surviving mousepox infection requires the complement system幸存的鼠痘感染需要补充系统.pdfVIP

Surviving Mousepox Infection Requires the Complement System 1 1 2 Elizabeth A. Moulton , John P. Atkinson , R. Mark L. Buller * 1 Rheumatology Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America, 2 Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, Saint Louis, Missouri, United States of America Abstract Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host’s immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3 2/ 2 mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C32/ 2 mice. In vitro, the ¨ complement system in naıve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral disseminat