Soil transmitted helminth infections remain one of the most neglected groups of infectious diseases and one of the greatest public health challenges worldwide, with an estimated two billion people infected. Importantly, recovery from helminth infection involves not only clearance of the parasite, but also successful repair of the inflamed, damaged intestine in order to restore tissue protection and these mechanisms of tissue protection are often conserved across non-infectious intestinal diseases. Thus, the development of successful immuno- therapies against soil-transmitted helminth parasites requires a more comprehensive understanding of the mechanisms that regulate both infection-induced immunity and intestinal tissue protection. This proposal will interrogate the role of group 2 innate lymphoid cells (ILC2s) in promoting anti-helminth immunity and regulating infectious and non-infectious intestinal tissue protection via activation of the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) pathway. In preliminary studies, we found that deletion of AREG resulted in dysregulated immune responses, impaired worm expulsion and failed intestinal repair following helminth infection. Critically, the importance of this pathway was not limited to pathogen infection, as AREG expression was also elevated in a murine model of non-infectious intestinal damage, and disruption in AREG-EGFR interactions resulted in exacerbated intestinal inflammation and impaired intestinal repair. We further identified ILC2s as a key source of this growth factor and found that therapeutic transfer of ILC2s or AREG protein can limit inflammation and promote tissue protection in mice. Despite these advances, the factors that regulate intestinal AREG responses, the cell-intrinsic requirements for AREG expression, the downstream mechanisms by which AREG influences epithelial cell responses, and whether differential AREG expression in humans is associated with intestinal inflammation, all remain unknown. Employing new in vivo tools, this competitive grant renewal will focus on delineating: (i) the signals and cell-intrinsic requirements for AREG in promoting immunity to helminth infection and restoration of intestinal tissue protection, (ii) the mechanisms by which ILC2-AREG regulates intestinal epithelial cell (IEC) progenitors to promote tissue protection, and (iii), whether therapeutic delivery of rAREG can reverse established chronic intestinal tissue damage and inflammation and restore tissue protection. We anticipate that defining the mechanisms by which the ILC2-AREG-EGFR pathway regulates both intestinal immunity and tissue protection is critical for the design of new immunologic intervention strategies to treat and prevent helminth infections and non-infectious inflammatory diseases such as IBD. !

Public Health Relevance

With infection rates estimated at two billion worldwide, intestinal helminth parasites remain one of the greatest public health and economic challenges globally. Successful recovery requires immune cell-mediated clearance of the parasite and repair of the damaged intestinal tissue to restore tissue protection, however the cellular and molecular mechanisms that can coordinately promote immunity and tissue protection following infectious or non-infectious insults in the intestine remain poorly understood. This proposal will interrogate how group 2 innate lymphoid cells (ILC2s) regulate intestinal immunity and tissue protection through activation of the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095466-07
Application #
9663251
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2011-08-15
Project End
2023-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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