Key Points
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Many successful pathogens manipulate signalling crosstalk interactions between innate immune receptors as a way to modify the host immune response and promote their adaptive fitness.
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These diverse 'crosstalk manipulation' tactics can be grouped into common themes. Pathogens can co-opt host inhibitory receptors; instigate signalling crosstalk pathways to synergistically induce immunosuppressive mediators; stimulate inside-out signalling to transactivate safe uptake pathways; selectively inhibit T helper 1 (TH1) cell-mediated immunity using complement–Toll-like receptor (TLR) regulatory crosstalk; exploit TLR–TLR cross-inhibition; and disrupt functional receptor interactions that are necessary for cooperative protective signalling.
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In co-opting inhibitory receptor crosstalk, pathogens mainly target receptors that signal through immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These receptors recruit phosphatases, such as SH2 domain-containing protein tyrosine phosphatase 1 (SHP1), that in turn attenuate signalling induced by juxtaposed activating receptors (such as TLRs).
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Effective mechanisms by which pathogens can take control of host receptors include the use of microbial structures that mimic host ligands or counter-receptors and virulence enzymes that convert host molecules (such as C5 and adenosine monophosphate) into active agonists.
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Several pathogens can exploit TLRs or other receptors to transactivate their 'safe' uptake by complement receptor 3, which is normally involved in the phagocytosis of apoptotic cells and is thus not linked to vigorous pro-inflammatory or microbicidal pathways (such as those activated by Fcγ receptor-mediated phagocytosis).
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Understanding the mechanisms by which pathogens manipulate signalling crosstalk between receptors of innate immunity is essential for developing interventional approaches to redirect the host response towards protective immunity.
Abstract
In the arms race of host–microbe co-evolution, successful microbial pathogens have evolved ingenious ways to evade host immune responses. In this Review, we focus on 'crosstalk manipulation' — the microbial strategies that instigate, subvert or disrupt the molecular signalling crosstalk between receptors of the innate immune system. This proactive interference undermines host defences and contributes to microbial adaptive fitness and persistent infections. Understanding how pathogens exploit host receptor crosstalk mechanisms and infiltrate the host signalling network is essential for developing interventions to redirect the host response and achieve protective immunity.
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References
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).
Ricklin, D., Hajishengallis, G., Yang, K. & Lambris, J. D. Complement: a key system for immune surveillance and homeostasis. Nature Immunol. 11, 785–797 (2010). A comprehensive review of the complement system, summarizing recent and emerging evidence that complement engages in reciprocal crosstalk interactions with other immune and physiological systems (such as TLRs and coagulation), aiming to fine-tune the host response to infection and other insults.
Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001).
Beutler, B. A. TLRs and innate immunity. Blood 113, 1399–1407 (2009).
Triantafilou, K., Triantafilou, M. & Dedrick, R. L. A CD14-independent LPS receptor cluster. Nature Immunol. 2, 338–345 (2001).
Hajishengallis, G. et al. Differential interactions of fimbriae and lipopolysaccharide from Porphyromonas gingivalis with the Toll-like receptor 2-centred pattern recognition apparatus. Cell. Microbiol. 8, 1557–1570 (2006).
Natarajan, M., Lin, K. M., Hsueh, R. C., Sternweis, P. C. & Ranganathan, R. A global analysis of cross-talk in a mammalian cellular signalling network. Nature Cell Biol. 8, 571–580 (2006). A systematic analysis of intracellular signalling crosstalk, showing that a large number of signalling pathways converge on a relatively limited set of interaction mechanisms, including both synergistic and antagonistic interactions.
Ivashkiv, L. B. Cross-regulation of signaling by ITAM-associated receptors. Nature Immunol. 10, 340–347 (2009).
Lee, M. S. & Kim, Y. J. Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem. 76, 447–480 (2007).
Zak, D. E. & Aderem, A. Systems biology of innate immunity. Immunol. Rev. 227, 264–282 (2009).
Hajishengallis, G. & Lambris, J. D. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 31, 154–163 (2010).
Goodridge, H. S. & Underhill, D. M. Fungal recognition by TLR2 and dectin-1. Handb. Exp. Pharmacol. 183, 87–109 (2008).
Ogawa, S. et al. Molecular determinants of crosstalk between nuclear receptors and Toll-like receptors. Cell 122, 707–721 (2005).
Lukashev, D., Ohta, A., Apasov, S., Chen, J. F. & Sitkovsky, M. Cutting edge: physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo. J. Immunol. 173, 21–24 (2004).
Lambris, J. D., Ricklin, D. & Geisbrecht, B. V. Complement evasion by human pathogens. Nature Rev. Microbiol. 6, 132–142 (2008).
Finlay, B. B. & McFadden, G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124, 767–782 (2006).
Bowie, A. G. & Unterholzner, L. Viral evasion and subversion of pattern-recognition receptor signalling. Nature Rev. Immunol. 8, 911–922 (2008).
Diacovich, L. & Gorvel, J. P. Bacterial manipulation of innate immunity to promote infection. Nature Rev. Microbiol. 8, 117–128 (2010).
Flannagan, R. S., Cosio, G. & Grinstein, S. Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nature Rev. Microbiol. 7, 355–366 (2009).
Sansonetti, P. J. & Di Santo, J. P. Debugging how bacteria manipulate the immune response. Immunity 26, 149–161 (2007).
Brodsky, I. E. & Medzhitov, R. Targeting of immune signalling networks by bacterial pathogens. Nature Cell Biol. 11, 521–526 (2009).
Bhavsar, A. P., Guttman, J. A. & Finlay, B. B. Manipulation of host-cell pathways by bacterial pathogens. Nature 449, 827–834 (2007).
Roy, C. R. & Mocarski, E. S. Pathogen subversion of cell-intrinsic innate immunity. Nature Immunol. 8, 1179–1187 (2007).
Carlin, A. F. et al. Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response. Blood 113, 3333–3336 (2009).
Carlin, A. F. et al. Group B Streptococcus suppression of phagocyte functions by protein-mediated engagement of human Siglec-5. J. Exp. Med. 206, 1691–1699 (2009).
Slevogt, H. et al. CEACAM1 inhibits Toll-like receptor 2-triggered antibacterial responses of human pulmonary epithelial cells. Nature Immunol. 9, 1270–1278 (2008).
Pinheiro da Silva, F. et al. CD16 promotes Escherichia coli sepsis through an FcRγ inhibitory pathway that prevents phagocytosis and facilitates inflammation. Nature Med. 13, 1368–1374 (2007). This paper provided the first demonstration that ITAMi can be exploited by bacteria, in this case to induce a crosstalk that inhibits phagocytosis, leading to uncontrolled E. coli infection and sepsis.
Reyburn, H. T. et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386, 514–517 (1997).
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. Immunity 26, 605–616 (2007).
Zhang, X., Majlessi, L., Deriaud, E., Leclerc, C. & Lo-Man, R. Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity 31, 761–771 (2009). References 29 and 30 identified TLR co-receptors (C-type lectins) and elucidated the underlying signalling pathways that explain how inflammatory TLRs can induce high levels of the anti-inflammatory cytokine IL-10.
Wang, M. et al. Microbial hijacking of complement–Toll-like receptor crosstalk. Sci. Signal. 3, ra11 (2010). This study was the first to show that anaphylatoxin generation by a virulence enzyme is exploited by the pathogen to induce subversive complement–TLR crosstalk that impairs protective immunity.
Hajishengallis, G., Wang, M., Liang, S., Triantafilou, M. & Triantafilou, K. Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function. Proc. Natl Acad. Sci. USA 105, 13532–13537 (2008).
Oliva, C., Turnbough, C. L. Jr & Kearney, J. F. CD14–Mac-1 interactions in Bacillus anthracis spore internalization by macrophages. Proc. Natl Acad. Sci. USA 106, 13957–13962 (2009).
Wang, M. et al. Fimbrial proteins of Porphyromonas gingivalis mediate in vivo virulence and exploit TLR2 and complement receptor 3 to persist in macrophages. J. Immunol. 179, 2349–2358 (2007).
Sumuth, S. D. et al. Aggregation substance promotes adherence, phagocytosis, and intracellular survival of Enterococcus faecalis within human macrophages and suppresses respiratory burst. Infect. Immun. 68, 4900–4906 (2000).
Ishibashi, Y., Claus, S. & Relman, D. A. Bordetella pertussis filamentous hemagglutinin interacts with a leukocyte signal transduction complex and stimulates bacterial adherence to monocyte CR3 (CD11b/CD18). J. Exp. Med. 180, 1225–1233 (1994).
Hawlisch, H. et al. C5a negatively regulates Toll-like receptor 4-induced immune responses. Immunity 22, 415–426 (2005).
Waggoner, S. N., Hall, C. H. & Hahn, Y. S. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. J. Leukoc. Biol. 82, 1407–1419 (2007).
Karp, C. L. et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science 273, 228–231 (1996). The first paper to show that a complement receptor (CD46) can downregulate IL-12 induction by TLR agonists, even though the concept of mammalian TLRs had not yet been established.
Simmons, D. P. et al. Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN and class I MHC antigen cross processing by TLR9. J. Immunol. 185, 2405–2415 (2010).
Dolganiuc, A. et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection. J. Immunol. 177, 6758–6768 (2006).
Capo, C. et al. Subversion of monocyte functions by Coxiella burnetii: impairment of the cross-talk between αvβ3 integrin and CR3. J. Immunol. 163, 6078–6085 (1999).
Lei, B. et al. Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nature Med. 7, 1298–1305 (2001). This study presents a novel concept according to which a virulence protein that mimics an innate immune receptor disrupts its cooperative interactions with another receptor, resulting in inhibition of crucial antimicrobial responses.
Melendez, A. J. et al. Inhibition of FcɛRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nature Med. 13, 1375–1381 (2007).
Turnbull, I. R. & Colonna, M. Activating and inhibitory functions of DAP12. Nature Rev. Immunol. 7, 155–161 (2007).
Wang, L. et al. Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Immunity 32, 518–530 (2010).
Pinheiro da Silva, F., Aloulou, M., Benhamou, M. & Monteiro, R. C. Inhibitory ITAMs: a matter of life and death. Trends Immunol. 29, 366–373 (2008).
Boyd, C. R. et al. Siglec-E is up-regulated and phosphorylated following lipopolysaccharide stimulation in order to limit TLR-driven cytokine production. J. Immunol. 183, 7703–7709 (2009).
Nakayama, M. et al. Paired Ig-like receptors bind to bacteria and shape TLR-mediated cytokine production. J. Immunol. 178, 4250–4259 (2007).
Chapman, T. L., Heikeman, A. P. & Bjorkman, P. J. The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603–613 (1999).
Lambert, A. A., Gilbert, C., Richard, M., Beaulieu, A. D. & Tremblay, M. J. The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways. Blood 112, 1299–1307 (2008).
Meyer-Wentrup, F. et al. DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production. J. Leukoc. Biol. 85, 518–525 (2009).
Meyer-Wentrup, F. et al. Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-α production. Blood 111, 4245–4253 (2008).
Cerf-Bensussan, N. & Gaboriau-Routhiau, V. The immune system and the gut microbiota: friends or foes? Nature Rev. Immunol. 10, 735–744 (2010).
Redpath, S., Ghazal, P. & Gascoigne, N. R. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86–92 (2001).
Confer, D. & Eaton, J. Phagocyte impotence caused by an invasive bacterial adenylate cyclase. Science 217, 948–950 (1982).
Turk, B. E. Manipulation of host signalling pathways by anthrax toxins. Biochem. J. 402, 405–417 (2007).
Vojtova, J., Kamanova, J. & Sebo, P. Bordetella adenylate cyclase toxin: a swift saboteur of host defense. Curr. Opin. Microbiol. 9, 69–75 (2006).
Conti, P. et al. IL-10, an inflammatory/inhibitory cytokine, but not always. Immunol. Lett. 86, 123–129 (2003).
Lavelle, E. C. et al. Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent. J. Leukoc. Biol. 75, 756–763 (2004).
Brenner, S. et al. cAMP-induced interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation. J. Biol. Chem. 278, 5597–5604 (2003).
Geijtenbeek, T. B. et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7–17 (2003).
Bergman, M. P. et al. Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J. Exp. Med. 200, 979–990 (2004).
Gringhuis, S. I., den Dunnen, J., Litjens, M., van der Vlist, M. & Geijtenbeek, T. B. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nature Immunol. 10, 1081–1088 (2009). This paper characterizes the composition of the DC-SIGN signalling complex, which depends on the sugar specificity of the activating DC-SIGN ligand; in turn, this determines the nature of the induced signalling pathway.
Madura Larsen, J. et al. BCG stimulated dendritic cells induce an interleukin-10 producing T-cell population with no T helper 1 or T helper 2 bias in vitro. Immunology 121, 276–282 (2007).
Dulphy, N. et al. Intermediate maturation of Mycobacterium tuberculosis LAM-activated human dendritic cells. Cell. Microbiol. 9, 1412–1425 (2007).
Hovius, J. W. et al. Salp15 binding to DC-SIGN inhibits cytokine expression by impairing both nucleosome remodeling and mRNA stabilization. PLoS Pathog. 4, e31 (2008). This paper presents the interesting concept of subversive receptor crosstalk being mediated by a pathogen and its arthropod vector, which contribute distinct agonists for TLRs and DC-SIGN, respectively.
Lundberg, K., Wegner, N., Yucel-Lindberg, T. & Venables, P. J. Periodontitis in RA — the citrullinated enolase connection. Nature Rev. Rheumatol. 6, 727–730 (2010).
Pihlstrom, B. L., Michalowicz, B. S. & Johnson, N. W. Periodontal diseases. Lancet 366, 1809–1820 (2005).
Hajishengallis, G. Porphyromonas gingivalis–host interactions: open war or intelligent guerilla tactics? Microbes Infect. 11, 637–645 (2009).
Pierce, D. L. et al. Host adhesive activities and virulence of novel fimbrial proteins of Porphyromonas gingivalis. Infect. Immun. 77, 3294–3301 (2009).
Hajishengallis, G., Ratti, P. & Harokopakis, E. Peptide mapping of bacterial fimbrial epitopes interacting with pattern recognition receptors. J. Biol. Chem. 280, 38902–38913 (2005).
Darveau, R. P. Periodontitis: a polymicrobial disruption of host homeostasis. Nature Rev. Microbiol. 8, 481–490 (2010).
Thammavongsa, V., Kern, J. W., Missiakas, D. M. & Schneewind, O. Staphylococcus aureus synthesizes adenosine to escape host immune responses. J. Exp. Med. 206, 2417–2427 (2009).
Zarek, P. E. et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111, 251–259 (2008).
Abram, C. L. & Lowell, C. A. The ins and outs of leukocyte integrin signaling. Annu. Rev. Immunol. 27, 339–362 (2009).
Harokopakis, E. & Hajishengallis, G. Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase. Eur. J. Immunol. 35, 1201–1210 (2005).
Sendide, K. et al. Cross-talk between CD14 and complement receptor 3 promotes phagocytosis of mycobacteria: regulation by phosphatidylinositol 3-kinase and cytohesin-1. J. Immunol. 174, 4210–4219 (2005). References 77 and 78 were the first to describe TLR signalling pathways that transactivate integrins through inside-out signalling.
Han, C. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nature Immunol. 11, 734–742 (2010).
Harokopakis, E., Albzreh, M. H., Martin, M. H. & Hajishengallis, G. TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae. J. Immunol. 176, 7645–7656 (2006).
Hajishengallis, G., Wang, M. & Liang, S. Induction of distinct TLR2-mediated proinflammatory and proadhesive signaling pathways in response to Porphyromonas gingivalis fimbriae. J. Immunol. 182, 6690–6696 (2009).
Arbibe, L. et al. Toll-like receptor 2-mediated NF-κB activation requires a Rac1-dependent pathway. Nature Immunol. 1, 533–540 (2000).
Lowell, C. A. Rewiring phagocytic signal transduction. Immunity 24, 243–245 (2006).
Caron, E. & Hall, A. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282, 1717–1721 (1998).
Gatfield, J. & Pieters, J. Essential role for cholesterol in entry of mycobacteria into macrophages. Science 288, 1647–1650 (2000).
Hajishengallis, G., Wang, M., Harokopakis, E., Triantafilou, M. & Triantafilou, K. Porphyromonas gingivalis fimbriae proactively modulate β2 integrin adhesive activity and promote binding to and internalization by macrophages. Infect. Immun. 74, 5658–5666 (2006).
Vanek, N. N. et al. Enterococcus faecalis aggregation substance promotes opsonin-independent binding to human neutrophils via a complement receptor type 3-mediated mechanism. FEMS Immunol. Med. Microbiol. 26, 49–60 (1999).
Rakita, R. M. et al. Enterococcus faecalis bearing aggregation substance is resistant to killing by human neutrophils despite phagocytosis and neutrophil activation. Infect. Immun. 67, 6067–6075 (1999).
Hellwig, S. M. et al. Targeting to Fcγ receptors, but not CR3 (CD11b/CD18), increases clearance of Bordetella pertussis. J. Infect. Dis. 183, 871–879 (2001). An elegant in vivo demonstration of the differential outcomes of FcγR- and CR3-mediated phagocytosis, with the latter being relatively ineffective in bacterial clearance; this explains why several pathogens proactively induce their uptake by CR3.
Zhang, X. et al. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110, 228–236 (2007).
Lappegård, K. T. et al. Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature. Proc. Natl Acad. Sci. USA 106, 15861–15866 (2009).
Fan, J. & Malik, A. B. Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nature Med. 9, 315–321 (2003).
la Sala, A., Gadina, M. & Kelsall, B. L. Gi-protein-dependent inhibition of IL-12 production is mediated by activation of the phosphatidylinositol 3-kinase-protein 3 kinase B/Akt pathway and JNK. J. Immunol. 175, 2994–2999 (2005).
Waggoner, S. N., Cruise, M. W., Kassel, R. & Hahn, Y. S. gC1q receptor ligation selectively down-regulates human IL-12 production through activation of the phosphoinositide 3-kinase pathway. J. Immunol. 175, 4706–4714 (2005).
Marth, T. & Kelsall, B. L. Regulation of interleukin-12 by complement receptor 3 signaling. J. Exp. Med. 185, 1987–1995 (1997).
Goriely, S., Neurath, M. F. & Goldman, M. How microorganisms tip the balance between interleukin-12 family members. Nature Rev. Immunol. 8, 81–86 (2008).
Manderson, A. P., Botto, M. & Walport, M. J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22, 431–456 (2004).
Sutterwala, F. S., Noel, G. J., Clynes, R. & Mosser, D. M. Selective suppression of interleukin-12 induction after macrophage receptor ligation. J. Exp. Med. 185, 1977–1985 (1997).
Liang, S. et al. The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss. J. Immunol. 186, 869–877 (2011).
Smith, A. et al. Selective suppression of IL-12 production by human herpesvirus 6. Blood 102, 2877–2884 (2003).
Santoro, F. et al. Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46. J. Biol. Chem. 278, 25964–25969 (2003).
Iacobelli-Martinez, M., Nepomuceno, R. R., Connolly, J. & Nemerow, G. R. CD46-utilizing adenoviruses inhibit C/EBPβ-dependent expression of proinflammatory cytokines. J. Virol. 79, 11259–11268 (2005).
Gaggar, A., Shayakhmetov, D. M. & Lieber, A. CD46 is a cellular receptor for group B adenoviruses. Nature Med. 9, 1408–1412 (2003).
Hahm, B., Cho, J. H. & Oldstone, M. B. Measles virus–dendritic cell interaction via SLAM inhibits innate immunity: selective signaling through TLR4 but not other TLRs mediates suppression of IL-12 synthesis. Virology 358, 251–257 (2007).
Gill, D. B. & Atkinson, J. P. CD46 in Neisseria pathogenesis. Trends Mol. Med. 10, 459–465 (2004).
Braun, L., Ghebrehiwet, B. & Cossart, P. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes. EMBO J. 19, 1458–1466 (2000).
Nguyen, T., Ghebrehiwet, B. & Peerschke, E. I. B. Staphylococcus aureus protein A recognizes platelet gC1qR/p33: a novel mechanism for staphylococcal interactions with platelets. Infect. Immun. 68, 2061–2068 (2000).
Nigou, J., Zelle-Rieser, C., Gilleron, M., Thurnher, M. & Puzo, G. Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J. Immunol. 166, 7477–7485 (2001).
Chieppa, M. et al. Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program. J. Immunol. 171, 4552–4560 (2003).
Urban, B. C., Willcox, N. & Roberts, D. J. A role for CD36 in the regulation of dendritic cell function. Proc. Natl Acad. Sci. USA 98, 8750–8755 (2001).
Urban, B. C. et al. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400, 73–77 (1999).
Patel, S. N. et al. Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo. J. Immunol. 178, 3954–3961 (2007).
D'Ombrain, M. C. et al. Plasmodium falciparum erythrocyte membrane protein-1 specifically suppresses early production of host interferon-γ. Cell Host Microbe 2, 130–138 (2007).
Long, K. H., Gomez, F. J., Morris, R. E. & Newman, S. L. Identification of heat shock protein 60 as the ligand on Histoplasma capsulatum that mediates binding to CD18 receptors on human macrophages. J. Immunol. 170, 487–494 (2003).
McGuirk, P. & Mills, K. H. Direct anti-inflammatory effect of a bacterial virulence factor: IL-10-dependent suppression of IL-12 production by filamentous hemagglutinin from Bordetella pertussis. Eur. J. Immunol. 30, 415–422 (2000).
Hajishengallis, G., Shakhatreh, M.-A. K., Wang, M. & Liang, S. Complement receptor 3 blockade promotes IL-12-mediated clearance of Porphyromonas gingivalis and negates its virulence in vivo. J. Immunol. 179, 2359–2367 (2007).
El Kasmi, K. C. et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nature Immunol. 9, 1399–1406 (2008).
Qualls, J. E. et al. Arginine usage in mycobacteria-infected macrophages depends on autocrine–paracrine cytokine signaling. Sci. Signal. 3, ra62 (2010).
Shirey, K. A., Cole, L. E., Keegan, A. D. & Vogel, S. N. Francisella tularensis live vaccine strain induces macrophage alternative activation as a survival mechanism. J. Immunol. 181, 4159–4167 (2008).
Netea, M. G. et al. The role of Toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J. Infect. Dis. 185, 1483–1489 (2002).
Netea, M. G. et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol. 172, 3712–3718 (2004).
Sing, A. et al. A hypervariable N-terminal region of Yersinia LcrV determines Toll-like receptor 2-mediated IL-10 induction and mouse virulence. Proc. Natl Acad. Sci. USA 102, 16049–16054 (2005). This study provides molecular evidence that virulence proteins might have evolved to interact with and exploit TLRs; this exploitative interaction contrasts with the concept of 'pattern recognition', which aims to promote innate immunity through TLR-mediated recognition of conserved microbial structures.
Petty, H. R., Worth, R. G. & Todd, R. F. Interactions of integrins with their partner proteins in leukocyte membranes. Immunol. Res. 25, 75–95 (2002).
Le Cabec, V., Cols, C. & Maridonneau-Parini, I. Nonopsonic phagocytosis of zymosan and Mycobacterium kansasii by CR3 (CD11b/CD18) involves distinct molecular determinants and is or is not coupled with NADPH oxidase activation. Infect. Immun. 68, 4736–4745 (2000).
Xia, Y. et al. Function of the lectin domain of Mac-1/complement receptor type 3 (CD11b/CD18) in regulating neutrophil adhesion. J. Immunol. 169, 6417–6426 (2002).
Rittirsch, D. et al. Cross-talk between TLR4 and FcγReceptorIII (CD16) pathways. PLoS Pathog. 5, e1000464 (2009).
Mantovani, A., Bonecchi, R. & Locati, M. Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nature Rev. Immunol. 6, 907–918 (2006).
Pathak, S. K. et al. Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nature Immunol. 8, 610–618 (2007).
Postma, B. et al. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J. Immunol. 172, 6994–7001 (2004).
Acknowledgements
The authors regret that several important studies could only be cited indirectly through comprehensive reviews, owing to space and reference number limitations. Work in the authors' laboratories is supported by US Public Health Service Grants DE015254, DE017138, DE018292 and DE021580 (to G.H.) and CA112162, AI68730, AI30040, AI72106, EB3968 and GM62134 (to J.D.L.).
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George Hajishengallis and John D. Lambris have pending patents regarding complement therapeutics.
Supplementary information
Supplementary information S1 (table)
Examples of microbial manipulation of innate immune receptor crosstalk (PDF 190 kb)
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Glossary
- Pattern recognition receptor
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(PRR). A host receptor that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. PRRs can be membrane bound (such as Toll-like receptors) or soluble cytoplasmic receptors (such as NOD-like receptors).
- Pathogen-associated molecular pattern
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(PAMP). A conserved molecular pattern that is found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind Toll-like receptors.
- Lipid raft
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A membrane microdomain rich in cholesterol, sphingolipids and glycosylphosphatidylinositol-anchored proteins. These domains partition receptors for various cellular signalling and trafficking processes.
- Inside-out signalling
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The process by which integrins (such as complement receptor 3) become activated (assume a high-affinity binding state) through intracellular signalling initiated by other receptors, such as anaphylatoxin receptors or Toll-like receptors. By contrast, outside-in signalling refers to intracellular signalling initiated by the activated and ligated integrins.
- Immunoreceptor tyrosine-based inhibitory motif
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(ITIM). A structural motif containing a tyrosine residue that is found in the cytoplasmic tails of several inhibitory receptors, such as Fcγ receptor IIB and paired immunoglobulin-like receptor B (PIRB). The consensus six-amino-acid ITIM sequence is (I/V/L/S)XYXX(L/V), in which X denotes any amino acid. Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family tyrosine kinases, which provides a docking site for the recruitment of cytoplasmic phosphatases.
- Immunoreceptor tyrosine-based activation motif
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(ITAM). A structural motif containing two tyrosine residues that is found in the cytoplasmic tails of several signalling adaptor molecules. The motif has the form YXX(L/I)X6-12YXX(L/I), in which X denotes any amino acid. The tyrosine residues are targets for phosphorylation by SRC-family protein tyrosine kinases and subsequent binding of proteins that contain SRC homology 2 (SH2) domains, such as spleen tyrosine kinase (SYK).
- Oxidative burst
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The process in phagocytic cells by which molecular oxygen is reduced by the NADPH oxidase system to produce reactive oxygen species, such as hydrogen peroxide and hydroxyl radicals. These are toxic oxidants that can destroy targeted microorganisms (for example, in the phagosome lumen).
- Extracellular DNA trap
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Often referred to by the acronym NET (neutrophil extracellular trap). Upon activation (for example, through Toll-like or Fcγ receptors), neutrophils release nuclear content such as chromatin (DNA, histones and other proteins). This forms a web-like scaffold for the exposure of released antimicrobial molecules at high local concentrations, resulting in the trapping and extracellular killing of bacteria.
- G protein-coupled receptors
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(GPCRs). Also known as seven-transmembrane-domain receptors, this large group of receptors can bind a diverse set of molecules (such as chemokines, complement anaphylatoxins, hormones and neurotransmitters) and can induce intracellular signalling by coupling to heterotrimeric GTP-regulated signalling proteins.
- Anaphylatoxins
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The pro-inflammatory fragments C3a and C5a that are generated during the activation of the complement system. They mediate various inflammatory responses through their corresponding G protein-coupled receptors, such as chemotaxis, oxidative burst and histamine release (from mast cells), but they (in particular, C5a) can also regulate other innate immune components (such as TLRs) through crosstalk signalling pathways.
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Hajishengallis, G., Lambris, J. Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol 11, 187–200 (2011). https://doi.org/10.1038/nri2918
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DOI: https://doi.org/10.1038/nri2918
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