Mechanism of Cytomegalovirus‐induced Mucosal Inflammation

University Of Alabama At Birmingham, Birmingham AL

Investigators

Abstract

Project Summary The mucosal immune response to CMV infection is severely altered in the setting of immunosuppression and in inflammatory bowel disease (IBD). The increasing use of immunosuppressive therapies to treat IBD will further increase the susceptibility for CMV mucosal disease, leading to IBD relapse, exacerbation, and resistance to medical therapy. Among immunosuppressed persons infected with CMV, the gastrointestinal tract is a major site of CMV infection, and intestinal macrophages play a central role in the inflammatory process. Paradoxically, intestinal macrophages in normal mucosa are uniquely and profoundly down-regulated for cytokine production (inflammation anergy). Resident intestinal macrophages are derived exclusively from blood monocytes that are recruited into the mucosa to replenish the resident macrophage population. Within the mucosa, extracellular matrix (stromal) products, including TGF-?, differentiate pro- inflammatory monocytes into inflammation anergic intestinal macrophages that are unable to activate NF-kB, inducing tolerance to bacterial products, as we have reported. I have shown that CMV infection of primary intestinal macrophages does not reverse inflammation anergy, but In sharp contrast, blood monocytes are markedly up-regulated for cytokine production after CMV infection. Accordingly, the central hypothesis of the proposed study is that CMV productively infects blood monocytes prior to their recruitment to the mucosa, and inhibits the differentiation of monocytes into inflammation anergic intestinal macrophages by hijacking the NF- ?B signal pathway, thereby potentiating and exacerbating cytokine responses in the mucosa. Using our established in vitro system to recapitulate monocyte-to-intestinal macrophage differentiation using cell-free stroma harvested from human intestinal tissue, I will (1) determine whether CMV inhibition of macrophage inflammation anergy is dependent on MyD88 and NF-?B-mediated signal transduction and (2) determine whether CMV replication is required to inhibit macrophage inflammation anergy and identify the CMV-encoded gene products that promote the retention of macrophage pro-inflammatory function in the mucosa. Successful completion of the proposed experiments will significantly advance our understanding of the factors that contribute to the development of CMV-associated inflammation and help develop mechanism-driven approaches to interdict CMV mucosal disease.