Sarah McDonald, PhD
Assistant Professor, Virginia Tech Carilion Research Institute
Assistant Professor, Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine
Assistant Professor of Medicine (Infectious Disease), Virginia Tech Carilion School of Medicine
Research Program Summary
RNA viruses are ubiquitous in nature, infecting every known organism on the planet. These viruses can also be notorious human pathogens with significant medical and economic burdens. The mission of the McDonald laboratory is to acquire fundamental mechanistic information about RNA virus biology that can be applied to the prevention and treatment of disease. Our primary research efforts focus on rotaviruses, which are eleven-segmented, double-stranded RNA viruses that cause life-threatening diarrhea and vomiting in young children. By combining sequenced-based and structure-function approaches, we are elucidating key events in the rotavirus lifecycle and tracking changes in the rotavirus genome during its spread in the human population. Specifically, our work involves two distinct yet interconnected projects:
Project 1: Rotavirus Genome Replication and Virion Assembly. The capacity of any virus to establish a productive infection and cause disease in humans requires that it (i) replicate its nucleic acid genome, (ii) assemble nascent virion particles, and (iii) coordinate these processes within the cell to maximize efficiency and avert cell-intrinsic defenses. Rotavirus represents an attractive experimental model to study how viral genome replication and virion assembly are coordinated, because it performs these tasks concurrently during its lifecycle. The overall objective of this research project is to provide insight into the early stages of rotavirus assembly and genome replication by (i) determining the first-ever macromolecular architectures of assembly-replication intermediates, (ii) identifying interaction interfaces among key viral proteins, and (iii) elucidating how disruption of specific protein interaction interfaces impacts the viral lifecycle.
Project 2: Rotavirus Evolution and Gene Reassortment Restriction. Viruses with segmented RNA genomes can increase their genetic diversity and evolve by two distinct mechanisms: (i) the accumulation of point mutations due to error-prone genome replication and (ii) the reassortment of gene segments during host co-infection. Compared to evolution by mutation, which occurs more slowly over several generations, gene reassortment can have immediate phenotypic consequences on the virus because it creates chimeras with genes derived from multiple parental strains. Our comparative genomic studies of rotaviruses have shown the vast majority of human strains do not reassort their genes frequently, and instead maintain them as very specific and stable gene constellations. The overall objectives of this project are to uncover the forces tempering rotavirus evolution and to apply that knowledge to prevention and treatment strategies.
For a full listing of Dr. McDonald's publications, visit PubMed.
Education and Training
- National Institute of Allergy and Infectious Disease: Postdoctoral fellowship
- Vanderbilt University: Ph.D.
- National Institutes of Allergy and Infectious Diseases, NIH
Senior Research Fellow, Laboratory of Infectious Diseases
Awards and Honors
- NIH Fellows Award for Research Excellence, 2008
- NIAID Merit Award, 2008
- Boudreaux CE, Kelly DF, McDonald SM. (2015). Electron microscopic analysis of rotavirus assembly-replication intermediates. Virology, in press.
- Zhang S, McDonald PW, Thompson TA, Dennis AF, Akopov A, Kirkness EF, Patton JT, McDonald SM. (2014). Analysis of human rotaviruses from a single location over an 18-year time span suggests that protein coadaption influences gene constellations. Journal of Virology 88, 9842-63.
- Boudreaux CE, Vile D, Gilmore B, Tanner J, Kelly DF, McDonald SM. (2013). Rotavirus core shell subdomains involved in polymerase encapsidation. Journal of General Virology 94, 1818-26.
- McDonald SM. (2013). RNA synthetic mechanisms employed by diverse families of RNA viruses. Wiley Interdisciplinary Reviews in RNA 4(4), 351-67.
- McKell AO, Nichols JC, McDonald SM. (2013). PCR-based approach to distinguish group A human rotavirus genotype 1 versus genotype 2 genes. Journal of Virological Methods.
- Gilmore BL, Showalter SP, Dukes M, Tanner JR, Demmert AC, McDonald SM, Kelly DF. (2013). Visualizing viral assemblies in a nanoscale biosphere. Lab on a Chip 13, 216-19.
- McDonald SM, McKell AO, Rippinger CM, McAllen JK, Akopov A, Kirkness E, Payne DC, Edwards KM, Chappell J, Patton JT. (2012). Diversity and relationships of co-circulating modern human rotaviruses revealed using large-scale comparative genomics. Journal of Virology 86(17), 9148-62.
- Trask ST, McDonald SM, Patton JT. (2012). Structural insights into regulation of rotavirus replication. Nature Reviews in Microbiology 10, 165-77.