Masters, marionettes and modulators: intersection of pathogen virulence factors and mammalian death receptor signaling

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Highlights

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    TNF and its receptor, TNFR1, help orchestrate an inflammatory response to pathogens.

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    TNFR1 signaling is therefore a frequent target of pathogen manipulation.

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    We describe how the TNFR1 signaling pathway is targeted by pathogen virulence factors and how the different arms of TNFR1 signaling react.

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    We examine recent data showing the importance of other members of the Death Receptor family in the immune response to pathogens.

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    We discuss how understanding pathogen inhibition suggests clinical applications.

TNF and its receptor, TNFR1, are members of the TNF superfamily and play important roles during infection by orchestrating an inflammatory response. The key role that TNFR1 signaling plays in host defense singles it out as a frequent target of pathogen manipulation. This review describes how the TNFR1 signaling pathway is attacked by pathogen virulence factors and how the different TNFR1 signaling pathways, in particular the death signaling response, have evolved to counteract these pathogen manipulations. We examine recent data showing that other ‘Death Receptors’ in the TNF superfamily, namely TRAIL-R and Fas, also participate in the immune response to pathogens. Finally we explore how knowledge of the inhibition of these pathways is being translated for clinical applications.

Introduction

TNFR1 is a master regulator of the inflammatory response and plays crucial roles in protecting the host from pathogen invaders including bacteria and viruses. TNFR1 belongs to a subset of receptors, called Death Receptors (DR), in the TNF superfamily. DR are defined by the presence of a, usually homotypic, protein–protein interaction domain called the Death Domain (DD). The DD engages and drives activation of proteins such as caspases and RIPK kinases that have the ability to induce cell death. An emerging theme in the field of host–pathogen responses is that other DR in addition to TNFR1, namely Fas and TRAIL-R, also play a role in protecting the host from pathogens. If bacteria and viruses are to propagate successfully they must therefore manipulate DR signaling and do so in a highly coordinated and specific fashion. In this review, we explain how the protagonists counter one another's moves and describe what we can learn from this evolutionary warfare.

Section snippets

Masters and strategems

TNF is a master regulator of inflammatory signaling and the founding member of the eponymous TNF superfamily. It is widely acknowledged to be a major player in resisting bacterial and viral infection. There are two receptors: TNFR2 (TNFRSF1B) expressed predominantly on subsets of T-cells, neuronal cell types and endothelial cells, and TNFR1 (TNFRSF1A), which is expressed ubiquitously. TNFR1 signaling is a significant part of the total inflammatory response to TNF and TNFR1 knock-out mice are

The manipulators — pathogenic bacteria

The diarrheal pathogen, enteropathogenic Escherichia coli (EPEC), is extracellular, but forms characteristic lesions known as attaching and effacing (A/E) lesions on intestinal epithelial cells. Although remaining extracellular, the pathogen manipulates intracellular host cell processes by injecting virulence effector proteins into the infected cell using a bacterial type III secretion system. Several of these effectors have been implicated in the inhibition of inflammatory signaling. For

TRAIL and pathogens

The idea that TNF might be used to treat tumors has an elegant link to the bacterial response. It was shown by William Coley in 1894 that mixtures of killed bacteria injected into a patient could drive the destruction of certain tumors and this finding led directly to the discovery of the Tumor Necrosis Factor (TNF) induced by LPS from the bacteria [27, 28]. Unfortunately, except in very special cases, TNF is useless as an anti-cancer drug because it induces life-threatening inflammation at

Fas and pathogens

Fas (TNFRSF12) has long been considered to be the archetypal DR. Its most notable role is in regulating T-lymphocyte numbers and Fas or FasL (TNFSF6) deficient mice and people ultimately succumb to an auto-immune lymphoproliferative disease [32]. Fas, like TNFR1, has the ability to promote cell proliferation and inflammation, probably principally depending upon whether FasL is membrane bound or soluble [33•]. Relevant to this review, FasL is also induced in response to infection and in a very

What have we learned?

Successful pathogens are great teachers. They highlight the key immune pathways required to limit their growth and give illustrative examples of how this can be achieved. One way that this knowledge can be applied is by using pathogen style approaches to block destructive inflammation. Decoy receptor and other anti-TNF reagents are very, albeit not completely, successful in the clinic in treating auto-inflammatory conditions but if we follow the pathogen lead maybe efficacy can be increased by

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to acknowledge the students, post-docs and other researchers in our respective labs that have helped us in developing the ideas expressed in this review. JS is funded by NHMRC grants 541901, 1025594 and 1046986. EH is funded by NHMRC grants 606788, 1044061 and an ARC Future Fellowship.

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