How the innate immune system discriminates pathogen attack from colonization with harmless commensal microbes is a fundamental unresolved question. One model suggests that the host responds to endogenous ligands generated as a consequence of the tissue damage associated with infection (DAMPs) and that these ligands must be encountered alongside the better-characterized Microbial-Associated Molecular Patterns to induce a robust inflammatory response. Another possibility is suggested by our recent discovery that host proteins that have undergone very specific post-translational modifications due to the activity of microbial-derived effectors or toxins may themselves trigger an innate immune response. These Virulence-Associated Molecular Patterns (VAMPs) can be considered as a subset of DAMPs that are found specifically after exposure to virulent pathogens that deliberately modify host proteins. Importantly, the response to these modified-self proteins occurs early in the course of infection and can induce strong and potentially protective immune responses. We refer to these as "effector-triggered immune" (ETI) responses. Here we propose studies to identify and better understand how the host senses and responds to bacterial effectors and the role that effector-triggered immunity plays in initiating and fine-tuning our response to virulent pathogens.

Public Health Relevance

Our immune system is constantly faced with the problem of distinguishing whether a microbe is one of the harmless and often beneficial bacteria with which we are colonized or a potential pathogen likely to do us harm. We have recently identified a new way for the host to sense the potential threat of a microbe: by monitoring for the presence of virulence factors and increasing the immune response accordingly. Here we propose studies to better understand this novel mechanism of immune sensing and to understand its role in regulating defense against virulent pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102482-03
Application #
8641405
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dunsmore, Sarah
Project Start
2013-04-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$324,900
Indirect Cost
$134,900
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101