Pathogenesis of H7 influenza A viruses associated with disease in humans.

摘要

H7 influenza viruses of high and low pathogenicity from the Netherlands, Canada, the United States, and the United Kingdom have resulted in over 90 cases of confirmed human infection with one fatality since 2002. To better understand the pathogenesis of selected H7 viruses associated with disease in humans, we first examined their ability to cause disease in the mouse and ferret models. We found that viruses from the Eurasian lineage (Netherlands isolates) exhibited enhanced virulence in both models as compared with North American lineage (Canada and US isolates) viruses. One virus, A/NL/219/03, isolated from the fatal case, was highly lethal for mice and caused severe disease in ferrets, similar to highly pathogenic H5N1 viruses. Elucidation of the receptor binding preference of these H7 viruses revealed that viruses within the Eurasian lineage maintain the classic avian binding preference for α2-3 linked sialic acids (SA), while viruses within the North American lineage possess a hemagglutinin with increased affinity towards α2-6 linked SA, the receptor preferentially bound by human influenza viruses. These Eurasian lineage viruses were not able to transmit efficiently by direct contact in the ferret; however, we identified a low pathogenic North American H7N2 virus isolated from an individual with respiratory disease in New York in 2003, A/NY/107/03, which was capable of transmission in this species by direct contact.;Unlike highly pathogenic H5N1 viruses, the majority of human infections associated with H7 viruses have resulted in ocular and not respiratory disease. Following ocular inoculation of mice, we found that both Eurasian and North American lineage H7 viruses were capable of replicating to significant titers in the mouse eye, unlike H5N1 and human influenza viruses. However, selected highly pathogenic H7 and H5 viruses were able to spread systemically following ocular inoculation and mount a lethal infection in mice, demonstrating the ability of viruses within multiple subtypes to use the eye as a portal of entry. To explore other potential subtype-specific differences between highly pathogenic H5 and H7 viruses, we investigated the early activation of the innate immune responses following infection of both polarized human bronchial epithelial cells and primary monocyte-derived macrophages. We found that highly pathogenic H7N7 and H7N3 influenza viruses exhibited an attenuated type 1 IFN response in addition to delayed and weakened production of proinflammatory cytokines and chemokines early after infection compared with a highly pathogenic H5N1 virus.;Effective vaccines and antiviral drugs will be essential tools for the control of the next influenza pandemic. Because the hemagglutinin subtype of future pandemic strains cannot be known in advance, an antiviral drug (DAS181) that confers protection against multiple subtypes of influenza virus was evaluated in the context of a highly pathogenic virus infection and found to function effectively as a prophylactic.