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 #
1R01GM102482-01A1
Application #
8513743
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
2013-04-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$330,600
Indirect Cost
$140,600
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Stuart, Lynda M; Lacy-Hulbert, Adam (2017) GOP-1: Helping phagosomes pass the acid test. J Cell Biol 216:1517-1519
Visvikis, Orane; Ihuegbu, Nnamdi; Labed, Sid A et al. (2014) Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. Immunity 40:896-909
Tam, Jenny M; Mansour, Michael K; Khan, Nida S et al. (2014) Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages. J Infect Dis 210:1844-54
Stuart, Lynda M; Paquette, Nicholas; Boyer, Laurent (2013) Effector-triggered versus pattern-triggered immunity: how animals sense pathogens. Nat Rev Immunol 13:199-206