Many pathogens continuously evolve to exploit host glycans that are abundantly distributed on target tissues to gain entry and initiate infection. In this class of pathogens is the Influenza A virus (IAV), which continues to pose annual pandemic risks and exerts a heavy financial burden on the US economy. Rapid detection of emerging phenotypic changes in IAV specificity for distinct host glycan classes can provide anearly indication of virus transmissibility and an assessment of infection potential at the onset of an outbreak. Currently, tech- niques that connect a phenotypic adaptation to a direct genomic change are time-, cost- and labor-intensive, causing significant delays in identification of unexpected new viral strains. Such delays may preclude timely production of vaccines and formulation of effective responses by health officials and agencies, often with disas- trous effects. Here we propose a new glycan array platform to rapidly identify genetic alterations underlying distinct shifts in glycan specificity in IAVs in primary isolates. We plan to achieve the high sensitivity required to detect low abundance viruses in these arrays by presenting glycans in synthetic polyvalent ligands with en- hanced avidity toward IAVs and by developing new detection reagents that utilize the activity of viral neurami- dase enzymes for signal amplification. Finally, we will develop microarray substrates that enable the collection and sequencing of captured IAVs based on their unique glycan-binding phenotype. We anticipate that charac- terization of IAV populations driven by their glycan binding phenotype that obviates the need for virus amplifi- cation prior to analysis will provide more efficient and accurate determination of viral strains with increased pandemic risks. The proposed glycan array and detection methods will provide a general tool that could be rapidly extended to other classes of pathogens that utilize glycan interactions to enter their hosts organism.

Public Health Relevance

Among the characteristics of an infectious phenotype in pathogens, such as the Influenza A virus (IAV), is their ability to engage specific glycan structures on host cells to gain entry and initiate infection. This proposal seeks to develop a new glycan array platform to link phenotypic adaptation in IAV populations with underlying ge- nomic changes. This technology would provide rapid assessment of pandemic risks and aid in the formulation of effective responses in emerging IAV strains.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Krafft, Amy
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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Huang, Mia L; Tota, Ember M; Verespy 3rd, Stephen et al. (2018) Glycocalyx Scaffolding to Control Cell Surface Glycan Displays. Curr Protoc Chem Biol 10:e40
Godula, Kamil (2018) Following sugar patterns in search of galectin function. Proc Natl Acad Sci U S A 115:2548-2550
Huang, Mia L; Purcell, Sean C; Verespy III, Stephen et al. (2017) Glycocalyx scaffolding with synthetic nanoscale glycomaterials. Biomater Sci 5:1537-1540