Modulation of adenovirus pathogenesis by prostaglandin E2

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DESCRIPTION (provided by applicant): Adenoviruses are common causes of respiratory infections. Adenovirus infections present with syndromes that range from mild upper respiratory tract infections to more severe, sometimes life-threatening manifestations. Immunocompromised patients are at risk for greatly increased morbidity and mortality from adenovirus infections. Adenovirus-induced pulmonary inflammation serves a protective role, aiding in the clearance of virus from the lungs. Adenovirus-induced inflammation also can be harmful; leading to damage that contributes to long-term residual lung disease. Prostaglandin E2 (PGE2) is a lipid-derived mediator that exerts a variety of effects on host immune function, in many cases via receptors that increase intracellular cAMP levels. PGE2 serves a variety of immunomodulatory functions, coordinating immune responses that protect from a pathogen while dampening inflammation in an effort to limit any lasting damage to the host. On the other hand, exaggerated PGE2 production in a mouse model of bone marrow transplantation (BMT) has been shown to result in an immunosuppressed state that increases the transplanted host's susceptibility to bacterial infection. Studies of human adenovirus pathogenesis are limited by the strict species specificity of the adenoviruses. As a consequence, very little is known about how PGE2 is stimulated by adenovirus infection and whether PGE2 modulates adenovirus pathogenesis. Mouse adenovirus type 1 (MAV-1) serves as an excellent model system to study the pathogenesis of an adenovirus in its natural host. This proposal uses MAV-1 to study interactions between PGE2 and adenovirus infection, characterizing the role of PGE2 in an immunocompetent host infected with an adenovirus and defining mechanisms by which PGE2 overproduction following BMT tips the scale towards immune dysfunction and enhanced adenovirus disease. Using a combination of in vitro and in vivo approaches, the research outlined in this proposal tests the hypothesis that a) PGE2 is an important factor regulating inflammatory responses that contribute to the pathogenesis of acute adenovirus respiratory infection in an immunocompetent host, but b) exaggerated PGE2 production induced by BMT increases host susceptibility to an adenovirus. These studies will provide detailed information regarding host immune function and adenovirus pathogenesis. In addition, we anticipate that the results of our work will contribute to the development of antiviral treatment strategies based on drugs that modulate PGE2 production, some of which are already approved for other indications. Because drugs used to treat adenovirus infections are limited in number and efficacy, novel strategies such as these will be important additions to the care of patients infected with adenoviruses. PUBLIC HEALTH RELEVANCE: Adenovirus infections cause substantial morbidity and mortality, particularly in immunocompromised patient populations. The results of this work will provide detailed information about the role of prostaglandin E2 in interactions between host immune function and adenovirus infection. We anticipate that our research will contribute to the development of antiviral treatment strategies based on drugs that modulate prostaglandin production.