Human adaptation of avian influenza viruses
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2012.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2013
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| Online Access: | http://hdl.handle.net/1721.1/78139 |
| _version_ | 1826216456529903616 |
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| author | Srinivasan, Karunya |
| author2 | Ram Sasisekharan. |
| author_facet | Ram Sasisekharan. Srinivasan, Karunya |
| author_sort | Srinivasan, Karunya |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2012. |
| first_indexed | 2024-09-23T16:47:41Z |
| format | Thesis |
| id | mit-1721.1/78139 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T16:47:41Z |
| publishDate | 2013 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/781392019-04-12T20:18:32Z Human adaptation of avian influenza viruses Srinivasan, Karunya Ram Sasisekharan. Massachusetts Institute of Technology. Dept. of Biological Engineering. Massachusetts Institute of Technology. Dept. of Biological Engineering. Biological Engineering. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2012. Cataloged from PDF version of thesis. Includes bibliographical references. Human adaptation of avian influenza viruses pose an enormous public health challenge as the human population is predominantly naive to avian influenza antigens. As such, constant surveillance is needed to monitor the circulating avian strains. Of particular importance are strains belonging to H5N1, H7N7, H7N2 and H9N2 subtypes that continue to circulate in birds worldwide and have on occasions caused infections in humans. A key step in influenza human adaptation is the accumulation of substitutions/mutations in the viral coat glycoprotein, hemagglutinin (HA), that changes HA's binding specificity and affinity towards glycan receptors in the upper respiratory epithelia (referred to as human receptors). Unlike for the H1, H2, H3 and more recently H5 HA a correlation between the quantitative binding of HA to human receptors and respiratory droplet transmissibility has not been established for H9 and H7 subtypes. This thesis is a systematic investigation of determinants that mediate changes in HA-glycan receptor binding specificity, with focus on the molecular environments within and surrounding the glycan receptor binding site (RBS) of avian HAs, particularly the H9 and H7 subtypes. The glycan receptor binding properties of HA were studied using a combination of biochemical and molecular biology approaches including dose dependent glycan binding, human tissue staining and structural modeling. Using these complementary analyses, it is shown that molecular interactions between amino acids in and proximal to the RBS, including interactions between the RBS and the glycan receptor converge to provide high affinity binding of avian HA to human receptors. For the H9 HA [alpha]2-->6 glycan receptor-binding affinity of a mutant carrying Thr-189-->Ala amino acid change correlated with the respiratory droplet transmission in ferrets conferred by this change. Further, it was demonstrated for the first time that two specific mutations; Gln226-->Leu and Gly228-->Ser in glycan receptor-binding site of H7 HA substantially increase its binding affinity to human receptors. These approaches and findings contribute to a framework for monitoring the evolution of HA and the development of general rules that govern human adaption applicable to strains beyond ones currently under study. by Karunya Srinivasan. Ph.D. 2013-03-28T18:07:30Z 2013-03-28T18:07:30Z 2012 2012 Thesis http://hdl.handle.net/1721.1/78139 828925791 eng MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 114 p. application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biological Engineering. Srinivasan, Karunya Human adaptation of avian influenza viruses |
| title | Human adaptation of avian influenza viruses |
| title_full | Human adaptation of avian influenza viruses |
| title_fullStr | Human adaptation of avian influenza viruses |
| title_full_unstemmed | Human adaptation of avian influenza viruses |
| title_short | Human adaptation of avian influenza viruses |
| title_sort | human adaptation of avian influenza viruses |
| topic | Biological Engineering. |
| url | http://hdl.handle.net/1721.1/78139 |
| work_keys_str_mv | AT srinivasankarunya humanadaptationofavianinfluenzaviruses |