Alpha-defensin-dependent enhancement of enteric viral infection

• Published in: PLoS pathogens 2017-06, Vol.13 (6), p.e1006446-e1006446
• Main Authors: Wilson, Sarah S, Bromme, Beth A, Holly, Mayumi K, Wiens, Mayim E, Gounder, Anshu P, Sul, Youngmee, Smith, Jason G
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - physiology; Adenoviridae Infections - virology; Adenoviruses; alpha-Defensins - genetics; alpha-Defensins - metabolism; Animals; Antimicrobial peptides; Antiviral agents; Biology and Life Sciences; Cell culture; Cell surface; Defensins; Dendritic cells; Epithelium; Female; Health services; Host-Pathogen Interactions; Humans; In vitro methods and tests; Infections; Infectious diseases; Inoculation; Intestine; Intestine, Small - metabolism; Intestine, Small - virology; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Oral infection; Pathogens; Peptides; Proteins; Public health; Research and Analysis Methods; Shedding; Small intestine; Stem cells; Studies; Viral infections; Virus diseases; Virus Shedding; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006446

The small intestinal epithelium produces numerous antimicrobial peptides and proteins, including abundant enteric α-defensins. Although they most commonly function as potent antivirals in cell culture, enteric α-defensins have also been shown to enhance some viral infections in vitro. Efforts to determine the physiologic relevance of enhanced infection have been limited by the absence of a suitable cell culture system. To address this issue, here we use primary stem cell-derived small intestinal enteroids to examine the impact of naturally secreted α-defensins on infection by the enteric mouse pathogen, mouse adenovirus 2 (MAdV-2). MAdV-2 infection was increased when enteroids were inoculated across an α-defensin gradient in a manner that mimics oral infection but not when α-defensin levels were absent or bypassed through other routes of inoculation. This increased infection was a result of receptor-independent binding of virus to the cell surface. The enteroid experiments accurately predicted increased MAdV-2 shedding in the feces of wild type mice compared to mice lacking functional α-defensins. Thus, our studies have shown that viral infection enhanced by enteric α-defensins may reflect the evolution of some viruses to utilize these host proteins to promote their own infection.