Influenza virus causes worldwide seasonal infections and occasional pandemics with high mortality rate. Human viruses are known to have a preference for ?2-6 linked sialic acids (NeuAc?2-6Gal), while avian viruses exhibit a preferenc for ?2-3 linked sialic acids (NeuAc?2-3Gal). This difference in receptor specificity is widely considered a major species barrier for transmission of avian viruses in the human population. Although this binary model of receptor specificity has been useful, it belies the true complexity o sialic acid containing glycans on host cells, it has becoming increasingly limiting since recent influenza viruses exhibit mixed specificities that are not distinct from avian viruses using standard assays of assessing receptor specificity. The use of glycan microarrays with dozens of ?2-3 and ?2-6 linked glycans has revealed that influenza viruses exhibit dramatic differences i their ability to recognize individual glycans within those broad groups. However, interpretation of these findings is confounded by the fact that there is little information on the types of glycans that are actually present on human airway epithelium, and whether the relevant glycans are represented on glycan microarrays. To address this gap in knowledge, we intend to 1) analyze the glycan structures on human airway epithelial cells, 2) to build a synthetic library of these glycans for constructing a custom glycan microarray, and 3) to evaluate the specificity of human influenza virus hemagglutinins (HAs) and neuraminidases (NAs) to identify receptor-binding properties that support their ability to transmit in humans. This information will identify recepto determinants on the human airway that are shared by human influenza viruses that transmit in the human population, and shed light on properties of the HA and NA that contribute to pandemic risk of influenza viruses from avian viruses that occasionally infect humans.

Public Health Relevance

This project will analyze the glycan structures of human airway epithelial cells to identify candidate receptors of influenza viruses. Candidate receptor glycans will be synthesized, elaborated on a glycan microarray, and used to survey the specificities of human and avian influenza viruses to define the role of airway receptors as a barrier for transmission of avian viruses in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI114730-01A1
Application #
8963149
Study Section
Virology - A Study Section (VIRA)
Program Officer
Hauguel, Teresa M
Project Start
2015-09-03
Project End
2020-02-29
Budget Start
2015-09-03
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
$316,948
Indirect Cost
$142,988
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yang, Yi-An; Lee, Sohyoung; Zhao, Jun et al. (2017) In vivo tropism of Salmonella Typhi toxin to cells expressing a multiantennal glycan receptor. Nat Microbiol :
Tzarum, Netanel; McBride, Ryan; Nycholat, Corwin M et al. (2017) Unique Structural Features of Influenza Virus H15 Hemagglutinin. J Virol 91:
Guo, Hongbo; de Vries, Erik; McBride, Ryan et al. (2017) Highly Pathogenic Influenza A(H5Nx) Viruses with Altered H5 Receptor-Binding Specificity. Emerg Infect Dis 23:220-231
Wu, Nicholas C; Zost, Seth J; Thompson, Andrew J et al. (2017) A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLoS Pathog 13:e1006682
Wu, Nicholas C; Xie, Jia; Zheng, Tianqing et al. (2017) Diversity of Functionally Permissive Sequences in the Receptor-Binding Site of Influenza Hemagglutinin. Cell Host Microbe 22:247-248
de Vries, Robert P; Tzarum, Netanel; Peng, Wenjie et al. (2017) A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human-type receptors. EMBO Mol Med 9:1314-1325
Zanin, Mark; Ko├žer, Zeynep A; Poulson, Rebecca L et al. (2017) Potential for Low-Pathogenic Avian H7 Influenza A Viruses To Replicate and Cause Disease in a Mammalian Model. J Virol 91:
Peng, Wenjie; de Vries, Robert P; Grant, Oliver C et al. (2017) Recent H3N2 Viruses Have Evolved Specificity for Extended, Branched Human-type Receptors, Conferring Potential for Increased Avidity. Cell Host Microbe 21:23-34
Tzarum, Netanel; de Vries, Robert P; Peng, Wenjie et al. (2017) The 150-Loop Restricts the Host Specificity of Human H10N8 Influenza Virus. Cell Rep 19:235-245
Dai, Meiling; McBride, Ryan; Dortmans, Jos C F M et al. (2017) Mutation of the Second Sialic Acid-Binding Site, Resulting in Reduced Neuraminidase Activity, Preceded the Emergence of H7N9 Influenza A Virus. J Virol 91:

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