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• W2124371255 abstract "Multicellular organisms possess very sophisticated defense mechanisms that are designed to effectively counter the continual microbial insult of the environment within the vertebrate host. However, successful microbial pathogens have in turn evolved complex and efficient methods to overcome innate and adaptive immune mechanisms, which can result in disease or chronic infections. Although the various virulence strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems that are shared between these diverse microbial pathogens. The success of each pathogen is directly dependant on its ability to mount an effective anti-immune response within the infected host, which can ultimately result in acute disease, chronic infection, or pathogen clearance. In this review, we highlight and compare some of the many molecular mechanisms that bacterial and viral pathogens use to evade host immune defenses. Multicellular organisms possess very sophisticated defense mechanisms that are designed to effectively counter the continual microbial insult of the environment within the vertebrate host. However, successful microbial pathogens have in turn evolved complex and efficient methods to overcome innate and adaptive immune mechanisms, which can result in disease or chronic infections. Although the various virulence strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems that are shared between these diverse microbial pathogens. The success of each pathogen is directly dependant on its ability to mount an effective anti-immune response within the infected host, which can ultimately result in acute disease, chronic infection, or pathogen clearance. In this review, we highlight and compare some of the many molecular mechanisms that bacterial and viral pathogens use to evade host immune defenses. The three biggest global infectious disease threats to humans are HIV, tuberculosis, and malaria, each killing one to two million people worldwide each year (Morens et al., 2004Morens D.M. Folkers G.K. Fauci A.S. The challenge of emerging and re-emerging infectious diseases.Nature. 2004; 430: 242-249Crossref PubMed Scopus (460) Google Scholar, Fauci, 2005Fauci A.S. The global challenge of infectious diseases: the evolving role of the National Institutes of Health in basic and clinical research.Nat. Immunol. 2005; 6: 743-747Crossref PubMed Scopus (8) Google Scholar). Each of these three causative agents (which represent a virus, a bacterium, and a parasite) have developed highly effective mechanisms to subvert the human immune system, which explains why developing vaccines and controlling these pathogens have been so difficult. Successful pathogens have evolved a range of anti-immune strategies to overcome both innate and acquired immunity (Table 1), which play critical roles in their abilities to cause disease. In this short review, we can highlight only a few of the myriad of molecular mechanisms that bacterial and viral pathogens use to effectively overcome host immune defenses. Although at first glance the immunomodulatory mechanisms used by viruses and bacteria might appear quite different, there are a surprising number of similarities and shared mechanistic concepts. Both types of pathogens have to overcome the same host immune mechanisms, and it is illustrative to see how they have developed parallel strategies to neutralize host immunity. Moreover, viral and bacterial diseases are often linked, exploiting weaknesses in host defenses that are caused by another pathogen. For example, influenza infections predispose humans for subsequent pneumococcal pneumonia, and HIV infections are often associated with an increased incidence of tuberculosis and salmonellosis.Table 1Anti-Immune Strategies of Viruses and BacteriaStrategyViral ExamplesBacterial Examples(1) Secreted modulators or toxins- ligand mimics (virokines)- many toxins- receptor mimics (viroceptors)- proteases(2) Modulators on the pathogen surface- complement inhibitors- Lipid A of LPS- coagulation regulators- carbohydrates such as capsules- immune receptors- outer membrane proteins- adhesion molecules- adhesins and invasins(3) Hide from immune surveillance- latency- avoid phagolysosomal fusion- infect immunopriviledged tissues- inhibit phagocytosis(4) Antigenic hypervariability- express error-prone replicase- vary many surface structures- escape from antibody recognition- pili, outer membrane proteins, LPS- “outrun” T cell recognition- strain to strain variation(5) Subvert or kill immune cells/phagocytes- infect and kill immune cells (DCs, APCs, lymphocytes, macrophage, etc.)- superantigens- inhibit CTL/NK cell killing pathways- avoid phagolysosomal fusion- alter immune cell signaling, effector functions, or differentiation- block inflammatory pathways by injecting effectors- express superantigens- replicate within and overrun immune cells(6) Block acquired immunity- downregulate MHC-I or –II- IgA proteases- block antigen presentation/proteosome- block antigen presentation- prevent induction of immune response genes(7) Inhibit complement- soluble inhibitors of complement cascade- proteases to degrade complement- viral Fc receptors- produce capsules and long chain LPS to avoid complement deposition and MAC attack(8) Inhibit cytokines/interferon/chemokines- inhibit ligand gene expression- block inflammatory pathways- ligand/receptor signaling inhibitors- activate alternate pathways- block secondary antiviral gene induction- secrete proteases to degrade- interfere with effector proteins(9) Modulate apoptosis/autophagy- inhibit or accelerate cell death- inhibit apoptosis- block death signaling pathways- activate death signaling pathways- scavenge free radicals- alter apoptotic sigaling pathways- downregulate death receptors or ligands- inactivate death sensor pathways(10) Interfere with TLRs- block or hijack TLR signaling- alter TLR ligands to decrease recognition- prevent TLR recognition- bind to TLR to dampen inflammation- inject effectors to inhibit downstream inflammation signaling(11) Block antimicrobial small molecules- prevent iNOS induction- secrete proteases to degrade- inhibit antiviral RNA silencing- alter cell surface to avoid peptide insertion- use pumps to transport peptide- directly sense small molecules to trigger defense mechanisms(12) Block intrinsic cellular pathways- inhibit RNA editing- alter ubiquitin pathway- regulate ubiquitin/ISGylation pathways- alter transcriptional programs Open table in a new tab The field of microbial “anti-immunology” is rapidly expanding. To comprehensively review the entire field of viral and bacterial mechanisms would require a very large review, and the reader is referred to other more comprehensive and specific reviews (Hornef et al., 2002Hornef M.W. Wick M.J. Rhen M. Normark S. Bacterial strategies for overcoming host innate and adaptive immune responses.Nat. Immunol. 2002; 3: 1033-1040Crossref PubMed Scopus (205) Google Scholar, Rosenberger and Finlay, 2003Rosenberger C.M. Finlay B.B. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens.Nat. Rev. Mol. Cell Biol. 2003; 4: 385-396Crossref PubMed Scopus (161) Google Scholar, Bieniasz, 2004Bieniasz P.D. Intrinsic immunity: a front-line defense against viral attack.Nat. Immunol. 2004; 5: 1109-1115Crossref PubMed Scopus (244) Google Scholar, Coombes et al., 2004Coombes B.K. Valdez Y. Finlay B.B. Evasive maneuvers by secreted bacterial proteins to avoid innate immune responses.Curr. Biol. 2004; 14: R856-R867Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, Hilleman, 2004Hilleman M.R. Strategies and mechanisms for host and pathogen survival in acute and persistent viral infections.Proc. Natl. Acad. Sci. USA. 2004; 101: 14560-14566Crossref PubMed Scopus (82) Google Scholar). Instead, we have chosen to highlight some key concepts that viral and bacterial pathogens use to ensure their success. These concepts are then followed by a small number of illustrative examples. We have also chosen to focus more on pathogens that cause human disease or mimic these diseases in animal models. The external surface of viral and bacterial pathogens is the central interface between host and pathogen, and recognition of the exposed surface by immune systems provides the host a key signature to initiate microbial clearance. It also affords the pathogen significant opportunity to present mimics of host immune modulators, to alter host immune responses (or avoid them), to express adhesins or receptor ligands to anchor the pathogen to host surfaces, and to present invasins or fusion proteins to mediate uptake into host cells. Other surface molecules, such as protective capsules or even captured host proteins, can enhance survival within the host. One of the first ways that an infecting virus can impinge on the immune system prior to infecting susceptible cells is via molecules that decorate the virion external surface. Virus particle surfaces not only can be studded with potentially immunomodulatory viral proteins but, particularly in the case of enveloped viruses, can also display a wide diversity of host-derived proteins (Cantin et al., 2005Cantin R. Methot S. Tremblay M.J. Plunder and stowaways: incorporation of cellular proteins by enveloped viruses.J. Virol. 2005; 79: 6577-6587Crossref PubMed Scopus (85) Google Scholar). These virion-embedded host proteins can be immunoregulators, CD-family receptors, complement inhibitors, signaling ligands, or adhesion molecules, any of which can transform the extracellular virus particle into a “macro-ligand” that can stimulate immunomodulatory responses even in nonpermissive host cells. The most extensively studied immune modulators located on virions are virus encoded, and one of the best studied examples of this is the gp120 env glycoprotein of HIV, which in addition to mediating virus binding and entry is a potent signaling ligand in its own right (Ahr et al., 2004Ahr B. Robert-Hebmann V. Devaux C. Biard-Piechaczyk M. Apoptosis of uninfected cells induced by HIV envelope glycoproteins.Retrovirology. 2004; 1: 1-12Crossref PubMed Scopus (45) Google Scholar, Badr et al., 2005Badr G. Borhis G. Treton D. Moog C. Garraud O. Richard Y. HIV type 1 glycoprotein 120 inhibits human B cell chemotaxis to CXC chemokine ligand (CXCL) 12, CC chemokine ligand (CCL) 20, and CCL21.J. Immunol. 2005; 175: 302-310PubMed Google Scholar, Perfetti et al., 2005Perfetti J.-L. Castedo M. Roumier T. Andreau K. Nardacci R. Placentini M. Kroemer G. Mechanisms of apoptosis induction by the HIV-1 envelope.Cell Death Differ. 2005; 12: 916-923Crossref PubMed Scopus (80) Google Scholar). Env is the only viral protein that protrudes through the HIV virion membrane, forming the characteristic virion spikes, and it is thought to play a significant role in the bystander killing of uninfected T lymphocytes during late-stage AIDS progression (Gougeon, 2005Gougeon M.L. To kill or be killed: how HIV exhausts the immune system.Cell Death Differ. 2005; 12: 845-854Crossref PubMed Scopus (26) Google Scholar, Petrovas et al., 2005Petrovas C. Mueller Y.M. Katsikis P.D. Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy.Cell Death Differ. 2005; 12: 859-870Crossref PubMed Scopus (16) Google Scholar). Although much is now known about the role of the major conformational shift that gp120 undergoes when it binds to the cellular receptors (Chen et al., 2005Chen B. Vogan E.M. Gong H. Skehel J.J. Wiley D.C. Harrison S.C. Structure of an unliganded simian immunodeficiency virus gp120 core.Nature. 2005; 433: 834-841Crossref PubMed Scopus (387) Google Scholar), less is known about how the virion bound gp120 mediates its effects as a signaling ligand. There are some clues, however, that gp120 bioactivity can be affected by host proteins on the virion because virus particles with higher levels of captured MHC-II and B7-2 are more efficient at killing uninfected CD4+ T cells (Holm and Gabuzda, 2005Holm G.H. Gabuzda D. Distinct mechanisms of CD4+ and CD8+ T-cell activation and bystander apoptosis induced by human immunodeficiency virus type 1 virions.J. Virol. 2005; 79: 6299-6311Crossref PubMed Scopus (53) Google Scholar). Consequently, the immunomodulatory properties of virion particles from other virus families may also depend on the precise synergism between host and viral proteins. Bacterial surfaces are complex structures which, from the host's viewpoint, present many diverse antigenic targets. A major difficulty for bacterial pathogens is hiding this complex surface of proteins and carbohydrates from immune surveillance and TLR recognition yet exposing key molecules such as adhesins and invasins. A common mechanism of masking bacterial surfaces is to express a carbohydrate capsule. This mechanism is used by most extracellular bacterial pathogens that circulate systemically within the body. For example, the pneumococcus (Streptococcus pneumoniae) relies extensively on its capsule to prevent antibody and complement deposition on its surface, thereby avoiding opsonization and phagocytic clearance. Similarly, bacteria that cause meningitis (Haemophilus influenzae, Escherchia coli K1, and Neisseria meningitidis) rely extensively on capsules to promote their extracellular lifestyle within the host by preventing antibody and complement deposition and insertion. Pathogens expressing surface capsules also often have filamentous adhesins (fimbriae and pili) that protrude through the capsular surface, enabling the adhesins to bind to host receptors yet keeping the bacterial surface hidden. Lipopolysaccharide (LPS) is a major surface-exposed component of the Gram negative bacteria. LPS is a key molecule from both the pathogens' and hosts' points of view. The essential core component of LPS, lipid A, is highly conserved among most Gram negative organisms and thus plays a central role in activation of TLRs such as TLR4. However, the outer part of LPS is made of highly variable carbohydrates, giving each strain their particular serotype (O antigen). Thus different strains of the same species can often reinfect the same host due solely to differences in O antigen. LPS is surface exposed, and a target of complement, but since it protrudes from the surface, membrane insertion by the membrane attack complex does not occur in the cellular membrane. Bacterial pathogens, especially Gram negatives, have developed secretion systems to export virulence factors across the bacterial membranes and either into the supernatant or even directly into host cells. In Gram negative organisms, these are named according to the type, and there are at least seven secretion systems in addition to the general secretion system. Secretion of virulence factors such as toxins and immune modulators is a major use of these secretion systems, as well as conjugal DNA transfer. In Gram negative pathogens, both type III secretion systems (T3SS) and type IV secretion systems (T4SS) can insert various molecules directly into host cells (Christie et al., 2005Christie P.J. Atmakuri K. Krishnamoorthy V. Jakubowski S. Cascales E. Biogenesis, architecture, and function of bacterial type iv secretion systems.Annu. Rev. Microbiol. 2005; 59: 451-485Crossref PubMed Scopus (330) Google Scholar, Mota and Cornelis, 2005Mota L.J. Cornelis G.R. The bacterial injection kit: type III secretion systems.Ann. Med. 2005; 37: 234-249Crossref PubMed Scopus (92) Google Scholar). These two types of systems are not genetically related, although they both have a very diverse repertoire of secreted molecules (called effectors) that can be delivered into host cells. These include toxins (to kill host cells), molecules that mediate bacterial uptake (invasion), effectors that reprogram vesicular transport to enhance intracellular parasitism, mechanisms to paralyze phagocytosis, molecules that form receptors for bacteria to adhere to, and many diverse effectors that alter immune functions to enhance immune evasion. Although Gram positive surfaces are more simple (one membrane surrounded by peptidoglycan), there are suggestions that even Gram positive organisms can form localized pores in host cells to deliver bacterial molecules into host cells. For example, Streptococcus pyogenes has a cholesterol-dependent cytolysin (making it host specific) that is needed to deliver a NAD-glycohydrolase into host cells to trigger cytotoxicity (Madden et al., 2001Madden J.C. Ruiz N. Caparon M. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in gram-positive bacteria.Cell. 2001; 104: 143-152Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Similarly, Mycobacterium tuberculosis has a specialized secretion system that is needed to deliver major T cell antigens (ESAT-6 and CFP-10) and presumably other proteins that are needed for bacterial replication inside macrophages and virulence (Stanley et al., 2003Stanley S.A. Raghavan S. Hwang W.W. Cox J.S. Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system.Proc. Natl. Acad. Sci. USA. 2003; 100: 13001-13006Crossref PubMed Scopus (196) Google Scholar). The ability to drive bacterial molecules directly into host cells is a major strategy used by diverse bacterial pathogens to subvert and overcome host defenses. The ability to avoid detection by either the innate or acquired immune system is a central feature for both viral and bacterial pathogens. One strategy is to camouflage the surface of the microbe or the infected cell such that it is not recognized by host surveillance systems, while another is to dampen immune responses such that a complete immune response is avoided. Unlike bacteria, which have their own secretory and protein trafficking pathways, viruses must rely on the infected host cell to provide the machinery for protein transport to the cell surface, and for secretion of virus-encoded immunomodulators into the extracellular environment. In general, viral proteins that interact directly with the immune system tend to be expressed at the infected cell membrane, the virion surface, or are secreted into the extracellular environment where they can act either locally or systemically. In the case of viral immunomodulators that are secreted and released from the infected cell, the literature is vast and includes host targets that range from cytokines, chemokines, interferons, complement, leukocytes, inflammatory cascades, and immune recognition pathways. For details, the reader is referred to some of the many specialty reviews for specific examples (Alcami, 2003Alcami A. Viral mimicry of cytokines, chemokines and their receptors.Nat. Rev. Immunol. 2003; 3: 36-50Crossref PubMed Scopus (270) Google Scholar, Seet et al., 2003Seet B.T. Johnston J.B. Brunetti C.R. Barrett J.W. Everett H. Cameron C. Sypula J. Nazarian S.H. Lucas A. McFadden G. Poxviruses and immune evasion.Annu. Rev. Immunol. 2003; 21: 377-423Crossref PubMed Scopus (327) Google Scholar, Nicholas, 2005Nicholas J. Human gammaherpesvirus cytokines and chemokine receptors.J. Interferon Cytokine Res. 2005; 25: 373-383Crossref PubMed Scopus (37) Google Scholar). One recent development of this field is that some of these secreted viral immunomodulatory proteins, which tend to exhibit potent anti-inflammatory or anti-immune properties, have been used as biopharmaceuticals to treat diseases of exacerbated inflammation or hyperacute inflammation (Lucas and McFadden, 2004Lucas A. McFadden G. Secreted immunomodulatory viral proteins as novel biotherapeutics.J. Immunol. 2004; 173: 4765-4774PubMed Google Scholar). The spectrum of viral proteins that traffic to the cell surface of the infected cell, and exhibit immunomodulatory properties, is remarkably diverse and includes superantigens, immune cell ligands, receptor mimics, CD-homologs, complement inhibitors, binding proteins that sequester cytokines, and regulators of leukocyte activation. Among the various classes of leukocytes that can be regulated by viral proteins, particular attention has been paid recently to NK cells, T cells, dendritic cells, and macrophage (Ambagala et al., 2005Ambagala A.P. Solheim J.C. Srikumaran S. Viral inteference with MHC class I antigen presentation pathway: the battle continues.Vet. Immunol. Immunopathol. 2005; 107: 1-15Crossref PubMed Scopus (26) Google Scholar, Andrews et al., 2005Andrews D.M. Andoniou C.E. Scalzo A.A. van Dommelen S.L.H. Wallace M.E. Smyth M.J. Degli-Esposti M.A. Cross-talk between dendritic cells and natural killer cells in viral infection.Mol. Immunol. 2005; 42: 547-555Crossref PubMed Scopus (58) Google Scholar, Lodoen and Lanier, 2005Lodoen M.B. Lanier L.L. Viral modulation of NK cell immunity.Nat. Rev. Microbiol. 2005; 3: 59-69Crossref PubMed Scopus (106) Google Scholar, Pollara et al., 2005Pollara G. Kwan A. Newton P.J. Handley M.E. Chain B.M. Katz D.R. Dendritic cells in viral pathogenesis: protective or defective.Int. J. Exp. Pathol. 2005; 86: 187-204Crossref PubMed Scopus (30) Google Scholar). Some of these viral cell-surface proteins mimic the structure or function of host receptors but alter their biologic properties to better suit the virus agenda. For example, herpesviruses and poxviruses are known to collectively encode over 40 viral members of the seven transmembrane-spanning G protein-coupled chemokine receptor (vGPCR) superfamily (Sodhi et al., 2004Sodhi A. Mantaner S. Gutkind J.S. Viral hijacking of G-protein coupled-receptor signalling networks.Nat. Rev. Mol. Cell Biol. 2004; 5: 998-1012Crossref PubMed Scopus (73) Google Scholar, Couty and Gershengorn, 2005Couty J.P. Gershengorn M.C. G-protein-coupled receptors encoded by human herpesviruses.Trends Pharmacol. Sci. 2005; 26: 405-411Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, Nicholas, 2005Nicholas J. Human gammaherpesvirus cytokines and chemokine receptors.J. Interferon Cytokine Res. 2005; 25: 373-383Crossref PubMed Scopus (37) Google Scholar, Rosenkilde, 2005Rosenkilde M.M. Virus-encoded chemokine receptors - putative novel antiviral drug targets.Neuropharmacology. 2005; 48: 1-13Crossref PubMed Scopus (19) Google Scholar). Dissecting how these viral vGPCRs contribute to the biology of the viruses that express them has only begun, but some exhibit properties, such as ligand-independent signaling, that allow the constitutive activation of intracellular pathways that are normally only inducible for uninfected cells. The spectrum of immunomodulatory viral membrane proteins is simply too broad to be covered here, but it is worth noting that many of these proteins are not just transiently en route to being incorporated into virions that bud from the surface but rather function as true anti-immune receptors at the infected cell surface. Camouflaging a complex bacterial surface is a major problem. Capsules are effective at hiding many bacterial surfaces and preventing opsonization. However, there are predominant molecules on bacterial surfaces that the host's immune system uses as key signatures. These are often TLR agonists such as lipid A of LPS, flagella, and peptidogycan. Bacterial pathogens have evolved ways of altering these molecules such that they are less well recognized by immune surveillance systems. Many Gram negative pathogens modify lipid A to alter TLR4 responses (Portnoy, 2005Portnoy D.A. Manipulation of innate immunity by bacterial pathogens.Curr. Opin. Immunol. 2005; 17: 25-28Crossref PubMed Scopus (30) Google Scholar). For example, Salmonella has a two-component sensor (PhoP/PhoQ) that senses host environments, regulating many virulence genes. Some of these genes are enzymes involved in lipid A modification, including a 3-O-deacylase (PagL) and a lipid A palmitoyltransferase (PagP) (Kawasaki et al., 2004Kawasaki K. Ernst R.K. Miller S.I. 3-O-deacylation of lipid A by PagL, a PhoP/PhoQ-regulated deacylase of Salmonella typhimurium, modulates signaling through Toll-like receptor 4.J. Biol. Chem. 2004; 279: 20044-20048Crossref PubMed Scopus (89) Google Scholar). These modified forms of lipid A are up to 100-fold less active for TLR4 activation and NFκB production. Although lipid A is fairly well conserved, some organisms produce lipid A structures that are not efficient TLR2 and 4 activators. For example, Porphyromonas gingivalis, a major dental pathogen, contains multiple lipid A species which function as both agonists and antagonists of TLR2 and 4 (Darveau et al., 2004Darveau R.P. Pham T.T. Lemley K. Reife R.A. Bainbridge B.W. Coats S.R. Howald W.N. Way S.S. Hajjar A.M. Porphyromonas gingivalis lipopolysaccharide contains multiple lipid A species that functionally interact with both toll-like receptors 2 and 4.Infect. Immun. 2004; 72: 5041-5051Crossref PubMed Scopus (210) Google Scholar), selectively moderating the inflammatory response. Another major signature of bacterial pathogens is peptidoglycan. Nod1 and Nod2 are leucine rich repeat (LRR) intracellular proteins that function analogously to TLRs to detect peptidoglycan inside host cells (Philpott and Girardin, 2004Philpott D.J. Girardin S.E. The role of Toll-like receptors and Nod proteins in bacterial infection.Mol. Immunol. 2004; 41: 1099-1108Crossref PubMed Scopus (169) Google Scholar, Inohara et al., 2005Inohara C. McDonald C. Nunez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease.Annu. Rev. Biochem. 2005; 74: 355-383Crossref PubMed Scopus (544) Google Scholar). Human Nod1 detects N-acetylglucosamine-N-acetylmuramic acid, a tripeptide motif characteristic of Gram negative organisms (Girardin et al., 2003aGirardin S.E. Boneca I.G. Carneiro L.A. Antignac A. Jehanno M. Viala J. Tedin K. Taha M.K. Labigne A. Zahringer U. et al.Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan.Science. 2003; 300: 1584-1587Crossref PubMed Scopus (774) Google Scholar), while Nod2 detects a N-acetylglucosamine-N-acetylmuramic acid dipeptide (Girardin et al., 2003bGirardin S.E. Travassos L.H. Herve M. Blanot D. Boneca I.G. Philpott D.J. Sansonetti P.J. Mengin-Lecreulx D. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2.J. Biol. Chem. 2003; 278: 41702-41708Crossref PubMed Scopus (325) Google Scholar). Activation of either Nod leads to NFκB activation and inflammatory responses. Bacterial pathogens have developed ways to avoid peptidoglycan processing and recognition by Nods (Boneca, 2005Boneca I.G. The role of peptidoglycan in pathogenesis.Curr. Opin. Microbiol. 2005; 8: 46-53Crossref PubMed Scopus (96) Google Scholar). Genes involved in peptidoglycan synthesis, turnover, and recycling have been identified as virulence factors. For example, Listeria monocytogenes resides in the cytosol of macrophages and other host cells. Surface-located and -secreted peptidoglycan hydrolases have been identified that are also virulence factors (Lenz et al., 2003Lenz L.L. Mohammadi S. Geissler A. Portnoy D.A. SecA2-dependent secretion of autolytic enzymes promotes Listeria monocytogenes pathogenesis.Proc. Natl. Acad. Sci. USA. 2003; 100: 12432-12437Crossref PubMed Scopus (139) Google Scholar, Cabanes et al., 2004Cabanes D. Dussurget O. Dehoux P. Cossart P. Auto, a surface associated autolysin of Listeria monocytogenes required for entry into eukaryotic cells and virulence.Mol. Microbiol. 2004; 51: 1601-1614Crossref PubMed Scopus (73) Google Scholar). This work suggests that cleavage of peptidoglycan promotes a virulence mechanism involving exploitation of Nod2 and the innate inflammatory response to promote Listeria pathogenesis (Lenz et al., 2003Lenz L.L. Mohammadi S. Geissler A. Portnoy D.A. SecA2-dependent secretion of autolytic enzymes promotes Listeria monocytogenes pathogenesis.Proc. Natl. Acad. Sci. USA. 2003; 100: 12432-12437Crossref PubMed Scopus (139) Google Scholar). Another classic mechanism viral, bacterial, and parasitic pathogens use to avoid immune responses is to vary immunodominant molecules (known as antigenic variation). Acquired immunity relies on memory of previous exposure to antigens, and thus antigenic variation is especially appropriate for circumventing humoral and cellular responses. There are few, if any, examples of antigenic variation being used to escape innate immunity. Although strain to strain variation in antigenic molecules is common, antigenic variation refers to a single strain specifically changing a subset of its antigens, either to sustain an ongoing infection or reinfect hosts even though the first infection was successfully cleared. The molecular mechanisms used by bacterial pathogens to cause antigenic variation are diverse but very well studied (Finlay and Falkow, 1997Finlay B.B. Falkow S. Common themes in microbial pathogenicity revisited.Microbiol. Mol. Biol. Rev. 1997; 61: 136-169Crossref PubMed Scopus (0) Google Scholar). These mechanisms usually involve one of three mechanisms: (1) having multiple but different copies of a molecule, each of which is under an independent on/off switch; (2) having one expression locus plus many silent copies of the gene, and constantly changing which gene is expressed; or (3) having a highly variable region in a molecule that is constantly changing. Neisseria species (which cause meningitis and gonorrhea) are perhaps the best bacterial models of antigenic variation, using all three of these concepts and emphasizing why a vaccine to these organisms has not been successful. The gonococcus contains 10–11 outer membrane Opa proteins, each of which is antigenically different. Each gene is under a genetic switch that independently controls expression of each Opa. During infection, multiple Opas are expressed in various combinations. The Neisseria pilu" @default.
• W2124371255 created "2016-06-24" @default.
• W2124371255 creator A5030919684 @default.
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• W2124371255 date "2006-02-01" @default.
• W2124371255 modified "2023-10-13" @default.
• W2124371255 title "Anti-Immunology: Evasion of the Host Immune System by Bacterial and Viral Pathogens" @default.
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