Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Given the various tools that were developed to study Glycosaminoglycan (GAG) mixtures (specific aims 1), studying glycan mixtures in the context of glycans present in the upper airways became an obvious extension of this work. The glycan mixtures - especially the sialylated glycans present in the epithelial cells- provided the important reference point to these being critical receptors for Influenza A viruses. We had furthermore established a foundation to study the protein-GAG interactions, using various GAG degrading enzymes over the years. Based on the fact that many of these enzymes, and other GAG or glycan binding proteins, have poor sequence identity [this includes key sulfatases, fibroblast growth factors or influenza virus hemagglutinin (HA)], we developed newer tools to study GAG-protein interactions, which were broadly applicable to protein-glycan interactions. Newer analytical and structural tools were developed under specific aims 1 and as part of specific aims 2. We developed not only GAG/glycan databases, but also protein structural databases to study the diversity of glycan- protein interactions. Integration of these two approaches-glycan conformation coupled with protein structure and database-enabled us to tackle a fundamental question related to glycan specificity of influenza A viruses, which turned out to be the ideal model system to validate our approach. Given extensive glycan diversity and the mixture of glycans present in the apical epithelium, for the first time we demonstrated that glycan topology is a key determinant for human adaptation of influenza viruses (published in Nature Biotechnology). Our prediction that the then emerging 2009 H1N1 """"""""swine flu"""""""" virus was not efficient in transmission (published in Science 2009) was further validated and observed due to poor transmission of this virus in humans (published in NEJM 2009). More recently, with the outbreak of the 2013 H7N9, we rapidly investigated the receptor specificity of the H7N9 HA and published our observations (along with our predictions on H5N1) back-to-back in the journal Cell. The R37 grant application will address key questions related to glycan topology and HA binding using complementary analytical and structural approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM057073-17
Application #
8730159
Study Section
Instrumentation and Systems Development Study Section (ISD)
Program Officer
Marino, Pamela
Project Start
1998-02-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
17
Fiscal Year
2014
Total Cost
$380,211
Indirect Cost
$132,711
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Tharakaraman, Kannan; Sasisekharan, Ram (2015) Influenza surveillance: 2014-2015 H1N1 ""swine""-derived influenza viruses from India. Cell Host Microbe 17:279-82
Zhu, Xueyong; Viswanathan, Karthik; Raman, Rahul et al. (2015) Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants. Cell Rep 13:1683-91
Lakdawala, Seema S; Jayaraman, Akila; Halpin, Rebecca A et al. (2015) The soft palate is an important site of adaptation for transmissible influenza viruses. Nature 526:122-5
Tharakaraman, Kannan; Subramanian, Vidya; Viswanathan, Karthik et al. (2015) A broadly neutralizing human monoclonal antibody is effective against H7N9. Proc Natl Acad Sci U S A 112:10890-5
Shriver, Zachary; Sasisekharan, Ram (2015) Capillary electrophoretic analysis of isolated sulfated polysaccharides to characterize pharmaceutical products. Methods Mol Biol 1229:161-71
Robinson, Luke N; Tharakaraman, Kannan; Rowley, Kirk J et al. (2015) Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope. Cell 162:493-504
Elli, Stefano; Macchi, Eleonora; Rudd, Timothy R et al. (2014) Insights into the human glycan receptor conformation of 1918 pandemic hemagglutinin-glycan complexes derived from nuclear magnetic resonance and molecular dynamics studies. Biochemistry 53:4122-35
Raman, Rahul; Tharakaraman, Kannan; Shriver, Zachary et al. (2014) Glycan receptor specificity as a useful tool for characterization and surveillance of influenza A virus. Trends Microbiol 22:632-41
Tharakaraman, Kannan; Subramanian, Vidya; Cain, David et al. (2014) Broadly neutralizing influenza hemagglutinin stem-specific antibody CR8020 targets residues that are prone to escape due to host selection pressure. Cell Host Microbe 15:644-51
Tharakaraman, Kannan; Jayaraman, Akila; Raman, Rahul et al. (2013) Glycan receptor binding of the influenza A virus H7N9 hemagglutinin. Cell 153:1486-93

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