期刊
JOURNAL OF VIROLOGY
卷 85, 期 24, 页码 13195-13203出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00859-11
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资金
- National Institute of General Medical Sciences [GM62116]
- National Institute of Allergy and Infectious Diseases
- Public Health Service
- NIAID
- Center for Research on Influenza Pathogenesis (CRIP) [HHSN266200700010C]
- Founding Research Centers for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science, and Technology
- Ministry of Health
- ERATO (Japan Science and Technology Agency)
- NIH National Center for Research Resources [P51 RR000167]
- Wisconsin National Primate Research Center
- National Heart, Lung and Blood Institute [1U01AI082982]
- U.S. Army Medical Research and Material Command [W81XWH-07-1-0550]
- Grants-in-Aid for Scientific Research [10J04699, 22790425] Funding Source: KAKEN
The first influenza pandemic of the 21st century was caused by novel H1N1 viruses that emerged in early 2009. An Asp-to-Gly change at position 222 of the receptor-binding protein hemagglutinin (HA) correlates with more-severe infections in humans. The amino acid at position 222 of HA contributes to receptor-binding specificity with Asp (typically found in human influenza viruses) and Gly (typically found in avian and classic H1N1 swine influenza viruses), conferring binding to human-and avian-type receptors, respectively. Here, we asked whether binding to avian-type receptors enhances influenza virus pathogenicity. We tested two 2009 pandemic H1N1 viruses possessing HA-222G (isolated from severe cases) and two viruses that possessed HA-222D. In glycan arrays, viruses possessing HA-222D preferentially bound to human-type receptors, while those encoding HA-222G bound to both avian-and human-type receptors. This difference in receptor binding correlated with efficient infection of viruses possessing HA-222G, compared to those possessing HA-222D, in human lung tissue, including alveolar type II pneumocytes, which express avian-type receptors. In a nonhuman primate model, infection with one of the viruses possessing HA-222G caused lung damage more severe than did infection with a virus encoding HA-222D, although these pathological differences were not observed for the other virus pair with either HA-222G or HA-222D. These data demonstrate that the acquisition of avian-type receptor-binding specificity may result in more-efficient infection of human alveolar type II pneumocytes and thus more-severe lung damage. Collectively, these findings suggest a new mechanism by which influenza viruses may become more pathogenic in mammals, including humans.
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