Host Inflammatory Responses to Adenovirus Respiratory Infection.

virus;pathogenesis;respiratory infection;myocarditis;mouse adenovirus type 1;Microbiology and Immunology;Health Sciences;Microbiology and Immunology

McCarthy, Mary KatherineSpindler, Katherine ;

University of Michigan

关键词: virus;    pathogenesis;    respiratory infection;    myocarditis;    mouse adenovirus type 1;    Microbiology and Immunology;    Health Sciences;    Microbiology and Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/110390/mkmccar_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Adenoviruses are common causes of acute respiratory infection and myocarditis. It is unclear if manifestations of adenovirus disease are mediated by virus-induced tissue damage or the host immune response to the virus. The main focus of this dissertation was to identify host factors that regulate inflammatory responses and contribute to pathogenesis of acute adenovirus respiratory infection. Due to the species-specificity of adenoviruses, which precludes animal studies with a human adenovirus, I used mouse adenovirus type 1 (MAV-1) to study the pathogenesis of an adenovirus in its natural host.PGE2 is a lipid mediator that promotes expression of a variety of cytokines during acute MAV-1 infection but is not essential for pulmonary immunity to MAV-1. IL-17, a cytokine that is induced during MAV-1 infection and can be upregulated by PGE2, is likewise not essential for control of virus infection or for virus-induced pulmonary inflammation. Exaggerated PGE2 production in hematopoietic stem cell transplantation has been linked to increased susceptibility to infections. Bone marrow transplant (BMT) mice display exaggerated PGE2 production and delayed MAV-1 clearance from the lungs. BMT-induced T cell dysfunction likely contributes to impaired virus clearance but is independent of PGE2 overproduction. Adenoviruses are also important causes of myocarditis. I used MAV-1 to establish a model of adenovirus myocarditis in neonatal mice. IFN-gamma is a proinflammatory mediator during MAV-1 myocarditis, and MAV-1 persistence contributes to ongoing cardiac dysfunction. IFN-gamma is important for induction of the immunoproteasome, a specialized type of proteasome that regulates inflammatory responses, following MAV-1 infection. Inhibition of the constitutive proteasome or the immunoproteasome impairs induction of some proinflammatory cytokines during MAV-1 myocarditis. We have gained insight into contributions of various host factors to MAV-1 acute disease and persistence that may aid the development of alternatives to antiviral drugs for treatment of patients with adenovirus infection. Suppressing some host responses during acute infection may be useful to prevent excess inflammation without affecting antiviral immunity. In immunocompromised hosts, interventions to restore anti-adenoviral immunity could prevent disease associated with excess viral replication. Finally, approaches to prevent or clear adenovirus persistence may lessen the impact of adenovirus-associated chronic disease.