title: Heterogeneous pathological outcomes after experimental pH1N1 influenza infection in ferrets correlate with viral replication and host immune responses in the lung.
abstract: The swine-origin pandemic (p) H1N1 influenza A virus causes mild upper-respiratory tract disease in most human patients. However, some patients developed severe lower-respiratory tract infections with fatal consequences, and the cause of these infections remain unknown. Recently, it has been suggested that different populations have different degrees of susceptibility to pH1N1 strains due to host genetic variations that are associated with inappropriate immune responses against viral genetic characteristics. Here, we tested whether the pathologic patterns of influenza strains that produce different disease outcomes in humans could be reproduced in a ferret model. Our results revealed that the severities of infection did not correspond to particular viral isolate and were not associated with the clinical phenotypes of the corresponding patients. Severe pathological outcomes were associated with higher viral replication, especially in alveolar areas, and with an exacerbated innate cellular immune response that was characterised by substantial phagocytic and cytotoxic cell migration into the lungs. Moreover, detrimental innate cellular responses were linked to the up-regulation of several proinflammatory cytokines and chemokines and the down-regulation of IFNα in the lungs. Additionally, severe lung lesions were associated with greater up-regulations of pro-apoptotic markers and higher levels of apoptotic neutrophils and macrophages. In conclusion, this study confirmed that the clinicopathological outcomes of pH1N1 infection in ferrets were not only due to viral replication abilities but also depended on the hosts' capacities to mount efficient immune responses to control viral infection of the lung.
authors.affiliation: Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain ; Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Vidaña
authors.affiliation: Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain ; Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Martínez
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain.
authors.forename: Pamela
authors.initials: P
authors.lastname: Martínez-Orellana
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: García Migura
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain ; Institut de Recerca i Tecnologia Agroalimentaria (IRTA), Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Montoya
authors.affiliation: Departament de Medicina i Cirurgia Animals, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Martorell
authors.affiliation: Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain ; Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Bellaterra Spain.
authors.forename: Natàlia
authors.initials: N
authors.lastname: Majó
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005289:Ferrets; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008297:Male; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D014779:Virus Replication / Q000502:physiology*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D051193:Toll-Like Receptors