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Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens

Key Points

  • A key strategy for pathogens to survive in a hostile host environment is to interfere with normal cell signalling to defuse the defences that are aimed at controlling and eliminating foreign invaders.

  • Macrophages are the immune system's journeymen that are well situated to recognize rapidly, internalize and degrade bacterial pathogens, and to contain an infection for long enough to initiate adaptive immunity. Macrophages function as both sentinels and the first line of defence against infection, and they are therefore an essential barrier that pathogens must overcome to be successful.

  • Many successful bacterial pathogens are able to alter their recognition, either by modifying their surface, interrupting the signalling that is triggered by receptor–ligand binding, or by engaging alternative receptors, ultimately escaping macrophage surveillance.

  • Different bacterial pathogens avoid uptake by, or trafficking within, macrophages to minimize damage from the cell's antimicrobial arsenal.

  • Microbial recognition initiates robust signalling by the extracellular signal-regulated kinase/mitogen-activated protein kinase, nuclear factor κB, and interferon-γ pathways, which are crucial for many responses to infection. They present a strategic target for bacterial subversion, which involves producing bacterial proteins that mimic, inhibit, or perturb the localization of eukaryotic signalling molecules.

  • Some pathogens capitalize on the destructive consequences of an over-exuberant inflammatory response on the host. Other pathogens persist by avoiding or attenuating the inflammatory response that is orchestrated by macrophages.

  • By altering macrophage signalling, pathogens can alter the production of, or response to, cytokines, which impairs the communication between cells that is necessary for clearance of the infection.

  • Disease can result from dysregulated macrophage signalling that is driven by the host or pathogen and does not necessarily benefit either player. It is therefore important to consider the net balance of signalling within a macrophage when determining if response to infection favours host or pathogen survival.

Abstract

Macrophages function at the front line of immune defences against incoming pathogens. But the ability of macrophages to internalize bacteria, migrate, recruit other immune cells to the site of infection and influence the nature of the immune response can provide unintended benefits for bacterial pathogens that are able to subvert or co-opt these normally effective defences. This review highlights recent advances in our understanding of the many interference strategies that are used by bacterial pathogens to undermine macrophage signalling.

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Figure 1: Bacterial pathogens subvert macrophage signalling and effector mechanisms.
Figure 2: Bacterial pathogens can benefit from targeting macrophages.
Figure 3: Macrophage surveillance systems to detect bacteria.
Figure 4: Pathogen avoidance of phagolysosomal degradation.
Figure 5: Disruption of NF-κB signalling by bacterial pathogens.
Figure 6: Disruption of MAPK signalling.

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Acknowledgements

We thank R. Fernandez, B. Vallance, S. Gruenheid, N. Brown and M. Zaharik for their helpful suggestions and discussions. Work in our laboratory is supported by grants from the Canadian Institutes of Health Research (CIHR), Genome Canada and a Howard Hughes International Research Scholar Awards to B.B.F.. C.M.R. is supported by studentships from the CIHR and the Michael Smith Foundation for Health Research.

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Correspondence to B. Brett Finlay.

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CSF-1

FimH

Fyb

IpaB

IRAK-M

LcrV

SipB

SUMO-1

TLR2

TLR4

TLR6

TLR9

YopE

YopH

YopJ

FURTHER INFORMATION

B. Brett Finlay's laboratory

Animation of MAPK activation

Macrophage micrographs

Animation of intracellular infection by Salmonella

Animation of pathogenic E. coli infection mechanism

Theriot lab collection of live cell microscopy movies of host-pathogen interactions

Glossary

ADAPTIVE IMMUNE RESPONSE

In this host defence system, which evolved in vertebrates, T and B cells respond specifically to a given antigen. This type of immune response includes antibody production and the killing of pathogen-infected cells, and is regulated by cytokines such as interferon-α.

NEUTROPHIL

A phagocytic cell of the myeloid lineage that has an important role in the inflammatory response, undergoing chemotaxis towards sites of infection or wounding.

DENDRITIC CELL

A 'professional' antigen-presenting cell that is found in T-cell areas of lymphoid tissues, but is also a minor cellular component in most tissues. These cells have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

INNATE IMMUNE RESPONSE

This is crucial during the early phase of host defence against infection by pathogens (such as bacteria and viruses), before the antigen-specific, adaptive immune response is induced.

TOLL-LIKE RECEPTORS

(TLRs). Receptors that are present on mammalian cells, mostly on those that are involved in innate or adaptive resistance to pathogens. They are homologous to the Toll receptor protein family in Drosophila melanogaster, members of which have important roles in both embryogenesis and defence against infection. TLRs have evolved to recognize molecular patterns that are conserved and shared by many microbial pathogens.

NUCLEAR FACTOR-κB

(NF-κB). A widely expressed transcription factor that is activated by cellular stress and can induce the expression of numerous proinflammatory and anti-apoptotic genes.

OXIDATIVE BURST

This consists of antibacterial reactive oxygen intermediates (ROIs), such as superoxide and hydroxyl radicals, that are produced by the phagocyte NADPH oxidase.

LIPOPOLYSACCHARIDE

(LPS). A component of the outer membrane of Gram-negative bacteria that is made of a lipid, a core oligosaccharide and an O-linked sugar side chain.

GRAM-POSITIVE BACTERIA

The cell walls of these bacteria retain a basic blue dye during the Gram-stain procedure. These cell walls are relatively thick (15–80 nm across) and consist of a network of peptidoglycans.

LIPOSOME

A lipid-based delivery system that is used to deliver DNA or protein into cells.

PHAGOCYTOSIS

An actin-dependent process, by which cells engulf external particulate material by extension and fusion of pseudopods.

GTPASE-ACTIVATING PROTEINS

Proteins that inactivate small GTP-binding proteins, such as Ras family members, by increasing their rate of GTP hydrolysis.

COMPLEMENT

Nine interacting serum proteins (C1–C9), mostly enzymes, that are activated in a coordinated way and participate in bacterial lysis and macrophage chemotaxis.

FIMH TYPE 1 PILUS

An attachment organelle that extends from the bacterial surface and contains an adhesin that is encoded by the FimH gene.

LYSOSOME

A membrane-bounded organelle with a low internal pH (4–5) that contains hydrolytic enzymes and that is the site of degradation of proteins in both the biosynthetic and the endocytic pathways.

PROTON ATPASE

A membrane protein that mediates proton influx and acidification of the phagolysosome.

METALLOPROTEINASE

A proteinase that has a metal ion at its active site.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). The genes encoding the MHC molecules are the most polymorphic in the genome. MHC molecules are a family of surface molecules that present antigenic peptides from foreign microbes to T cells and help the immune system to recognize self from non-self — they are the ones recognized by T cells during transplant rejection.

CREB

(cyclic AMP response-element-binding protein). A transcription factor that functions in glucose homeostasis and growth-factor-dependent cell survival, and has also been implicated in learning and memory.

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Rosenberger, C., Finlay, B. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens. Nat Rev Mol Cell Biol 4, 385–396 (2003). https://doi.org/10.1038/nrm1104

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