MHV68 Latency Modulates the Host Immune Response to Influenza A Virus
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MHV68 Latency Modulates the Host Immune Response to Influenza A Virus Fumitake Saito,1 Toshihiro Ito,2 Judith M. Connett,3 Matthew A. Schaller,3 William F. Carson IV,3 Cory M. Hogaboam,3 Rosemary Rochford,4 and Steven L. Kunkel3,5
Abstract—Murine gammaherpesvirus 68 (MHV68) is a natural rodent pathogen that has been used as a model to study the pathogenesis of human gammaherpesviruses. Like other herpesviruses, MHV68 causes acute infection and establishes life-long latency in the host. Recently, it has been shown that mice latently infected with MHV68 have resistance to unrelated pathogens in secondary infection models. We therefore hypothesized that latent MHV68 infection could modulate the host response to influenza A virus. To test this hypothesis, mice were infected intranasally with influenza virus following the establishment of MHV68 latency. Mice latently infected with MHV68 showed significantly higher survival to influenza A virus infection than did PBS mock-infected mice. Latent MHV68 infection led to lower influenza viral loads and decreased inflammatory pathology in the lungs. Alveolar macrophages of mice latently infected with MHV68 showed activated status, and adoptive transfer of those activated macrophages into mice followed the infection with influenza A virus had significantly greater survival rates than control mice, suggesting that activated alveolar macrophages are a key mechanistic component in protection from secondary infections. KEY WORDS: gammaherpesvirus; influenza A virus; alveolar macrophages; neutrophils.
INTRODUCTION Humans in a natural environment are exposed to multiple pathogens, and face a constant risk of infection. It has been demonstrated that in certain cases infection with one pathogen can affect the immune response to subsequent infection with non-related pathogens, leading to “cross-protective immunity” or “heterologous immunity” [1–5]. This protective effect has been shown between diverse pathogens, including viruses, bacteria, and fungi. 1
Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan 2 Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan 3 Immunology Program, Department of Pathology, University of Michigan Medical School 4701 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA 4 Department of Immunol/Micro, SUNY Upstate Med Univ, Syracuse, NY, USA 5 To whom correspondence should be addressed at Immunology Program, Department of Pathology, University of Michigan Medical School 4701 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 481092200, USA. E-mail: [email protected]
Gammaherpesviruses such as Epstein-Barr virus (EBV) are double-stranded DNA viruses that are important pathogens in humans and animals. Most of the world’s population is latently infected with multiple herpesviruses; however, these infections are usually asymptomatic in immunocompetent persons. Murine gam
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