and neutrophils that help to eliminate the pathogen but also cause tissue damage. In the case of Chlamydia trachomatis infection, an ex vivo human Fallopian tube organ culture system showed that inflammation can lead to tissue damage and potentially infertility through an IL-1 mediated mechanism.Citation32 NLRP3 inflammasome activation and IL-1β production by C. trachomatis have also been shown to lead to inflammation and cell death in the THP-1 human monocytes cell line.Citation33 In a model of corneal infection with Pseudomonas aeruginosa, caspase-1 deficient mice had reduced cytokine and chemokine production with reduced polymorphonuclear leukocytes (PMN) infiltration and subsequently less corneal damage, thus demonstrating the negative consequences of unchecked inflammasome mediated inflammation.Citation34 Recently in a mouse model of pneumonia, the rhsT gene of P. aeruginosa was shown to activate the inflammasome which enhanced lung pathology and facilitated bacterial colonization, as bacteria lacking rhsT were cleared but WT P. aeruginosa persisted, which resulted in enhanced lethality.Citation35 Finally, infection with Mycobacterium marinum in mice demonstrated that the Esx-1 (type VII) secretion system activates the NLRP3 inflammasome. However, inflammasome activation leads to increased tissue damage but does not resolve the infection.Citation36

Another common pathology associated with inflammasome activation is neuronal damage. Pneumococcal meningitis results in inflammasome activation and IL-1β release in the cerebral spinal fluid, which correlates with the severity of disease. In a mouse model of pneumococcal meningitis, caspase-1 deficient mice, or mice treated with inflammasome inhibitors, showed reduced neuronal damage and improved clinical outcomes.Citation37 HIV-1 associated dementia (HAD) is the result of virus dissemination to the central nervous system where increased apoptosis of neuronal cells and resident immune cells is thought to mediate disease. Interestingly, the HIV surface glycoprotein gp120 alone is capable of activating the inflammasome.Citation38 Intra-cerebral injection of gp120 actives caspase-1 and leads to IL-1β maturation as well as cell death in the neocortex of rats.Citation39 This pathology can be reduced by treatment with inhibitors of caspase-1 or IL-1 receptor antagonist.Citation40-Citation42 Ectromelia virus also activates caspase-1 in brain tissue of infected mice and this may play a role in inflammation and pyroptosis induced cell death.Citation43 During dengue virus infection of mice, caspase-1 expression increases and inflammasome activation results in pyroptotic cell death. However, treatment with the caspsase-1 inhibitor YVAD reduced cell death without significantly enhancing virus replication.Citation44 These findings suggest that, especially in the case of encephalitis, inhibition of inflammasome activation may prevent nerve damage and host death.

In addition to bacteria and viruses, the intracellular parasite Plasmodium, which includes the causative agent of malaria, also activates the NLRP3 inflammasome through the production of a heme metabolite called hemozoin. Intriguingly, NLRP3 inflammasome or IL-1β deficient mice survive longer than wildtype mice during infection with Plasmodium chabaudi adami DS.Citation45 Furthermore, Plasmodium berghei infection in mice results in cerebral malaria and NLRP3 inflammasome deficient mice had reduced cerebral inflammation and improved survival.Citation46

Due to the negative effects of inflammasome activation by certain pathogens, treatment of severe inflammation with inflammasome inhibitors has promising therapeutic potential. Indeed, treatment with the caspase-1 inhibitor glyburide was able to delay death in a mouse model of endotoxic shock.Citation47 As discussed above, treatment of encephalitis with YVAD provides a proof of principle for reduced neuronal death. However, there are many factors that will likely affect the utility of such treatments including the effect of inflammasome inhibition on pathogen burden and eventual clearance, as well as the ability of inhibitors to cross the blood brain barrier. Combination of treatments with antimicrobial agents and inflammasome inhibitors will therefore likely provide the greatest therapeutic potential.

Pathogen-Mediated Inflammasome Activation in Virulence

As inflammasome activation leads to inflammation, most pathogens seek to avoid or suppress inflammasome activation. However, some pathogens are able to replicate despite inflammasome activation and still others require inflammasome activation for efficient replication or dissemination. It was demonstrated for C. trachomatis that inflammasome activation within infected HeLa cells is required for efficient bacterial replication.Citation48 It should be noted that epithelial cells, though they possess an inflammasome and make substantial amounts of IL-18, generally express minimal levels of IL-1β, and therefore do not induce the same inflammatory signaling that macrophages containing an activated inflammasome are capable of producing.Citation32,Citation49,Citation50 Alternatively, another group recently published that chlamydial protease-like activity factor (CPAF) inhibition results in breakdown of the C. trachomatis vacuole in HeLa cells or mouse lung fibroblasts and subsequent inflammasome mediate cell death with concurrent inhibition of pathogen replication.Citation51 It is therefore unclear what role inflammasome activation may play in clearance or growth of C. trachomatis, but one possibility that explains the differences observed between these group may be the level of caspase-1 activation, as one group inhibited caspase-1 and the other induced its activation through blockade of CPAF. Some inflammasome activation may be beneficial, but too much may be detrimental. Finally, another Chlamydia species, C. pneumoniae, has also been shown to benefit from inflammasome activation and cell death.Citation52 In this instance, inflammasome mediated cell death in T cells during pulmonary infection in mice leads to both the persistence of inflammation as well as impaired T cell mediated clearance of the pathogen. In all, it appears that some level of inflammasome activation during Chlamydia infection may be beneficial to the pathogen, but further studies are clearly needed.

Another instance of a pathogen benefiting from inflammasome activation is during Salmonella infection. Gastrointestinal infection with Salmonella leads to macrophage infection and the subsequent delivery of the sipB virulence factor via the bacterial TTSS, which activates the NLRC4 inflammasome and induces cell death.Citation53,Citation54 This results in inflammation and damage to the intestinal epithelium in a murine model and allows for colonization of Peyer’s patches and disseminated infection.Citation55,Citation56

Pathogen-Mediated Inflammasome Inhibition in Virulence

Direct inhibition of caspase-1

As obligate intracellular pathogens, it is not surprising that many viruses evade or inhibit the inflammasome to preserve the life of their host cells. Several viruses are known to encode proteins capable of interfering with inflammasome signaling (). Not surprisingly, inflammasome signaling is generally disrupted at the adaptor protein ASC or caspase-1 itself (Fig. 1).Citation57 For example, baculovirus protein p35 is capable of binding to and directly inhibiting a wide variety of caspases, including caspsase-1, in its natural insect hosts and mammalian cells.Citation58,Citation59 Poxviruses also encode a variety of serpine like protease inhibitors. The CrmA protein (also known as SPI-2) of cowpox virus inhibits several caspases, including caspase-1, through a direct but reversible inhibition of the enzymatic active site.Citation60,Citation61 This subsequently inhibits cleavage of pro-IL-1β.Citation62,Citation63 Pulmonary infection of mice with CrmA mutants of cowpox or SPI-2 mutants of rabbit poxvirus demonstrated that they are attenuated in inflammation and viral replication compared with wild type viruses.Citation64 Intradermal infection with CrmA mutant cowpox also resulted in rapid viral clearance but with a more robust inflammatory response.Citation65 Additional pox viruses also encode CrmA homologs. Serp2 is the CrmA homolog found in myxoma virus.Citation66 Deletion of Serp2 results in severe attenuation of the virus in rabbits.Citation67 Vaccinia virus (VV) has been shown to activate both the NLRP3Citation68 and AIM2Citation10,Citation69 inflammasomes. VV also encodes a SPI-2 protein (B13R) which is able to inhibit caspase-1 activation in a cell free assay; however, VV B13R mutants were not attenuated.Citation70,Citation71 Instead, fever reduction and weight loss were dependent on VV encoded IL-1β scavenger receptor (vIL-1βR).Citation70 Finally, ectromelia virus SPI-2 protein also inhibits caspase-1 activation, though what role this may play in vivo has not been examined.Citation72 It is apparent that poxviruses have a variety of inhibitors for inflammasomes. The differential requirement for SPI-2 family proteins may, therefore, be the result of differentially encoded additional inhibitors or the result of different natural host ranges of these viruses, as rodents are the natural host for cowpox but not VV.Citation73

Antagonists to inflammasome assembly

Poxviruses have evolved multiple inhibitors that interfere with innate and adaptive immunity ( and Fig. 1).Citation74 The myxoma virus M13L and Shope fibroma virus S013L proteins contain a pyrin domain (PYD) and interact with ASC to suppress inflammasome activation by blocking the ability of ASC to bid to and activate caspase-1.Citation75,Citation76 M13L-PYD is required for pathogenesis of myxoma virus and deletion results in severe attenuation in vivo characterized by decreased viremia due to inefficient replication in lymphocytes and leukocytes and increased inflammation at the initial site of infection. In cell culture, myxoma virus lacking M13L-PYD increases activation of caspase-1 and increases the levels of IL-1β and IL-18.Citation76 Although M13L could theoretically inhibit any inflammasome due to direct inhibitory action on ASC, the NLRP3 inflammasome appears to be most critical during myxoma virus infection.Citation77 Poxvirus PYD proteins therefore inhibit inflammasomes at the level of the adaptor ASC and potentially prevent all upstream PRRs from efficiently activating inflammasomes. Orf63 of Kaposi's sarcoma-associated herpesvirus (KSHV) was shown to encode an antagonistic NLR homolog which inhibits the NLRP1 inflammasome. In addition, Orf63 could interact with other NLRs, NLRP3 and NLRC2, potentially indicating multiple inhibitory roles for this protein in the KSHV life-cycle. Mutation of this Orf not only leads to increased inflammasome activation, IL-1β and IL-18 processing but also leads to reduced virus reactivation and progeny virus production.Citation78

Gene expression modulation

It was recently discovered that the NLRP3 inflammasome requires increased expression of NLRP3 for full activation,Citation14 thus implicating gene expression as one potential mechanism for inflammasome inhibition. Indeed, inflammasome activation by Legionella pneumophila infection is suppressed due to reduced NLRC4 and ASC mRNA and subsequent protein expression (). The downregulation of these genes allows L. pneumophila to suppress inflammasome activation and replicate in human macrophages.Citation79 However, it is unclear how L. pneumophila inhibits production of NLRC4 and ASC mRNA.

Indirect inflammasome inhibition

Influenza A/PR/8/34 H1N1 virus (PR8) NS1protein, in addition to blocking type-I interferon responses, is also capable of blocking inflammasome activation. The N-terminus of PR/8 NS1 possesses an inflammasome inhibitory function and PR8 lacking the N-terminus of NS1 is attenuated in cell culture and induces higher levels of IL-1β and pyroptosis. This caspase-1 inhibitory function appears to be indirect, as blocking the RNA dependent protein kinase PKR in PR/8 NS1 mutants was able to suppress renewed caspase-1 activation.Citation80 However, the ability of NS1 to block inflammasome activation appears to be strain specific, as NS1 from highly pathogenic H5N1 bird flu reportedly activates caspases and induce apoptosis.Citation81 It is interesting to speculate that the ability of the NS1 protein from different strains of influenza A virus to inhibit caspase-1 may play a role in host range and zoonotic transmission; with those viruses adapting the ability to inhibit human caspase-1 being able to more efficiently transmit between humans.

In the case of Mycobacterium tuberculosis (Mtb), the zmp1 protein is a potential Zn2+ metalloprotease which represses inflammasome activation likely through the regulation of superoxide, an NLRP3 coactivator. Zmp1 mutant Mtb are cleared faster from the lungs of infected mice and more efficiently activate macrophages leading to phagosomal maturation and bacterial killing.Citation82 The ExoU and ExoS proteins of P. aeruginosa inhibit the NLRC4 inflammasome upon TTSS delivery to the cytosol and are required for pathogenicity.Citation83,Citation84 ExoU was shown to indirectly inhibit the NLRC4 inflammasome through its phospholipase A2 activity; however, it is not altogether clear how this enzymatic activity of ExoU inhibits caspase-1 activation.Citation83 ExoS similarly inhibits caspase-1 activation through its ADP ribosyltransferase activity through an undefined mechanism.Citation84 Additional bacterial inhibitors include the YopT, YopE and YopK proteins from various Yersinia species, which are delivered to the cytosol via the TTSS. YopE and YopT inhibit inflammasome activation through an indirect mechanism that involves inhibiting oligomerization and self cleavage of caspase-1 through the Rho-GTPase Rac-1 and LIM kinase-1.Citation85 This inhibitory mechanism is particularly intriguing as it may indicate the requirement for cytoskeletal proteins in the induced proximity required for caspase-1 self cleavage upon inflammasome activation. In the case of YopK, indirect inhibition or masking of the TTSS appear to be involved, as YopK cannot block inflammasome activation in Trans and YopK directly interacts with the TTSS which is recognized by NLRC4.Citation86

Antigenic stealth

During infection, some pathogens use stealth to avoid inflammasome activation (). One example of stealth is the S. aureus enzyme PGN O-acetyltransferase A, which acetylates peptidoglycan in the bacterial cell wall and prevents lysosomal degradation of the cell wall and subsequent sensing of the bacteria by NLRs.Citation87 Francisella novicida deficient in membrane-associate proteins like MviN (a lipid II flippase) or proteins required for cell wall synthesis are also known to more efficiently activate the inflammasome; however, this appears to be due to increased bacterial lysis, due to insufficient cell wall synthesis or instability of the cell wall/membrane, and not from any direct inhibitory mechanism.Citation88,Citation89 Another example is that of S. pneumoniae pulmonary infection, where bacteria lacking pneumolysin, or possessing non-hemolytic pneumolysin, are not detected by the NLRP3 inflammasome and become more invasive.Citation90 L. pneumophila also employs an antigen masking strategy through its SdhA protein which is important for maintaining the L. pneumophila replication vacuole and preventing cytosolic recognition of antigens by the inflammasome.Citation91 In all, a diverse range of inflammasome repression mechanisms are utilized by an equally diverse group of pathogens to evade immune detection and allow for pathogen dissemination.

Inflammasome Modulation during Fungal Infection

Many examples of inflammasome activation or inhibition from bacterial or viral pathogens have been shown to regulate virulence. However, much less is known regarding the ability of fungal pathogens to inhibit or enhance inflammasome activation. Multiple fungal pathogens have been shown to activate the NLRP3 inflammasome through the activation of cell surface Dectin receptors and the tyrosine kinase Syk including Saccharomyces cerevisiae,Citation92 Candida albicansCitation93,Citation94 and Aspergillus fumigatus.Citation95 In addition, the NLRC4 inflammasome in epithelial cells was recently reported to be required for the efficient clearance of C. albicans during mucosal infections.Citation96 In all of these infections, inflammasome activation is critical for fungal clearance. It does not appear from the current literature, however, that fungi actively suppress inflammasome activation to perpetuate or enhance their infectivity in the same manner as viruses or bacteria. The one mechanism that is apparent is stealth. Most fungal spores mask their PAMPs, such as zymosan or mannan, thus avoiding inflammasome activation ().Citation95,Citation97 Once the spores or yeast mature into hyphae, the signals for inflammasome activation are exposed and the fungi are rapidly cleared through an inflammasome dependent Th17 mediated immune response.Citation98,Citation99 Therefore, fungal infections are generally only pathogenic in immunocompromised hosts such as transplant recipients or chemotherapy patients. However, there are some polymorphisms in the NLRP3 gene that have been linked to recurrent vulvovaginal candidiasis which result in reduced IL-1β secretion.Citation100 Thus, genetic polymorphisms in the host that result in reduced inflammasome activation or IL-1β signaling may predispose patients to fungal infections.

Conclusion

In all, it is apparent that inflammasome modulation is a critical component of pathogen virulence. The host has developed a multitude of inflammasome activators and regulatory mechanisms to control inflammasome activation and, in general, inflammasome activation facilitates pathogen clearance and is beneficial to the host. However, pathogens modulate inflammasomes differently according to their specific niche to promote immune evasion or enhance inflammation, which allows for optimal dissemination. In some instances, inflammasome activation appears to be detrimental to the host and inflammasome inhibition in these situations may be therapeutically useful.

As seen with influenza, overt inflammation can occur following transmission from birds to humans with one possible cause being the inability of the virus to effectively inhibit inflammasome activation in humans.Citation81 Further research into the field of emerging infectious diseases will likely be of interest to determine if differences in virulence between the natural host and humans is the result of inflammasome modulation. Continued research in the area of therapeutics which target the inflammasome, or its downstream substrates, will also improve our understanding of the importance of inflammasome modulation in infectious disease.

Figure 1. Pathogen activation and repression pathways of the inflammasome. The host has evolved a complex and multilayered pathogen and damage sensing pathway which regulates inflammasome activation. Activation sensors include NLRs, NAIPs and PYHIN (AIM2) family members, which converge on the adaptor ASC. The pathway culminates with caspase-1 activation and inflammatory cytokine processing (IL-1β/IL-18) as well as cell death (pyroptosis). Pathogens employ a surprising array of mechanisms to inhibit inflammasomes. It is also interesting to note that certain groups of pathogens, particularly pox viruses, appear to have evolved more direct inhibitory pathways which are common to the entire family of pox viruses.

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Table 1. Pathogen virulence factors that inhibit or evade inflammasomes

Acknowledgments

We would like to thank John Lukens for helpful comments on the manuscript. This work was supported by the US National Institutes of Health grants (AR056296, AI1010935) and the American Syrian Lebanese Associated Charities to T.-D.K.

Abbreviations:
TTSS

type III secretion system

NS1

nonstructural protein 1

PRR

pattern recognition receptors

ASC

apoptosis-associated speck-like protein containing a CARD

NLR

NOD-like receptor

LRR

leucine-rich repeat

AIM2

absent in melanoma 2

IL-1β

interleukin-1β

IL-18

interleukin-18

HAD

HIV-1 associated dementia

CPAF

chlamydial protease-like activity factor

KSHV

Kaposi sarcoma-associated herpes virus

VV

vaccinia virus

vIL-1βR

IL-1β scavenger receptor

PR8

Influenza A/PR/8/34 H1N1 virus

References

  • Harton JA, Linhoff MW, Zhang J, Ting JP. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol 2002; 169:4088 - 93; PMID: 12370334  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Inohara N, Nuñez G. The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 2001; 20:6473 - 81; http://dx.doi.org/10.1038/sj.onc.1204787; PMID: 11607846  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, et al. The NLR gene family: a standard nomenclature. Immunity 2008; 28:285 - 7; http://dx.doi.org/10.1016/j.immuni.2008.02.005; PMID: 18341998  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 2010; 11:1136 - 42; http://dx.doi.org/10.1038/ni.1960; PMID: 21057511  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Terra JK, Cote CK, France B, Jenkins AL, Bozue JA, Welkos SL, et al. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. J Immunol 2010; 184:17 - 20; http://dx.doi.org/10.4049/jimmunol.0903114; PMID: 19949100  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lamkanfi M, Dixit VM. Manipulation of host cell death pathways during microbial infections. Cell Host Microbe 2010; 8:44 - 54; http://dx.doi.org/10.1016/j.chom.2010.06.007; PMID: 20638641  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature 2011; 479:117 - 21; http://dx.doi.org/10.1038/nature10558; PMID: 22002608  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 2009; 10:266 - 72; http://dx.doi.org/10.1038/ni.1702; PMID: 19158679  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 2009; 458:509 - 13; http://dx.doi.org/10.1038/nature07710; PMID: 19158676  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009; 458:514 - 8; http://dx.doi.org/10.1038/nature07725; PMID: 19158675  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 2009; 323:1057 - 60; http://dx.doi.org/10.1126/science.1169841; PMID: 19131592  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Tsuchiya K, Hara H, Kawamura I, Nomura T, Yamamoto T, Daim S, et al. Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J Immunol 2010; 185:1186 - 95; http://dx.doi.org/10.4049/jimmunol.1001058; PMID: 20566831  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 2006; 38:240 - 4; http://dx.doi.org/10.1038/ng1724; PMID: 16429160  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 2009; 183:787 - 91; http://dx.doi.org/10.4049/jimmunol.0901363; PMID: 19570822  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Hara H, Tsuchiya K, Nomura T, Kawamura I, Shoma S, Mitsuyama M. Dependency of caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin, listeriolysin O, after evasion from phagosome into the cytoplasm. J Immunol 2008; 180:7859 - 68; PMID: 18523249  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Harder J, Franchi L, Muñoz-Planillo R, Park JH, Reimer T, Núñez G. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol 2009; 183:5823 - 9; http://dx.doi.org/10.4049/jimmunol.0900444; PMID: 19812205  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Craven RR, Gao X, Allen IC, Gris D, Bubeck Wardenburg J, McElvania-Tekippe E, et al. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One 2009; 4:e7446; http://dx.doi.org/10.1371/journal.pone.0007446; PMID: 19826485  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lamkanfi M, Dixit VM. The inflammasomes. PLoS Pathog 2009; 5:e1000510; http://dx.doi.org/10.1371/journal.ppat.1000510; PMID: 20041168  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?. Nat Rev Immunol 2010; 10:210 - 5; http://dx.doi.org/10.1038/nri2725; PMID: 20168318  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lamkanfi M, Kanneganti TD. Nlrp3: an immune sensor of cellular stress and infection. Int J Biochem Cell Biol 2010; 42:792 - 5; http://dx.doi.org/10.1016/j.biocel.2010.01.008; PMID: 20079456  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 2007; 3:e111; http://dx.doi.org/10.1371/journal.ppat.0030111; PMID: 17696608  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A 2010; 107:3076 - 80; http://dx.doi.org/10.1073/pnas.0913087107; PMID: 20133635  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 2011; 477:596 - 600; http://dx.doi.org/10.1038/nature10510; PMID: 21918512  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lightfield KL, Persson J, Brubaker SW, Witte CE, von Moltke J, Dunipace EA, et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol 2008; 9:1171 - 8; http://dx.doi.org/10.1038/ni.1646; PMID: 18724372  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lightfield KL, Persson J, Trinidad NJ, Brubaker SW, Kofoed EM, Sauer JD, et al. Differential requirements for NAIP5 in activation of the NLRC4 inflammasome. Infect Immun 2011; 79:1606 - 14; http://dx.doi.org/10.1128/IAI.01187-10; PMID: 21282416  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Kofoed EM, Vance RE. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 2011; 477:592 - 5; http://dx.doi.org/10.1038/nature10394; PMID: 21874021  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lamkanfi M, Amer A, Kanneganti TD, Muñoz-Planillo R, Chen G, Vandenabeele P, et al. The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation. J Immunol 2007; 178:8022 - 7; PMID: 17548639  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Miao EA, Ernst RK, Dors M, Mao DP, Aderem A. Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci U S A 2008; 105:2562 - 7; http://dx.doi.org/10.1073/pnas.0712183105; PMID: 18256184  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, Long EM, et al. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr Biol 2003; 13:27 - 36; http://dx.doi.org/10.1016/S0960-9822(02)01359-3; PMID: 12526741  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med 2010; 207:1745 - 55; http://dx.doi.org/10.1084/jem.20100257; PMID: 20603313  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Fang R, Tsuchiya K, Kawamura I, Shen Y, Hara H, Sakai S, et al. Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection. J Immunol 2011; 187:4890 - 9; http://dx.doi.org/10.4049/jimmunol.1100381; PMID: 21957143  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Hvid M, Baczynska A, Deleuran B, Fedder J, Knudsen HJ, Christiansen G, et al. Interleukin-1 is the initiator of Fallopian tube destruction during Chlamydia trachomatis infection. Cell Microbiol 2007; 9:2795 - 803; http://dx.doi.org/10.1111/j.1462-5822.2007.00996.x; PMID: 17614966  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Abdul-Sater AA, Saïd-Sadier N, Padilla EV, Ojcius DM. Chlamydial infection of monocytes stimulates IL-1beta secretion through activation of the NLRP3 inflammasome. Microbes Infect 2010; 12:652 - 61; http://dx.doi.org/10.1016/j.micinf.2010.04.008; PMID: 20434582  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Thakur A, Barrett RP, McClellan S, Hazlett LD. Regulation of Pseudomonas aeruginosa corneal infection in IL-1 beta converting enzyme (ICE, caspase-1) deficient mice. Curr Eye Res 2004; 29:225 - 33; http://dx.doi.org/10.1080/02713680490516710; PMID: 15590467  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Kung VL, Khare S, Stehlik C, Bacon EM, Hughes AJ, Hauser AR. An rhs gene of Pseudomonas aeruginosa encodes a virulence protein that activates the inflammasome. Proc Natl Acad Sci U S A 2012; 109:1275 - 80; http://dx.doi.org/10.1073/pnas.1109285109; PMID: 22232685  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Carlsson F, Kim J, Dumitru C, Barck KH, Carano RA, Sun M, et al. Host-detrimental role of Esx-1-mediated inflammasome activation in mycobacterial infection. PLoS Pathog 2010; 6:e1000895; http://dx.doi.org/10.1371/journal.ppat.1000895; PMID: 20463815  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Koedel U, Winkler F, Angele B, Fontana A, Flavell RA, Pfister HW. Role of Caspase-1 in experimental pneumococcal meningitis: Evidence from pharmacologic Caspase inhibition and Caspase-1-deficient mice. Ann Neurol 2002; 51:319 - 29; http://dx.doi.org/10.1002/ana.10103; PMID: 11891827  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Corasaniti MT, Bilotta A, Strongoli MC, Navarra M, Bagetta G, Di Renzo G. HIV-1 coat protein gp120 stimulates interleukin-1beta secretion from human neuroblastoma cells: evidence for a role in the mechanism of cell death. Br J Pharmacol 2001; 134:1344 - 50; http://dx.doi.org/10.1038/sj.bjp.0704382; PMID: 11704656  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Corasaniti MT, Turano P, Bilotta A, Malorni W, Stringaro AR, Nisticò R, et al. Evidence that increases of mitochondrial immunoreactive IL-1beta by HIV-1 gp120 implicate in situ cleavage of pro-IL-1beta in the neocortex of rat. J Neurochem 2001; 78:611 - 8; http://dx.doi.org/10.1046/j.1471-4159.2001.00441.x; PMID: 11483664  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Corasaniti MT, Russo R, Amantea D, Gliozzi M, Siviglia E, Stringaro AR, et al. Neuroprotection by the caspase-1 inhibitor Ac-YVAD-(acyloxy)mk in experimental neuroAIDS is independent from IL-1beta generation. Cell Death Differ 2005; 12:Suppl 1 999 - 1001; http://dx.doi.org/10.1038/sj.cdd.4401644; PMID: 15846371  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Corasaniti MT, Bellizzi C, Russo R, Colica C, Amantea D, Di Renzo G. Caspase-1 inhibitors abolish deleterious enhancement of COX-2 expression induced by HIV-1 gp120 in human neuroblastoma cells. Toxicol Lett 2003; 139:213 - 9; http://dx.doi.org/10.1016/S0378-4274(02)00436-8; PMID: 12628757  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Bagetta G, Corasaniti MT, Berliocchi L, Nisticó R, Giammarioli AM, Malorni W, et al. Involvement of interleukin-1beta in the mechanism of human immunodeficiency virus type 1 (HIV-1) recombinant protein gp120-induced apoptosis in the neocortex of rat. Neuroscience 1999; 89:1051 - 66; http://dx.doi.org/10.1016/S0306-4522(98)00363-7; PMID: 10362294  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Krzyzowska M, Cymerys J, Winnicka A, Niemiałtowski M. Involvement of Fas and FasL in Ectromelia virus-induced apoptosis in mouse brain. Virus Res 2006; 115:141 - 9; http://dx.doi.org/10.1016/j.virusres.2005.08.001; PMID: 16169110  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Nasirudeen AM, Liu DX. Gene expression profiling by microarray analysis reveals an important role for caspase-1 in dengue virus-induced p53-mediated apoptosis. J Med Virol 2009; 81:1069 - 81; http://dx.doi.org/10.1002/jmv.21486; PMID: 19382257  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Shio MT, Eisenbarth SC, Savaria M, Vinet AF, Bellemare MJ, Harder KW, et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog 2009; 5:e1000559; http://dx.doi.org/10.1371/journal.ppat.1000559; PMID: 19696895  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Dostert C, Guarda G, Romero JF, Menu P, Gross O, Tardivel A, et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One 2009; 4:e6510; http://dx.doi.org/10.1371/journal.pone.0006510; PMID: 19652710  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 2009; 187:61 - 70; http://dx.doi.org/10.1083/jcb.200903124; PMID: 19805629  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Abdul-Sater AA, Koo E, Häcker G, Ojcius DM. Inflammasome-dependent caspase-1 activation in cervical epithelial cells stimulates growth of the intracellular pathogen Chlamydia trachomatis. J Biol Chem 2009; 284:26789 - 96; http://dx.doi.org/10.1074/jbc.M109.026823; PMID: 19648107  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 2006; 126:1135 - 45; http://dx.doi.org/10.1016/j.cell.2006.07.033; PMID: 16990137  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • VanderBrink BA, Asanuma H, Hile K, Zhang H, Rink RC, Meldrum KK. Interleukin-18 stimulates a positive feedback loop during renal obstruction via interleukin-18 receptor. J Urol 2011; 186:1502 - 8; http://dx.doi.org/10.1016/j.juro.2011.05.046; PMID: 21855933  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Jorgensen I, Bednar MM, Amin V, Davis BK, Ting JP, McCafferty DG, et al. The Chlamydia protease CPAF regulates host and bacterial proteins to maintain pathogen vacuole integrity and promote virulence. Cell Host Microbe 2011; 10:21 - 32; http://dx.doi.org/10.1016/j.chom.2011.06.008; PMID: 21767809  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Olivares-Zavaleta N, Carmody A, Messer R, Whitmire WM, Caldwell HD. Chlamydia pneumoniae inhibits activated human T lymphocyte proliferation by the induction of apoptotic and pyroptotic pathways. J Immunol 2011; 186:7120 - 6; http://dx.doi.org/10.4049/jimmunol.1100393; PMID: 21543647  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Hoffmann C, Galle M, Dilling S, Käppeli R, Müller AJ, Songhet P, et al. In macrophages, caspase-1 activation by SopE and the type III secretion system-1 of S. typhimurium can proceed in the absence of flagellin. PLoS One 2010; 5:e12477; http://dx.doi.org/10.1371/journal.pone.0012477; PMID: 20814576  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Hersh D, Monack DM, Smith MR, Ghori N, Falkow S, Zychlinsky A. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci U S A 1999; 96:2396 - 401; http://dx.doi.org/10.1073/pnas.96.5.2396; PMID: 10051653  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Guiney DG. The role of host cell death in Salmonella infections. Curr Top Microbiol Immunol 2005; 289:131 - 50; http://dx.doi.org/10.1007/3-540-27320-4_6; PMID: 15791954  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Monack DM, Hersh D, Ghori N, Bouley D, Zychlinsky A, Falkow S. Salmonella exploits caspase-1 to colonize Peyer’s patches in a murine typhoid model. J Exp Med 2000; 192:249 - 58; http://dx.doi.org/10.1084/jem.192.2.249; PMID: 10899911  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Johnston JB, Rahman MM, McFadden G. Strategies that modulate inflammasomes: insights from host-pathogen interactions. Semin Immunopathol 2007; 29:261 - 74; http://dx.doi.org/10.1007/s00281-007-0080-5; PMID: 17717669  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Crook NE, Clem RJ, Miller LK. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 1993; 67:2168 - 74; PMID: 8445726  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Zhou Q, Krebs JF, Snipas SJ, Price A, Alnemri ES, Tomaselli KJ, et al. Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/p35 complex. Biochemistry 1998; 37:10757 - 65; http://dx.doi.org/10.1021/bi980893w; PMID: 9692966  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Zhou Q, Snipas S, Orth K, Muzio M, Dixit VM, Salvesen GS. Target protease specificity of the viral serpin CrmA. Analysis of five caspases. J Biol Chem 1997; 272:7797 - 800; http://dx.doi.org/10.1074/jbc.272.12.7797; PMID: 9065443  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Callus BA, Vaux DL. Caspase inhibitors: viral, cellular and chemical. Cell Death Differ 2007; 14:73 - 8; http://dx.doi.org/10.1038/sj.cdd.4402034; PMID: 16946729  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, Salvesen GS, et al. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 1992; 69:597 - 604; http://dx.doi.org/10.1016/0092-8674(92)90223-Y; PMID: 1339309  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Komiyama T, Ray CA, Pickup DJ, Howard AD, Thornberry NA, Peterson EP, et al. Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition. J Biol Chem 1994; 269:19331 - 7; PMID: 8034697  [PubMed], [Web of Science ®], [Google Scholar]
  • Thompson JP, Turner PC, Ali AN, Crenshaw BC, Moyer RW. The effects of serpin gene mutations on the distinctive pathobiology of cowpox and rabbitpox virus following intranasal inoculation of Balb/c mice. Virology 1993; 197:328 - 38; http://dx.doi.org/10.1006/viro.1993.1594; PMID: 8212568  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • MacNeill AL, Moldawer LL, Moyer RW. The role of the cowpox virus crmA gene during intratracheal and intradermal infection of C57BL/6 mice. Virology 2009; 384:151 - 60; http://dx.doi.org/10.1016/j.virol.2008.10.041; PMID: 19056101  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Petit F, Bertagnoli S, Gelfi J, Fassy F, Boucraut-Baralon C, Milon A. Characterization of a myxoma virus-encoded serpin-like protein with activity against interleukin-1 beta-converting enzyme. J Virol 1996; 70:5860 - 6; PMID: 8709205  [PubMed], [Web of Science ®], [Google Scholar]
  • Messud-Petit F, Gelfi J, Delverdier M, Amardeilh MF, Py R, Sutter G, et al. Serp2, an inhibitor of the interleukin-1beta-converting enzyme, is critical in the pathobiology of myxoma virus. J Virol 1998; 72:7830 - 9; PMID: 9733819  [PubMed], [Web of Science ®], [Google Scholar]
  • Delaloye J, Roger T, Steiner-Tardivel QG, Le Roy D, Knaup Reymond M, Akira S, et al. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog 2009; 5:e1000480; http://dx.doi.org/10.1371/journal.ppat.1000480; PMID: 19543380  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 2010; 11:395 - 402; http://dx.doi.org/10.1038/ni.1864; PMID: 20351692  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Kettle S, Alcamí A, Khanna A, Ehret R, Jassoy C, Smith GL. Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1beta-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1beta-induced fever. J Gen Virol 1997; 78:677 - 85; PMID: 9049422  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Kettle S, Blake NW, Law KM, Smith GL. Vaccinia virus serpins B13R (SPI-2) and B22R (SPI-1) encode M(r) 38.5 and 40K, intracellular polypeptides that do not affect virus virulence in a murine intranasal model. Virology 1995; 206:136 - 47; http://dx.doi.org/10.1016/S0042-6822(95)80028-X; PMID: 7831769  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Turner SJ, Silke J, Kenshole B, Ruby J. Characterization of the ectromelia virus serpin, SPI-2. J Gen Virol 2000; 81:2425 - 30; PMID: 10993930  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Chantrey J, Meyer H, Baxby D, Begon M, Bown KJ, Hazel SM, et al. Cowpox: reservoir hosts and geographic range. Epidemiol Infect 1999; 122:455 - 60; http://dx.doi.org/10.1017/S0950268899002423; PMID: 10459650  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Seet BT, Johnston JB, Brunetti CR, Barrett JW, Everett H, Cameron C, et al. Poxviruses and immune evasion. Annu Rev Immunol 2003; 21:377 - 423; http://dx.doi.org/10.1146/annurev.immunol.21.120601.141049; PMID: 12543935  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Dorfleutner A, Talbott SJ, Bryan NB, Funya KN, Rellick SL, Reed JC, et al. A Shope Fibroma virus PYRIN-only protein modulates the host immune response. Virus Genes 2007; 35:685 - 94; http://dx.doi.org/10.1007/s11262-007-0141-9; PMID: 17676277  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Johnston JB, Barrett JW, Nazarian SH, Goodwin M, Ricciuto D, Wang G, et al. A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection. Immunity 2005; 23:587 - 98; http://dx.doi.org/10.1016/j.immuni.2005.10.003; PMID: 16356857  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Rahman MM, McFadden G. Myxoma virus lacking the pyrin-like protein M013 is sensed in human myeloid cells by both NLRP3 and multiple Toll-like receptors, which independently activate the inflammasome and NF-κB innate response pathways. J Virol 2011; 85:12505 - 17; http://dx.doi.org/10.1128/JVI.00410-11; PMID: 21957307  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Gregory SM, Davis BK, West JA, Taxman DJ, Matsuzawa S, Reed JC, et al. Discovery of a viral NLR homolog that inhibits the inflammasome. Science 2011; 331:330 - 4; http://dx.doi.org/10.1126/science.1199478; PMID: 21252346  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Abdelaziz DH, Gavrilin MA, Akhter A, Caution K, Kotrange S, Khweek AA, et al. Apoptosis-associated speck-like protein (ASC) controls Legionella pneumophila infection in human monocytes. J Biol Chem 2011; 286:3203 - 8; http://dx.doi.org/10.1074/jbc.M110.197681; PMID: 21097506  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Stasakova J, Ferko B, Kittel C, Sereinig S, Romanova J, Katinger H, et al. Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1beta and 18. J Gen Virol 2005; 86:185 - 95; http://dx.doi.org/10.1099/vir.0.80422-0; PMID: 15604446  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lam WY, Tang JW, Yeung AC, Chiu LC, Sung JJ, Chan PK. Avian influenza virus A/HK/483/97(H5N1) NS1 protein induces apoptosis in human airway epithelial cells. J Virol 2008; 82:2741 - 51; http://dx.doi.org/10.1128/JVI.01712-07; PMID: 18199656  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Master SS, Rampini SK, Davis AS, Keller C, Ehlers S, Springer B, et al. Mycobacterium tuberculosis prevents inflammasome activation. Cell Host Microbe 2008; 3:224 - 32; http://dx.doi.org/10.1016/j.chom.2008.03.003; PMID: 18407066  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med 2007; 204:3235 - 45; http://dx.doi.org/10.1084/jem.20071239; PMID: 18070936  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Galle M, Schotte P, Haegman M, Wullaert A, Yang HJ, Jin S, et al. The Pseudomonas aeruginosa Type III secretion system plays a dual role in the regulation of caspase-1 mediated IL-1beta maturation. J Cell Mol Med 2008; 12:5A 1767 - 76; http://dx.doi.org/10.1111/j.1582-4934.2007.00190.x; PMID: 18081695  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Schotte P, Denecker G, Van Den Broeke A, Vandenabeele P, Cornelis GR, Beyaert R. Targeting Rac1 by the Yersinia effector protein YopE inhibits caspase-1-mediated maturation and release of interleukin-1beta. J Biol Chem 2004; 279:25134 - 42; http://dx.doi.org/10.1074/jbc.M401245200; PMID: 15060067  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Brodsky IE, Palm NW, Sadanand S, Ryndak MB, Sutterwala FS, Flavell RA, et al. A Yersinia effector protein promotes virulence by preventing inflammasome recognition of the type III secretion system. Cell Host Microbe 2010; 7:376 - 87; http://dx.doi.org/10.1016/j.chom.2010.04.009; PMID: 20478539  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Shimada T, Park BG, Wolf AJ, Brikos C, Goodridge HS, Becker CA, et al. Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1beta secretion. Cell Host Microbe 2010; 7:38 - 49; http://dx.doi.org/10.1016/j.chom.2009.12.008; PMID: 20114027  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Ulland TK, Buchan BW, Ketterer MR, Fernandes-Alnemri T, Meyerholz DK, Apicella MA, et al. Cutting edge: mutation of Francisella tularensis mviN leads to increased macrophage absent in melanoma 2 inflammasome activation and a loss of virulence. J Immunol 2010; 185:2670 - 4; http://dx.doi.org/10.4049/jimmunol.1001610; PMID: 20679532  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Peng K, Broz P, Jones J, Joubert LM, Monack D. Elevated AIM2-mediated pyroptosis triggered by hypercytotoxic Francisella mutant strains is attributed to increased intracellular bacteriolysis. Cell Microbiol 2011; 13:1586 - 600; http://dx.doi.org/10.1111/j.1462-5822.2011.01643.x; PMID: 21883803  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Witzenrath M, Pache F, Lorenz D, Koppe U, Gutbier B, Tabeling C, et al. The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol 2011; 187:434 - 40; http://dx.doi.org/10.4049/jimmunol.1003143; PMID: 21646297  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Creasey EA, Isberg RR. The protein SdhA maintains the integrity of the Legionella-containing vacuole. Proc Natl Acad Sci U S A 2012; 109:3481 - 6; http://dx.doi.org/10.1073/pnas.1121286109; PMID: 22308473  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Kumar H, Kumagai Y, Tsuchida T, Koenig PA, Satoh T, Guo Z, et al. Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal beta-glucan. J Immunol 2009; 183:8061 - 7; http://dx.doi.org/10.4049/jimmunol.0902477; PMID: 20007575  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Gross O, Poeck H, Bscheider M, Dostert C, Hannesschläger N, Endres S, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 2009; 459:433 - 6; http://dx.doi.org/10.1038/nature07965; PMID: 19339971  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Joly S, Sutterwala FS. Fungal pathogen recognition by the NLRP3 inflammasome. Virulence 2010; 1:276 - 80; http://dx.doi.org/10.4161/viru.1.4.11482; PMID: 21178453  [Taylor & Francis Online], [Google Scholar]
  • Saïd-Sadier N, Padilla E, Langsley G, Ojcius DM. Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PLoS One 2010; 5:e10008; http://dx.doi.org/10.1371/journal.pone.0010008; PMID: 20368800  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Tomalka J, Ganesan S, Azodi E, Patel K, Majmudar P, Hall BA, et al. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog 2011; 7:e1002379; http://dx.doi.org/10.1371/journal.ppat.1002379; PMID: 22174673  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Joly S, Ma N, Sadler JJ, Soll DR, Cassel SL, Sutterwala FS. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J Immunol 2009; 183:3578 - 81; http://dx.doi.org/10.4049/jimmunol.0901323; PMID: 19684085  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Cheng SC, van de Veerdonk FL, Lenardon M, Stoffels M, Plantinga T, Smeekens S, et al. The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans. J Leukoc Biol 2011; 90:357 - 66; http://dx.doi.org/10.1189/jlb.1210702; PMID: 21531876  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • van de Veerdonk FL, Joosten LA, Shaw PJ, Smeekens SP, Malireddi RK, van der Meer JW, et al. The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis. Eur J Immunol 2011; 41:2260 - 8; http://dx.doi.org/10.1002/eji.201041226; PMID: 21681738  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  • Lev-Sagie A, Prus D, Linhares IM, Lavy Y, Ledger WJ, Witkin SS. Polymorphism in a gene coding for the inflammasome component NALP3 and recurrent vulvovaginal candidiasis in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2009; 200:303 - , e1-6; http://dx.doi.org/10.1016/j.ajog.2008.10.039; PMID: 19254587  [Crossref], [PubMed], [Web of Science ®], [Google Scholar]

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