The human intestine is colonized by a diverse array of nearly 100 trillion bacteria that are essential for health and are in constant contact with the host. As a result, human gut epithelial cells have adapted an array of strategies for diminishing bacterial cell contact and further invasion, thus preserving a mutually beneficial host- micro biot relationship. An unregulated host response of microbe-epithelia interactions results in inflammation and can lead to chronic diseases such as inflammatory bowel diseases (IBD). To protect its epithelial surface, the host initially responds by secreting an array of antimicrobial proteins that function to modulate the composition of intestinal bacterial communities and restrict their interactions with host tissues. The research outlined in this proposal will test the hypothesis that resistin-like molecule (RELM beta) also functions as an antimicrobial protein that limits microbial interaction with intestinal epithelial cells. This hypothesis is based on extensiv preliminary data that suggest an antimicrobial function for RELM beta. This proposal will 1) Determine the biological function of RELM beta using in vitro approaches;and 2) Determine the function of RELM beta in regulating host-pathogen interactions in vivo. These studies should shed light on the mechanism of host protection by RELM beta and how a deficiency of this protein can remodel the microbial community, thereby changing the nature of the host-micro biome relationship. Furthermore, these studies will likely contribute to our understanding of how innate immunity contributes to maintaining a healthy and symbiotic intestinal micro biota.
Commensal intestinal microbes typically establish and maintain symbiotic relationships with their hosts by producing nutrients and small molecules that are beneficial to human health. To maintain stability of this mutually-beneficial relationship, the host produces antimicrobial proteins to deter deleterious microbial strains from invading intestinal tissues and causing disease. This proposal aims at demonstrating the role of resistin- like molecule (RELM beta) in the antimicrobial defense of intestinal epithelial surfaces in humans and other mammals.
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