AEROMONAS IMMUNE MODULATOR PROTEINS INTERACT WITH HOST LIPOCALIN-2 TO MEDIATE INFLAMMATION THROUGH BOTH HOST- AND MICROBIOME-SPECIFIC MECHANISMS

Abstract Inflammatory bowel diseases (IBD) are a prevalent and growing clinical health problem worldwide. The etiology of IBD involves complicated interactions between immunological genetic variants, environmental factors, and the intestinal microbiome. Current therapies for IBD include corticosteroids and biologics, which can ameliorate overproduction of pro-inflammatory cytokines, and other inflammatory mediators, but which do not treat the microbiome dysbiosis that often triggers or propagates inflammation. Therefore, an urgent need exists for more effective therapies for IBD that treat both inflammation and microbiome dysbiosis. Health-associated microbes are under-explored sources of mechanisms that maintain tissue and immune homeostasis. Our research team at the University of Oregon has identified a novel family of anti-inflammatory proteins secreted by a zebrafish gut symbiont, Aeromonas, which we named Aeromonas immune modulator (Aim) proteins. Host Lipocalin-2 (LCN2) limits the growth of tissue-resident microbes through sequestration of iron, an essential micronutrient, by binding bacterial iron-laden siderophore molecules. Aim proteins allow the zebrafish symbiont Aeromonas to overcome this LCN2-mediated iron starvation. Structurally, Aim proteins contain lipocalin folds and we discovered that Aims and LCN2 physically interact, suggesting that Aim proteins allow Aeromonas to recapture siderophores sequestered by LCN2. In addition to supporting the growth of Aeromonas in the zebrafish intestine, Aim proteins decrease host tissue inflammation both in microbially-induced and injury models. In the context of infection with a zebrafish pathogenic Vibrio, Aim proteins decrease tissue inflammation while simultaneously increasing Vibrio growth, suggesting that Vibrio exploits Aim proteins to overcome nutritional immunity and down-regulate programs of tissue destruction. In addition to siderophores, LCN2 and other LCNs binds a wide array of hydrophobic molecules, including immunomodulatory lipid hormones such as prostaglandins. We hypothesize that Aim proteins exert their diverse effects on bacterial growth and tissue homeostasis through their binding to LCN2 and other LCNs. This work suggests a new molecular mechanisms through which resident microbes promote tissue homeostasis by counteracting nutritional immunity, alleviating bacterial tissue destruction, and dampening the action of pleotropic host immunomodulatory LCNs. Furthermore, Aim proteins have the potential to be developed as a novel therapeutic for IBD, unique in its ability to both target a primary mediator of inflammation, neutrophils, and facilitate restoration of microbiome dysbiosis.