The innate immune response is a critical component of host defense against infection. Defensins, one family of antimicrobial peptides, are an evolutionarily conserved class of innate immune effectors with well-described anti-bacterial activity;however, their role in anti-viral immunity is less well understood. The potent neutralization of diverse viruses by alpha-defensins has been described in vitro and in cell culture. To uncover general rules that dictate alpha-defensin activity against non-enveloped viruses, we will compare the molecular mechanisms of inhibition of human adenovirus and papillomavirus. These studies will combine biochemical, genetic, and structural studies to identify defensin binding determinants on the viral capsids. We will also identify the stage in human papillomavirus entry that is blocked by defensins. Using a novel 3D organoid culture system, we will then determine whether naturally secreted human and mouse alpha-defensins are anti- viral and block infection of primary intestinal epithelium. This investigation will provide a foundation for and aid in the interpretation of in vivo experiments to test the impact of alpha-defensin expression on viral pathogenesis. Thus, we will gain insight into the function of a critical component of the immune system that may be a common first line of defense against many viral pathogens. Development of 3D intestinal organoids, as part of these studies, will be valuable for dissecting a broad range of host interactions with enteric pathogens. And, these studies may aid in the development of alpha-defensins as therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104920-01A1
Application #
8629146
Study Section
Virology - B Study Section (VIRB)
Program Officer
Leitner, Wolfgang W
Project Start
2014-04-10
Project End
2018-03-31
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$534,762
Indirect Cost
$126,525
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wilson, S S; Tocchi, A; Holly, M K et al. (2015) A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol 8:352-61
Tenge, Victoria R; Gounder, Anshu P; Wiens, Mayim E et al. (2014) Delineation of interfaces on human alpha-defensins critical for human adenovirus and human papillomavirus inhibition. PLoS Pathog 10:e1004360
Wiens, Mayim E; Wilson, Sarah S; Lucero, Carissa M et al. (2014) Defensins and viral infection: dispelling common misconceptions. PLoS Pathog 10:e1004186