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  • Review Article
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Microbial manipulation of receptor crosstalk in innate immunity

Nature Reviews Immunology volume 11, pages 187–200 (2011)Cite this article

Subjects

Key Points

  • 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.

  • 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.

  • 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).

  • 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.

  • 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).

  • 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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Figure 1: Inhibition of cell activation by pathogen-ligated ITIM-bearing or ITAMi-coupled receptors.
Figure 2: Pathogen-induced host receptor crosstalk to stimulate IL-10 production.
Figure 3: Integration of subversive crosstalk pathways, leading to inhibition of pathogen killing.
Figure 4: Pathogen-induced transactivation of CR3-mediated internalization.
Figure 5: Selective inhibition of TLR-induced IL-12 production by pathogen-instigated PRR crosstalk.
Figure 6: MYD88-dependent arginase induction prevents nitric oxide production in both infected and uninfected macrophages.

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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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Authors and Affiliations

  1. University of Louisville Department of Microbiology and Immunology, Oral Health and Systemic Disease Research Group, 501 South Preston Street, Louisville, 40292, Kentucky, USA

    George Hajishengallis

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    John D. Lambris

  3. John D. Lambris

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George Hajishengallis and John D. Lambris have pending patents regarding complement therapeutics.

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Supplementary information S1 (table)

Examples of microbial manipulation of innate immune receptor crosstalk (PDF 190 kb)

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Glossary

Pattern recognition receptor

(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

(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

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

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

(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

(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

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

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

(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

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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