Rotavirus is the major cause of severe, life-threatening gastroenteritis in young children and animals. Rotaviruses are large (1000 Angstroms), complex, icosahedral assemblies. This virus has been the subject of extensive biochemical, genetic and structural studies because of its medical relevance, intriguing structural complexity, and unique strategies of replication and morphogenesis. Rotaviruses contain 11 segments of double-stranded RNA encapsidated within three concentric capsid layers. Of the 12 proteins encoded by the genome, six are structural (VP 1-7), and six are non-structural (NSP 1-6). In the last four years, we have made exciting new discoveries that have provided a better characterization of the rotavirus structure and a deeper insight into the structural basis of various virus functions such as trypsin-enhanced infectivity, virus assembly, endogenous transcription, and genome replication and packaging. These recent developments, together with other developments in the molecular biology of rotaviruses, have allowed us to plan more in-depth dissection of structure-function correlations in rotavirus using a combination of high-resolution cryo-EM and X-ray crystallographic techniques. The specific objectives of the proposed project are: 1) To further investigate the mechanism of protease-enhanced infectivity and spike assembly, and structural basis of receptor-mediated cell entry of rotavirus. 2) To further our understanding of the structural basis of endogenous transcription in rotavirus by characterizing the structural alterations in response to transcriptional activation using high-resolution cryo-EM techniques. 3) To dissect the structural mechanisms of rotavirus genome replication/packaging using X-ray crystallographic techniques. Our structural information in conjunction with continued advances in the molecular virology of rotavirus would have the potential to enhance the development of more effective methods of disease prevention and control. More importantly, we expect to continue to discover new fundamental structural information to help understand how these complex viruses gain entry into host cells, assemble, transcribe, replicate, and package their genomes.
| Ramani, Sasirekha; Stewart, Christopher J; Laucirica, Daniel R et al. (2018) Human milk oligosaccharides, milk microbiome and infant gut microbiome modulate neonatal rotavirus infection. Nat Commun 9:5010 |
| Criglar, Jeanette M; Anish, Ramakrishnan; Hu, Liya et al. (2018) Phosphorylation cascade regulates the formation and maturation of rotaviral replication factories. Proc Natl Acad Sci U S A 115:E12015-E12023 |
| Hu, Liya; Sankaran, Banumathi; Laucirica, Daniel R et al. (2018) Glycan recognition in globally dominant human rotaviruses. Nat Commun 9:2631 |
| Shanker, Sreejesh; Hu, Liya; Ramani, Sasirekha et al. (2017) Structural features of glycan recognition among viral pathogens. Curr Opin Struct Biol 44:211-218 |
| Ramani, Sasirekha; Hu, Liya; Venkataram Prasad, B V et al. (2016) Diversity in Rotavirus-Host Glycan Interactions: A ""Sweet"" Spectrum. Cell Mol Gastroenterol Hepatol 2:263-273 |
| Ogden, Kristen M; Prasad, B V Venkataram (2015) Quelling an innate response to dsRNA. Oncotarget 6:28535-6 |
| Hu, Liya; Ramani, Sasirekha; Czako, Rita et al. (2015) Structural basis of glycan specificity in neonate-specific bovine-human reassortant rotavirus. Nat Commun 6:8346 |
| Ogden, Kristen M; Hu, Liya; Jha, Babal K et al. (2015) Structural basis for 2'-5'-oligoadenylate binding and enzyme activity of a viral RNase L antagonist. J Virol 89:6633-45 |
| Criglar, Jeanette M; Hu, Liya; Crawford, Sue E et al. (2014) A novel form of rotavirus NSP2 and phosphorylation-dependent NSP2-NSP5 interactions are associated with viroplasm assembly. J Virol 88:786-98 |
| Venkataram Prasad, B V; Shanker, Sreejesh; Hu, Liya et al. (2014) Structural basis of glycan interaction in gastroenteric viral pathogens. Curr Opin Virol 7:119-27 |
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