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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-014-0085-8) contains supplementary material, which is available to authorized users.
Highlights
In 2009, the swine-origin H1N1 influenza A virus (IAV) emerged and caused outbreaks of respiratory illness in humans around the world, and the World Health Organisation (WHO) declared a worldwide pandemic [1]
It has been suggested that genetic polymorphisms that affect the polymerase complex and the hemagglutinin (HA) subunit may contribute to the pathogenicity of certain pandemic H1N1 (pH1N1) strains by conferring on them the ability to produce higher viral titres or the ability to replicate over a prolonged period of time [9,10]
The pathogenic features of severe IAV infection result from complex and dynamic processes that involve various components of the host immune system and their responses to virus-induced changes. Understanding both virus and host response characteristics in individuals who develop mild or severe disease is important for the future development of therapeutic strategies for cases of severe influenza infection
Summary
In 2009, the swine-origin H1N1 influenza A virus (IAV) emerged and caused outbreaks of respiratory illness in humans around the world, and the World Health Organisation (WHO) declared a worldwide pandemic [1]. In contrast to seasonal influenza, which is more likely to cause severe illness in the elderly, children and immunocompromised patients, the pandemic H1N1 (pH1N1) caused serious disease in young adults and previously. The striking heterogeneity of the clinicopathological outcomes observed after pH1N1 infection in humans lead to numerous studies initially focused on the impact of viral evolution and mutation on the virulence of the infection. Virulence markers have been mapped to the polymerase genes (PB1, PB2 and PA), neuraminidases (NAs), and the non-structural proteins (NS1s) of the highly pathogenic avian influenza viruses and the 1918 pandemic H1N1 strains [8]. The importance of these mutations in the pathogenicity of pH1N1 still needs to be clarified [11]
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