| There are three types of influenza viruses (A, B and C).The type A can cause influenza pandemic. Low pathogenic avian influenza virus H6subtype is one of the most commonly recognized subtypes in birds in North America and Europe. This subtype has a broad host range, the epidemic and spread show upward. It can infect chickens, mice and mink directly, even can infect people. Thus, H6subtype AIV could constitute a potential pandemic threat to public health.Very little is known about the replicative capacity, immunogenicity, and correlates of protective immunity for H6AIV in mammals. People often because of its low pathogenicity ignore the potential harm to human health. The high level of homology of the internal protein genes of H6N1A/teal/Hong Kong/W312/97(teal/HK/97)-like viruses to those of the1997human H5N1viruses raises concerns about W312-like H6viruses. The continuing prevalence of H6viruses and frequently reasserts in avian populations highlight the potential for H6viruses and H6reassortants to cross the species barrier to infect humans and cause human-to-human transmission.In this study, we focus on the molecular mechanism of transmission and pathogenicity of H6subtype AIV to mammals. First, we analy the whole genome sequencing and evolution of the A/H6N1subtype avian influenza virus (A/Mallard/SanJiang/275/2007) and the biological characteristics of H6subtype AIV using mice and dogs for mammalian model. Second, H6subtype AIV cannot spread effectively in mammals, in order to study the transmission about H6subtype AIV further and potential pandemic threat to public health, we observe the reassortment of H1N1AIV which pandemic in2009and H6subtype AIV in mammals. Third, in order to investigate the genetic basis of H6subtype AIV pathogenicity in mammals, we generated a mouse-adapted H6subtype AIV that possessed significantly higher virulence than wide-type virus. Increased virulence was detectable after8sequential lung passages in mice. The amino acid which is critical for the increased pathogenicity of H6subtype AIV is detected in vivo and in vitro. This research obtains the following results:1. This study successfully sequence the completed genomes of A/H6N1subtype avian influenza virus (A/Mallard/SanJiang/275/2007) from duck and analy the origin and evolution of the strain, the source of this strain is complicated and easy to reassortant with other subtype influenza virus. Also, we found the mammalian model of A/H6N1subtype AIV by mice and dogs, analy the biological characteristics of A/H6N1subtype AIV. The A/H6N1subtype AIV can infect mammals and has the potential to cross the species barrier.2. We successfully establish the A/H6N1subtype AIV reverse genetics system, which settled the foundation for further research on pathogenicity and transmission mechanism. 3. The transmission of A/H6N1subtype avian influenza virus is studied:The A/H6N1subtype AIV cannot spread effectively in mammals by the guinea pig model. A/H6N1AIV and A/H1N1have good genetic compatibility in mammals, can reassortant in mammals. The H6subtype reassortant virus also cannot effectively contact transmission in mammals. This suggest the A/H6N1subtype AIV has the potential to spread, but needs the continue evolution and adaptation.4. The pathogenicity of A/H6N1subtype avian influenza virus is studied:Mice are ideal animal models for investigating pathogenic mechanisms of influenza viruses. We obtain3strains mouse-adapted H6subtype AIV after8lung passages in mice and analyze the whole genome sequence and biological characteristics. Two amino acid substitutions can enhance pathogenicity in the genome of H6subtype AIV. Assessments of replication in mice showed that PB2-E627K and PA-T97I increased virus replication, The PB2-E627K and PA-T97I amino acid substitution enhanced viral polymerase activity and replication. Thus, our results show that the combination of PB2-E627K and PA-T97I are critical for the pathogenicity of H6subtype AIV in mammalian host. |
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