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  • Review Article
  • Published:

Bacterial manipulation of innate immunity to promote infection

Nature Reviews Microbiology volume 8, pages 117–128 (2010)Cite this article

Subjects

Key Points

  • Although an arsenal of antimicrobial mechanisms is deployed to kill bacteria in infected cells, pathogens have learnt how to manipulate host defence mechanisms to survive and eventually replicate. This Review focuses on the different mechanisms used by pathogenic intracellular bacteria to subvert host innate immune responses.

  • At the level of pathogen entry, membrane receptors and cofactors involved in the internalization and cytoskeleton rearrangements are targeted by pathogens to promote their own entry into host cells.

  • Pathogens can also subvert innate immune responses by expressing protein effectors, which directly interfere with Toll-like receptor signalling pathways.

  • After internalization, pathogenic bacteria can use endocytic, phagocytic and exocytic pathways by expressing proteic and lipid bacterial effectors to escape from their vacuole, to relocate in a safe membrane compartment or to stop the maturation process of their vacuole with the aim of establishing a suitable replication niche.

  • In response to inflammatory stimuli generated by internalized pathogens, macrophages and neutrophils produce chemically reactive molecules such as antimicrobial peptides, reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI). Again, pathogens have developed mechanisms to detoxify ROS and RNI, and thereby avoid elimination.

  • Although autophagy is a defence mechanism, some pathogens use autophagy for their own benefit, whereas others secrete bacterial effectors involved in the camouflage against autophagic recognition.

  • Finally, microbial molecules or intermediary signals induced by these molecules are thought to stimulate response mechanisms leading to inflammasome activation. Controlling caspase 1 activation and cell death is an important aspect of virulence for several intracellular pathogens.

  • The coordinate action of bacterial effectors is important for pathogenic intracellular bacteria to maintain membrane homeostasis of vacuoles, acquire nutrients and avoid damage caused by the host immune system.

Abstract

The mammalian innate immune response provides a barrier against invading pathogens. Innate immune mechanisms are used by the host to respond to a range of bacterial pathogens in an acute and conserved fashion. Host cells express pattern recognition receptors that sense pathogen-associated molecular patterns. After detection, an arsenal of antimicrobial mechanisms is deployed to kill bacteria in infected cells. Innate immunity also stimulates antigen-specific responses mediated by the adaptive immune system. In response, pathogens manipulate host defence mechanisms to survive and eventually replicate. This Review focuses on the control of host innate immune responses by pathogenic intracellular bacteria.

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Figure 1: Manipulation of host innate immunity by intracellular pathogenic bacteria.
Figure 2: Intracellular pathogens manipulate host membrane trafficking to resist innate immunity and promote survival and replication.
Figure 3: Survival niches of pathogenic bacteria.
Figure 4: Autophagy and inflammasome activation can be manipulated by intracellular pathogens.

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Acknowledgements

We thank Suzana Salcedo, Stéphane Méresse, Hughes Lelouard, Steve Garvis and Chantal de Chastellier for critical reading of the manuscript. We apologize to all those authors whose work could not be cited because of space limitations. We are grateful to Chantal de Chastellier and Stéphane Méresse for electron microscopy and immunofluorescence micrographs. L.D. is a fellow the European Molecular Biology Organization. This work has been supported by institutional grants from Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique.

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Authors and Affiliations

  1. Centre d'Immunologie de Marseille-Luminy, 1 Aix Marseille Université, Faculté des Sciences de Luminy, Institut National de la Santé et de la Recherche Médicale, U631 and Centre National de la Recherche Scientifique, UMR6102, Marseille, F-13,288, France

    Lautaro Diacovich & Jean-Pierre Gorvel

  2. Foundation FINOVI, Lyon, F-69,007, France

    Jean-Pierre Gorvel

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  1. Lautaro Diacovich
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Correspondence to Jean-Pierre Gorvel.

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DATABASES

Entrez Genome Project

Brucella abortus

Brucella melitensis

Chlamydia trachomatis

Escherichia coli

Francisella tularensis

Legionella pneumophila

Listeria monocytogenes

Mycobacterium bovis

Mycobacterium tuberculosis

S. enterica subsp. enterica serovar Typhimurium

Shigella flexneri

Yersinia pestis

FURTHER INFORMATION

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Glossary

Pattern recognition receptor

A receptor of the innate immune system that recognizes and responds to conserved microorganism-associated molecular patterns.

NOD-like receptor

An intracellular sensor that detects cytosolic microbial components, cell injury and 'danger' signals (such as ATP and toxins).

Inflammasome

A molecular complex of several proteins that on assembly cleaves pro-interleukin-1 (IL-1), thereby producing active IL-1. Based on the pyrin-domain containing Nod-like receptors (NLR) NALP1 and NALP3, which require ASC to bridge the NLRs to pro-caspase 1.

Muramyl dipeptide

A peptidoglycan constituent of both Gram-positive and Gram-negative bacteria. It is composed of N-acetylmuramic acid linked by its lactic acid moiety to the amino terminus of an L-alanine D-isoglutamine dipeptide.

Reactive oxygen species

These include superoxide (O2·−), hydroxyl radicals (OH−) and hydrogen peroxide (H2O2). They are generated as products of normal respiration from the electron transport chain that is present in the mitochondria or in the endoplasmic reticulum, or they can be catalysed by a wide array of enzymes (NADPH oxidase, xanthine oxidase, peroxidases and NADPH oxidase isoform).

Reactive nitrogen intermediates

These include nitric oxide (NO·) and its derivates such as NONOates, S-nitrosothiols, peroxynitrite, nitrite and nitrous acid. NO· is a highly reactive and diffusible free radical, soluble in both lipids and water, and capable of reacting with oxygen and reactive oxygen species to form reactive nitrogen intermediates, NO2, NO2−, NO3−, N2O3, and the highly mycobactericidal ONOO−.

Proteasome

A giant multicatalytic protease that resides in the cytosol and nucleus.

Caspase 1

A cysteine protease that contains a cysteine residue in the active site and that cleaves its substrate after an aspartic acid residue. It was previously known as interleukin-1 β-converting enzyme.

Pyroptosis

An inflammatory process of cellular self-destruction that causes cell lysis and the secretion of interleukin-1β (IL-1β) and IL-18, in a caspase 1-dependent way.

Pathogenicity island

A large region of genomic DNA that encodes genes associated with virulence. A pathogenicity island is typically transferred horizontally between bacterial strains and is often inserted into tRNA genes in the genome.

Arp2/3 complex

A complex that consists of seven subunits comprising two Arp proteins and five highly conserved protein subunits: p16, p20, p21, p34 and p40e. The Arp2 and Arp3 subunits are structurally related to actin.

T4SS

(Type IV secretion system). A well-characterized secretion apparatus, encoded by the virB operon from Agrobacterium spp., which can transport DNA and proteins into host cells. Helicobacter pylori, Bordetella pertussis, Brucella spp. and Legionella pneumophila have homologous operons that are used to secrete proteins and toxins into the eukaryotic cytoplasm.

NADPH oxidase

An enzyme composed of five core polypeptides, p22phox, gp91phox p47phox, p67phox and p40phox, and two low-molecular-mass guanine nucleotide-binding proteins, Rac (p21rac) and Rap1A.

Nitric oxide synthase

(NOS). An enzyme that uses electrons derived from NADPH to convert (oxidize) L-arginine to L-citrulline and NO·. Three NOS isoforms are known, NOS1, NOS2 and NOS3. NOS2 has also been termed iNOS, for inducible and independent (of increased intracellular Ca2+) and was first cloned from mouse macrophage cell line RAW 264.7.

Ezrin–radixin–moesin-binding phosphoprotein 50

A scaffolding protein that is responsible for the anchoring of various cellular proteins to the actin cytoskeleton through its linkage to ezrin, radixin and moesin.

Autophagosome

An intracytoplasmic vacuole that contains components of the cytoplasm. It fuses with a lysosome to form an autophagolysosome, thereby subjecting its contents to enzymatic digestion.

Apoptosis-associated speck-like protein containing a CARD

(ASC). A protein that contains a CARD domain in its carboxy-terminal region and a pyrin domain in the amino-terminal region. Both domains allow ASC to recruit other pyrin domain- and CARD-containing proteins through homotypic protein–protein interactions.

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Diacovich, L., Gorvel, JP. Bacterial manipulation of innate immunity to promote infection. Nat Rev Microbiol 8, 117–128 (2010). https://doi.org/10.1038/nrmicro2295

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