Description of Research: Adam Lauring
The rapid evolution of RNA viruses complicates the management of chronic infections and the control of emerging infectious agents. The ongoing global AIDS pandemic and the resurgence of influenza highlight the difficulties associated with these genetically labile pathogens. While high mutation rates make RNA viruses particularly challenging targets for vaccines and antiviral drugs, a clearer understanding of their unique evolutionary dynamics may suggest novel approaches for control. Our research objective is to understand mechanisms of viral evolution as they relate to pathogenesis and antiviral resistance in infected hosts. We study aspects of evolutionary theory in the context of the host-pathogen interface using molecular virology, small animal models, and newer genomic technologies.
We are particularly interested in defining the relationship between population diversity and viral phenotype in poliovirus, influenza, and other medically important RNA viruses. These viruses have extremely high mutation rates, which ensures that the vast majority of newly replicated genomes will be genetically distinct from their parents. In contrast, much of our understanding of pathogenesis derives from studies of viral consensus sequences, which represent the average sequence of a population. As a frame of reference, the consensus sequence obscures the inherent diversity of viral populations, and may not reveal many of the most important aspects of a virus’ evolutionary dynamics. Furthermore, the fleeting existence and mutability of each viral genome means that genetic information is stored within a diverse mutant swarm as opposed to in any individual sequence. RNA virus populations are better represented as dynamic networks in which sequences are continuously regenerated by mutation of related sequences. Defining this population structure is essential to unraveling the intricate patterns of RNA virus evolution.
We’ve also recently begun to explore the host genetics of viral infections. Humans exhibit significant variation in their susceptibility to infectious diseases, and abundant evidence suggests that much of this variability is genetically determined. Until recently, most studies of genetic susceptibility to infection have focused on primary immunodeficiencies – rare Mendelian disorders of the immune system that lead to multiple infections in childhood. Much less is known about the role of genetics in adult-onset infectious diseases, where one or more genes may modulate disease severity. An understanding of these genetic factors may elucidate biological pathways important in pathogen-specific immunity. With recent advances in DNA sequencing and genotyping technologies, it is now possible to identify candidate gene polymorphisms on a genomewide scale in individual patients. Genetic lesions that mediate disease susceptibility are likely to be enriched in individuals who experience rare and severe outcomes from relatively common infections. We hope to discover new risk alleles by intensively studying the genomes of these individuals.
Webster, DR, Hekele, A, Lauring, AS, Fischer K, Li, H, Andino, R, and DeRisi, J (2009) An enhanced single base extension technique for the analysis of complex viral populations. PLoS One, 4(10):e7453.
Lauring, AS, Jones, JO, and Andino, R (2010) Rationalizing the development of live attenuated virus vaccines. Nature Biotechnology, 28(6):573-579.
Lauring, AS and Andino, R (2010) Quasispecies theory and the behavior of RNA viruses, PLoS Pathogens, 6(7):e1001005.
Lauring, AS and Andino, R (2011) Exploring the fitness landscape of an RNA virus by using a universal barcode microarray, Journal of Virology 85(8):3780-3791.
Lauring, AS, Acevedo, A, Cooper, SB, and Andino, R (2012) Codon usage determines the
mutational robustness, evolutionary capacity and virulence of an RNA virus, Cell Host and
Lauring, AS, Lee TH, Martin JN, Hunt PW, Deeks SG, and Busch M (2012) Lack of
evidence for mtDNA as a biomarker of innate immune activation in HIV infection, PLoS
Lauring, AS, Frydman J, and Andino R (2013) The role of mutational robustness in RNA
virus evolution, Nature Reviews Microbiology, 11(5):327-336.
Venkatesan A, Tunkel A, Bloch K, Lauring AS, Sejvar J, Bitnun A, Stahl JP, Mailles A,
Drebot M, Rupprecht C, Yoder J, Cope JR, Wilson M, Whitley R, Sullivan J, Granerod J,
Jones C, Eastwood K, Ward K, Durrheim D, Solbrig MV, Guo-Duong L, and Glaser CA on
behalf of the International Encephalitis Consortium (2013) Guidelines and priorities in
Encephalitis: Consensus of the International Encephalitis Consortium, Clinical Infectious
Wang H, Perry JW, Lauring AS, Neddermann P, De Francesco R, and Tai AW (2014)
Oxysterol-binding protein is a phosphatidylinositol 4-kinase effector required for HCV
replication membrane integrity and cholesterol trafficking, Gastroenterology, 146(5):1373-
Long D, Fix O, Seielstad M, and Lauring AS (2014) Whole genome sequencing
identifies candidate risk alleles for severe outcomes of hepatitis A virus infection, Under