title: Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract.
abstract: Factors from the virus and the host contribute to influenza virus pathogenicity and to the development of immunity. This study thoroughly examined the effects of an initial infectious dose of virus and unveiled new findings concerning the antiviral and inflammatory responses, innate and adaptive immunity, memory responses, and protection against secondary heterologous infection. Our results demonstrated that the initial infectious dose significantly affects the gene expression of antiviral (IFN-β) and inflammatory (TNF-α, IL-6, IL-1β) cytokines and of enzymes involved in nitrosative/oxidative stress (iNOS, HO-1, NQO1) early in the response to influenza. This response correlated with significantly increased recruitment of innate immune cells into the lungs of infected mice. We showed that this response also alters the subsequent accumulation of activated IFN-γ(+) CD44(hi) CD62L(lo) influenza-specific CD8(+) T cells into the lungs of infected mice through increased T cell-recruiting chemokine gene expression (CCL3, CCL4, CCL5, CXCL10). Furthermore, we demonstrated that the initial infectious dose determines the generation and the distribution of memory CD8(+) T cell subsets without affecting trafficking mechanisms. This impacted on immune protection against heterologous infection. Lastly, we showed that the effects on innate and adaptive immunity were not dependent on influenza strain or on the genetic background of the host. Collectively, our data show for the first time and in detail that the initial infectious dose of influenza determines the development of several aspects of antiviral immunity. This study provides new insights on virus-host interaction in the generation of the global immune response to influenza.
authors.affiliation: Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centrede Recherche Clinique Étienne-Le Bel, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marois
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cloutier
authors.forename: Émilie
authors.initials: É
authors.lastname: Garneau
authors.forename: Martin V
authors.initials: MV
authors.lastname: Richter
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000821:virology; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009975:Orthomyxoviridae / Q000472:pathogenicity; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D014779:Virus Replication
chemical_list: D016207:Cytokines; D012333:RNA, Messenger