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 provie 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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Singleton, Kentner L
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University of Washington
Schools of Medicine
United States
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Singh, Abhimanyu K; Nguyen, Thanh H; Vidovszky, Márton Z et al. (2018) Structure and N-acetylglucosamine binding of the distal domain of mouse adenovirus 2 fibre. J Gen Virol 99:1494-1508
Holly, Mayumi K; Smith, Jason G (2018) Paneth Cells during Viral Infection and Pathogenesis. Viruses 10:
Holly, Mayumi K; Smith, Jason G (2018) Adenovirus infection of human enteroids reveals interferon sensitivity and preferential infection of goblet cells. J Virol :
Wilson, Sarah S; Bromme, Beth A; Holly, Mayumi K et al. (2017) Alpha-defensin-dependent enhancement of enteric viral infection. PLoS Pathog 13:e1006446
Holly, Mayumi K; Diaz, Karina; Smith, Jason G (2017) Defensins in Viral Infection and Pathogenesis. Annu Rev Virol 4:369-391
Wiens, Mayim E; Smith, Jason G (2017) ?-Defensin HD5 Inhibits Human Papillomavirus 16 Infection via Capsid Stabilization and Redirection to the Lysosome. MBio 8:
Wilson, Sarah S; Wiens, Mayim E; Holly, Mayumi K et al. (2016) Defensins at the Mucosal Surface: Latest Insights into Defensin-Virus Interactions. J Virol 90:5216-5218
Gounder, Anshu P; Myers, Nicolle D; Treuting, Piper M et al. (2016) Defensins Potentiate a Neutralizing Antibody Response to Enteric Viral Infection. PLoS Pathog 12:e1005474
Smith, Jason G (2016) Directed Evolution of Adenoviruses. Methods Mol Biol 1382:187-96
Wiens, Mayim E; Smith, Jason G (2015) Alpha-defensin HD5 inhibits furin cleavage of human papillomavirus 16 L2 to block infection. J Virol 89:2866-74

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