Abstract
Host defence against microbial pathogens requires appropriate coordination of multiple signalling pathways. These pathways are triggered by innate immune recognition of conserved microbial molecules, and initiate an inflammatory cascade that involves recruitment of leukocytes to the site of infection, activation of antimicrobial effector mechanisms and induction of an adaptive immune response that promotes clearance of infection and long-term immune memory. Microbial pathogens possess specialized proteins termed virulence factors, which interfere with host defence at several levels. Many virulence factors from diverse pathogens have been identified in recent years and their functions linked to disruption of essential processes of immune defence, from signalling to phagocytosis. Although the diversity of pathogens and virulence factors is immense, common themes have emerged with regard to how microbial pathogens interfere with immune responses. Here we discuss recent advances in our understanding of how virulence factors target innate and adaptive immune responses, focusing on bacterial pathogens. We also propose that pathogens responsible for causing acute infection tend to target central components (hubs) of cellular signalling pathways, causing global disruption of the host response. By contrast, pathogens that cause chronic or persistent infections tend to target more peripheral signalling network components (nodes) to promote pathogen persistence.
This is a preview of subscription content, access via your institution
Access options
Similar content being viewed by others
References
Monack, D. M., Mueller, A. & Falkow, S. Persistent bacterial infections: the interface of the pathogen and the host immune system. Nature Rev. Microbiol 2, 747–765 (2004).
Seifert, H. S. & DiRita, V. J. Evolution of microbial pathogens (ASM Press, Washington, DC, 2006).
Wickham, M. E., Brown, N. F., Boyle, E. C., Coombes, B. K. & Finlay, B. B. rulence is positively selected by transmission success between mammalian hosts. Curr. Biol. 17, 783–788 (2007).
Baumler, A. J., Tsolis, R. M., Ficht, T. A. & Adams, L. G. Evolution of host adaptation in Salmonella enterica. Infect. Immun. 66, 4579–4587 (1998).
Mills, S. D. et al. Yersinia enterocolitica induces apoptosis in macrophages by a process requiring functional type III secretion and translocation mechanisms and involving YopP, presumably acting as an effector protein. Proc. Natl Acad. Sci. USA 94, 12638–12643 (1997).
Monack, D. M., Mecsas, J., Ghori, N. & Falkow, S. Yersinia signals macrophages to undergo apoptosis and YopJ is necessary for this cell death. Proc. Natl Acad. Sci. USA 94, 10385–10390 (1997).
Orth, K. et al. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285, 1920–1923 (1999).
Collier-Hyams, L. S. et al. Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-κB pathway. J. Immunol. 169, 2846–2850 (2002).
Jones, R. M. et al. Salmonella AvrA coordinates suppression of host immune and apoptotic defenses via JNK pathway blockade. Cell Host Microbe 3, 233–244 (2008).
Mazurkiewicz, P. et al. SpvC is a Salmonella effector with phosphothreonine lyase activity on host mitogen-activated protein kinases. Mol. Microbiol. 67, 1371–1383 (2008).
Arbibe, L. et al. An injected bacterial effector targets chromatin access for transcription factor NF-κB to alter transcription of host genes involved in immune responses. Nature Immunol. 8, 47–56 (2007).
Li, H. et al. The phosphothreonine lyase activity of a bacterial type III effector family. Science 315, 1000–1003 (2007).
Duesbery, N. S. et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280, 734–737 (1998).
Kim, D. W. et al. The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc. Natl Acad. Sci. USA 102, 14046–14051 (2005).
Rohde, J. R., Breitkreutz, A., Chenal, A., Sansonetti, P. J. & Parsot, C. Type III secretion effectors of the IpaH family are E3 ubiquitin ligases. Cell Host Microbe 1, 77–83 (2007).
Diao, J., Zhang, Y., Huibregtse, J. M., Zhou, D. & Chen, J. Crystal structure of SopA, a Salmonella effector protein mimicking a eukaryotic ubiquitin ligase. Nature Struct. Mol. Biol. 15, 65–70 (2008).
Rytkonen, A. et al. SseL, a Salmonella deubiquitinase required for macrophage killing and virulence. Proc. Natl Acad. Sci. USA 104, 3502–3507 (2007).
Zhang, Y., Higashide, W. M., McCormick, B. A., Chen, J. & Zhou, D. The inflammation-associated Salmonella SopA is a HECT-like E3 ubiquitin ligase. Mol. Microbiol. 62, 786–793 (2006).
Bhavsar, A. P., Guttman, J. A. & Finlay, B. B. Manipulation of host-cell pathways by bacterial pathogens. Nature 449, 827–834 (2007).
Rytkonen, A. & Holden, D. W. Bacterial interference of ubiquitination and deubiquitination. Cell Host Microbe 1, 13–22 (2007).
Jeong, H., Tombor, B., Albert, R., Oltvai, Z. N. & Barabasi, A. L. The large-scale organization of metabolic networks. Nature 407, 651–654 (2000).
Albert, R. Scale-free networks in cell biology. J. Cell Sci. 118, 4947–4957 (2005).
Eisenberg, E. & Levanon, E. Y. Preferential attachment in the protein network evolution. Phys. Rev. Lett. 91, 138701 (2003).
Jeong, H., Mason, S. P., Barabasi, A. L. & Oltvai, Z. N. Lethality and centrality in protein networks. Nature 411, 41–42 (2001).
Albert, R., Jeong, H. & Barabasi, A. L. Error and attack tolerance of complex networks. Nature 406, 378–382 (2000).
Park, J. M., Greten, F. R., Li, Z. W. & Karin, M. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297, 2048–2051 (2002).
Zhang, Y., Ting, A. T., Marcu, K. B. & Bliska, J. B. Inhibition of MAPK and NF-κB pathways is necessary for rapid apoptosis in macrophages infected with Yersinia. J. Immunol. 174, 7939–7949 (2005).
Yamamoto, M., Takeda, K. & Akira, S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol. Immunol. 40, 861–868 (2004).
O'Neill, L. A. & Bowie, A. G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Rev. Immunol. 7, 353–364 (2007).
Cirl, C. et al. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nature Med. 14, 399–406 (2008).
Newman, R. M., Salunkhe, P., Godzik, A. & Reed, J. C. Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins. Infect. Immun. 74, 594–601 (2006).
Blander, J. M. & Medzhitov, R. Regulation of phagosome maturation by signals from toll-like receptors. Science 304, 1014–1018 (2004).
Chen, G., Zhuchenko, O. & Kuspa, A. Immune-like phagocyte activity in the social amoeba. Science 317, 678–681 (2007).
Cosson, P. & Soldati, T. Eat, kill or die: when amoeba meets bacteria. Curr. Opin. Microbiol. 11, 271–276 (2008).
Bliska, J. B., Guan, K. L., Dixon, J. E. & Falkow, S. Tyrosine phosphate hydrolysis of host proteins by an essential Yersinia virulence determinant. Proc. Natl Acad. Sci. USA 88, 1187–1191 (1991).
Rosqvist, R., Bolin, I. & Wolf-Watz, H. Inhibition of phagocytosis in Yersinia pseudotuberculosis: a virulence plasmid-encoded ability involving the Yop2b protein. Infect. Immun. 56, 2139–2143 (1988).
Andersson, K. et al. YopH of Yersinia pseudotuberculosis interrupts early phosphotyrosine signalling associated with phagocytosis. Mol. Microbiol. 20, 1057–1069 (1996).
Yao, T., Mecsas, J., Healy, J. I., Falkow, S. & Chien, Y. Suppression of T and B lymphocyte activation by a Yersinia pseudotuberculosis virulence factor, yopH. J. Exp. Med. 190, 1343–1350 (1999).
Gerke, C., Falkow, S. & Chien, Y. H. The adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation. J. Exp. Med. 201, 361–371 (2005).
Marketon, M. M., DePaolo, R. W., DeBord, K. L., Jabri, B. & Schneewind, O. Plague bacteria target immune cells during infection. Science 309, 1739–1741 (2005).
Deleuil, F., Mogemark, L., Francis, M. S., Wolf-Watz, H. & Fallman, M. Interaction between the Yersinia protein tyrosine phosphatase YopH and eukaryotic Cas/Fyb is an important virulence mechanism. Cell Microbiol. 5, 53–64 (2005).
Monack, D. M., Bouley, D. M. & Falkow, S. Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNγ neutralization. J. Exp. Med. 199, 231–241 (2004).
Dye, C., Scheele, S., Dolin, P., Pathania, V. & Raviglione, M. C. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282, 677–686 (1999).
Saunders, B. M. & Cooper, A. M. Restraining mycobacteria: role of granulomas in mycobacterial infections. Immunol. Cell Biol. 78, 334–341 (2000).
Chan, J. & Flynn, J. The immunological aspects of latency in tuberculosis. Clin.mmunol. 110, 2–12 (2004).
Flynn, J. L. & Chan, J. Immunology of tuberculosis. Annu. Rev. Immunol. 19, 93–129 (2001).
Cosma, C. L., Humbert, O. & Ramakrishnan, L. Superinfecting mycobacteria home to established tuberculous granulomas. Nature Immunol. 5, 828–835 (2004).
Davis, J. M. & Ramakrishnan, L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136, 37–49 (2009).
Viala, J. et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nature Immunol. 5, 1166–1174 (2004).
Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nature Immunol. 7, 569–575 (2006).
Stetson, D. B. & Medzhitov, R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006).
Shin, S. et al. Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila. PLoS Pathog. 4, e1000220 (2008).
Briken, V., Porcelli, S. A., Besra, G. S. & Kremer, L. Mycobacterial lipoarabinomannan and related lipoglycans: from biogenesis to modulation of the immune response. Mol. Microbiol. 53, 391–403 (2004).
Reed, M. B. et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431, 84–87 (2004).
Geijtenbeek, T. B. et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7–17 (2003).
Gringhuis, S. I. et al. C-Type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-κB. 26, 605–616 (2007).
Constant, P. et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated phydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J.Biol. Chem. 277, 38148–38158 (2002).
McKinney, J. D. et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406, 735–738 (2000).
Munoz-Elias, E. J. & McKinney, J. D. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nature Med. 11, 638–644 (2005).
Fang, F. C., Libby, S. J., Castor, M. E. & Fung, A. M. Isocitrate lyase (AceA) is required for Salmonella persistence but not for acute lethal infection in mice. Infect. Immun. 73, 2547–2549 (2005).
Lawley, T. D. et al. Genome-wide screen for Salmonella genes required for long-term systemic infection of the mouse. PLoS Pathog. 2, e11 (2006).
Sassetti, C. M. & Rubin, E. J. Genetic requirements for mycobacterial survival during infection. Proc. Natl Acad. Sci. USA 100, 12989–12994 (2003).
Yazdankhah, S. P. et al. Distribution of serogroups and genotypes among disease associated and carried isolates of Neisseria meningitidis from the Czech Republic, Greece and Norway. J. Clin. Microbiol. 42, 5146–5153 (2004).
Mulks, M. H., Plaut, A. G., Feldman, H. A. & Frangione, B. IgA proteases of two distinct specificities are released by Neisseria meningitidis. J. Exp. Med. 152, 1442–7 (1980).
Woof, J. M. & Kerr, M. A. The function of immunoglobulin A in immunity. J. pathol. 208, 270–282 (2006).
Cebra, J. J., Periwal, S. B., Lee, G., Lee, F. & Shroff, K. E. Development and maintenance of the gut-associated lymphoid tissue (GALT): the roles of enteric bacteria and viruses. Dev. Immunol. 6, 13–18 (1998).
Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).
Mulks, M. H. & Plaut, A. G. IgA protease production as a characteristic distinguishing pathogenic from harmless Neisseriaceae. N. Engl. J. Med. 299, 973–976 (1978).
Polissi, A. et al. Large-scale identification of virulence genes from Streptococcus pneumoniae. Infect. Immun. 66, 5620–5629 (1998).
Vitovski, S., Read, R. C. & Sayers, J. R. Invasive isolates of Neisseria meningitidis possess enhanced immunoglobulin A1 protease activity compared to colonizing strains. FASEB J. 13, 331–337 (1999).
Gallos, L. K., Cohen, R., Argyrakis, P., Bunde, A. & Havlin, S. Stability and topology of scale-free networks under attack and defense strategies. Phys. Rev. Lett. 94, 188701 (2005).
Lyczak, J. B., Cannon, C. L. & Pier, G. B. Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. Microbes Infect. 2, 1051–1060 (2000).
Fu, Y. & Galan, J. E. A Salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Nature 401, 293–297 (1999).
Acknowledgements
We thank members of the Medzhitov lab for scientific discussion, and Jelena Bezbradica, Elizabeth Kopp, Noah Palm and Dominik Schenten for critical reading of the manuscript.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brodsky, I., Medzhitov, R. Targeting of immune signalling networks by bacterial pathogens. Nat Cell Biol 11, 521–526 (2009). https://doi.org/10.1038/ncb0509-521
Issue Date:
DOI: https://doi.org/10.1038/ncb0509-521
This article is cited by
-
Bacterial virulence mediated by orthogonal post-translational modification
Nature Chemical Biology (2020)
-
Fecal microbiota transplant rescues mice from human pathogen mediated sepsis by restoring systemic immunity
Nature Communications (2020)
-
Metabolomics to reveal biomarkers and pathways of preterm birth: a systematic review and epidemiologic perspective
Metabolomics (2019)
-
Outrunning the Red Queen: bystander activation as a means of outpacing innate immune subversion by intracellular pathogens
Cellular & Molecular Immunology (2017)
-
NF-κB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection
Scientific Reports (2017)