title: Infection with a Mouse-Adapted Strain of the 2009 Pandemic Virus Causes a Highly Severe Disease Associated with an Impaired T Cell Response.
abstract: Despite a relatively low fatality rate, the 2009 H1N1 pandemic virus differed from other seasonal viruses in that it caused mortality and severe pneumonia in the young and middle-aged population (18-59 years old). The mechanisms underlying this increased disease severity are still poorly understood. In this study, a human isolate of the 2009 H1N1 pandemic virus was adapted to the mouse (MAp2009). The pathogenicity of the MAp2009 virus and the host immune responses were evaluated in the mouse model and compared to the laboratory H1N1 strain A/Puerto Rico/8/1934 (PR8). The MAp2009 virus reached consistently higher titers in the lungs over 14 days compared to the PR8 virus, and caused severe disease associated with high morbidity and 85% mortality rate, contrasting with the 0% death rate in the PR8 group. During the early phase of infection, both viruses induced similar pathology in the lungs. However, MAp2009-induced lung inflammation was sustained until the end of the study (day 14), while there was no sign of inflammation in the PR8-infected group by day 10. Furthermore, at day 3 post-infection, MAp2009 induced up to 10- to 40-fold more cytokine and chemokine gene expression, respectively. More importantly, the numbers of CD4+ T cells and virus-specific CD8+ T cells were significantly lower in the lungs of MAp2009-infected mice compared to PR8-infected mice. Interestingly, there was no difference in the number of dendritic cells in the lung and in the draining lymph node. Moreover, mice infected with PR8 or MAp2009 had similar numbers of CCR5 and CXCR3-expressing T cells, suggesting that the impaired T cell response was not due to a lack of chemokine responsiveness or priming of T cells. This study demonstrates that a mouse-adapted virus from an isolate of the 2009 pandemic virus interferes with the adaptive immune response leading to a more severe disease.
authors.affiliation: Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.affiliation: Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Québec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Morisseau
authors.affiliation: Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Québec, Canada.
authors.forename: Émilie
authors.initials: É
authors.lastname: Garneau
authors.affiliation: Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marois
authors.affiliation: Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cloutier
authors.affiliation: Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Québec, Canada.
authors.forename: Martin V
authors.initials: MV
authors.lastname: Richter
mesh_terms: D000222:Adaptation, Physiological / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000302:isolation & purification; D007251:Influenza, Human / Q000453:epidemiology / Q000821:virology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice / Q000276:immunology; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D058873:Pandemics; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology