The human intestinal microbiome includes viruses that replicate in eukaryotic cells, plants, fungi or bacteria. However, very little is known on how viral recognition shapes mucosal immune responses. Furthermore, a detailed understanding of the signaling intermediates that confer the sensing of viruses for induction of type I interferons s critical for strategies to curtail viral mechanisms that impede innate immune defenses. Our work identified the guanine nucleotide exchange factor H1 (GEF-H1), encoded by the arhgef2 gene, as a central component of host defense activation during viral infections. We hypothesize that GEF-H1 serves as a gatekeeper for innate host defenses by controlling interferon response factor activation, which is part of signaling pathways induced by recognition of bacteria and viruses. Defining the functional role of this newly discovered central component of microbial pattern recognition should provide pivotal insights into the integration of antiviral host defenses into immune activation pathways that control the microbiota in the intestine.

Public Health Relevance

A detailed understanding of sensing of microbial components for the induction of host defenses is critical for strategies to curtail microbial mechanisms that disable immune responses or induce chronic inflammation. We aim to unravel the mechanisms that make GEF-H1 a central signaling component that controls the expression of type I interferons and proinflammatory mediators for the defense against viral and bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI113333-03
Application #
9112860
Study Section
Immunity and Host Defense (IHD)
Program Officer
Rothermel, Annette L
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Kim, Young-In; Song, Joo-Hye; Ko, Hyun-Jeong et al. (2018) CX3CR1+ Macrophages and CD8+ T Cells Control Intestinal IgA Production. J Immunol 201:1287-1294
Mohanan, Vishnu; Nakata, Toru; Desch, A Nicole et al. (2018) C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions. Science 359:1161-1166
Ravindran, Ethiraj; Hu, Hao; Yuzwa, Scott A et al. (2017) Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation. PLoS Genet 13:e1006746
Bouziat, Romain; Hinterleitner, Reinhard; Brown, Judy J et al. (2017) Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356:44-50
Li, Yang; Basavappa, Megha; Lu, Jinfeng et al. (2016) Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells. Nat Microbiol 2:16250
O'Keeffe, Michael S; Song, Joo-Hye; Liao, Gongxian et al. (2015) SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 148:991-1001.e4
Lammers, Karen M; Chieppa, Marcello; Liu, Lunhua et al. (2015) Gliadin Induces Neutrophil Migration via Engagement of the Formyl Peptide Receptor, FPR1. PLoS One 10:e0138338