The innate immune response is a critical component of host defense against infection. Alpha-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 viral immunity is less well understood. The potent neutralization of diverse viruses by alpha-defensins has been described in vitro and in cell culture. By focusing on human adenovirus and papillomavirus, we have identified a common mechanism whereby alpha-defensins bind to the viral capsid and alter uncoating during cell entry to block infection. Recently, we have found that viruses transmitted by the oral/fecal route (e.g., rotavirus and enteric adenovirus) are selectively resistant to the antiviral activity of alpha-defensins from their host species while remaining sensitive to non-host alpha- defensins. In some cases, the host alpha-defensins even increase or enhance the infection of these viruses, leading us to hypothesize that enteric viruses have evolved to either evade or hijack these host defense peptides to increase infection and transmission. To test this hypothesis, we will study the enhancement and neutralization of rotavirus by host and non-host alpha-defensins. Rotaviruses are important human pathogens and a deeper understanding of host factors that dictate their tropism is important for understanding transmission. These studies will combine biochemical and genetic approaches to identify alpha-defensin binding determinants on the viral capsids and to identify alpha-defensin properties that differentiate neutralizing and enhancing activities. We will also identify the mechanisms of rotavirus neutralization and enhancement. Finally, we will determine whether or not these mechanisms alter viral infection in vivo. To determine whether the antiviral mechanism that we have uncovered in our studies of adenovirus and HPV is general, we will also dissect the mechanism of parvovirus inhibition. Parvoviruses, particularly adeno- associated virus, are important viral vectors. In addition, there are well known (e.g., B19) and emerging (e.g., bocavirus) parvoviruses that are important human pathogens. These studies will be facilitated by high resolution structural studies of clinically relevant viral vectors. From these comparative studies of two disparate families of non-enveloped viruses in combination with our prior insights from human adenovirus and papillomavirus, we will gain a deeper understanding of the function of a critical component of the immune system that may be a common factor in the pathogenesis of many viruses. These studies may also aid in the development of alpha-defensins as therapeutics and inform vaccine design.

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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