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Principal Investigator: Bidadi Venkataram Prasad
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2022
Award: $642,137
Funding agency: National Institute of Allergy and Infectious Diseases
The long-term goal of our research is to understand the structural basis of the complex processes that regulate
the replication cycle of rotaviruses (RVs), which are the global pathogens causing life-threatening infantile
gastroenteritis. During 2013-2016, our studies have answered several questions we previously asked, raised
a new set of questions, and revealed novel concepts. As a result, we plan to pursue exciting new directions
during the MERIT extension period (2018-2023) through four new AIMS. In pursuing these AIMs, we will use
a multipronged approach involving glycan array screening, X-ray crystallography, single-particle cryo-EM,
cryo-electron tomography of RV-infected cells, and functional assays. In AIM1, considering that specific
recognition of host cell glycans is a critical factor in host cell attachment and cross-species transmission, we
will address new questions such as: (i) what is the glycan specificity in sialidase-insensitive animal RVs with
zoonotic potential?; (ii) do these viruses show similar correlated glycan specificity with the human RVs we
discovered in bovine and human P[11] RVs to cross the species barrier?; (iii) does glycan binding affect spike
structure in the intact virion to influence downstream cell entry processes?; and (iv) do VP8*-specific human
mAbs block glycan binding in human RVs?. In AIM 2, our goal is to understand the structural aspects of the
viral capping enzyme VP3, how it associates with the viral polymerase VP1 to gain insight into the mechanistic
basis of endogenous transcription, and the possible role of VP3 in capsid assembly and genome encapsidation
that occurs in the specialized replication factories called viroplasms. Experiments in AIM 3 are designed to
probe further into understanding protein-protein interaction networks that regulate viroplasm-associated
activities using structural techniques and cryo-ET of RV-infected cells at different time points post infection. In
AIM 4, our goal is to provide structure-based mechanistic insights into how RVs antagonize cellular antiviral
responses by understanding structural aspects of RV proteins such as NSP1 that inhibit IFN pathways and the
phosphodiesterase domain embedded in VP3 of group-A RVs that inactivates OAS/RNase-L pathway, and
the dsRNA-binding domain in NSP3 of group-C RVs that inhibits dsRNA-dependent protein kinase.
Terms: <0-11 years old><ATP-protein phosphotransferase><Acylneuraminyl hydrolase><Address><Affect><Animals><Anti-Viral Response><Antiviral Response><Assay><Attenuated><BCAR3><BCAR3 gene><Binding><Binding Sites><Bioassay><Biologic Assays><Biological Assay><Biology><Blood Group Antigens><Bovine Species><Breast Cancer Anti-Estrogen Resistance 3><Breast Cancer Anti-Estrogen Resistance 3 Protein><C-terminal><Capsid><Cattle><Cell Attachment><Cell Body><Cell-Matrix Adhesions><Cell-Matrix Junction><Cells><Child><Child Youth><Children (0-21)><Combining Site><Complex><Core Protein><Cryo-electron Microscopy><Cryo-electron tomography><Cryoelectron Microscopy><Crystallization><Cues><Diarrhea><Double-Stranded RNA><Drug Targeting><Electron Cryomicroscopy><Enzyme Gene><Enzymes><Event><Exhibits><Gametes><Gastroenteritis><Gene Transcription><Generations><Genes><Genetic Transcription><Genetic Translation><Genome><Genomics><Genotype><Germ Cells><Germ-Line Cells><Glycans><Goals><Grant><Host Defense><Hu-mABs><Human><IFN><IFN antagonist><Infection><Innate Immunity><Interferons><Kinase Family Gene><Lead><Life><Mediating><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutate><N-Acetylneuraminic Acids><N-Acylneuraminate Glycohydrolases><NSP1><NSP2><NSP3><Native Immunity><Natural Immunity><Neonatal><Neuraminidase><Non-Specific Immunity><Nonspecific Immunity><Novel SH2-Containing Protein 2><Oligosaccharide Sialidase><Pathogenesis><Pathway interactions><Pb element><Phosphodiesterases><Play><Polymerase><Polysaccharides><Predisposition><Process><Property><Protein Kinase><Proteins><RNA Binding><RNA Expression><RNA Nucleases><RNA bound><RNase><Reactive Site><Receptor Protein><Reproductive Cells><Research><Resolution><Ribonuclease Family Protein><Ribonucleases><Role><Rotavirus><Rotavirus Vaccines><SH2D3A><SH2D3A gene><SH2D3B><SH2D3C><SH2D3C gene><Serotyping><Sex Cell><Sialic Acids><Sialidase><Single Crystal Diffraction><Specificity><Structural Protein><Structure><Susceptibility><System><Techniques><Time><Transcription><Tropism><Vaccines><Variant><Variation><Viral><Virion><Virulence><Virus><Virus Particle><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><Zoonoses><Zoonotic><Zoonotic Infection><adaptive immunity><base><bovid><bovine><conformation><conformational conversion><conformational state><conformational transition><cow><cross-species spillover><cross-species transmission><cryo-EM><cryo-EM tomography><cryoEM><cryoEM tomography><cryoelectron tomography><design><designing><dsRNA><electron cryo-tomography><exo alpha sialidase><experiment><experimental research><experimental study><fascinate><glycogen synthase a kinase><heavy metal Pb><heavy metal lead><host jump><host switching><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><hydroxyalkyl protein kinase><infancy><infantile><initial cell><insight><interferon antagonist><interspecies transmission><mRNA Translation><neutralizing antibody><novel><particle><pathogen><pathway><phosphoric diester hydrolase><phosphorylase b kinase kinase><protein protein interaction><receptor><scaffold><scaffolding><screening><sexual cell><skills><social role><transmission across species><transmission between species><transmitted across species><transmitted between species><transmitted cross-species><youngster>