Neuropathological diversity associated with viral infection based on host genetic background
 
Candice Brinkmeyer-Langford^1*, Raquel Rech¹, Colin Young¹, Katia Amstalden¹, C. Jane Welsh¹, David Threadgill^2
1Texas A&M University College of Veterinary Medicine; ²Texas A&M University College of Medicine
*Corresponding Author
  
Infection by a given virus can cause diverse neurological outcomes and disease pathologies, influenced by the genetic background of the host. In mice, Theiler's murine encephalomyelitis virus (TMEV) infection leads to heterogeneous neurological conditions, depending on mouse strain infected. The relevance of TMEV infection as a tool for studying virus-induced neurological conditions in humans identifies a critical need to determine genetic variants and their mechanisms to link TMEV infection to disease outcome.
Different mouse strains respond to TMEV infection differently in ways that closely approximate human neurological conditions ranging from epilepsy to demyelination. Comparisons among inbred mouse strains indicate that different haplotypes of the major histocompatibility complex (MHC; known in mice as the H2 region) correlate with different susceptibilities to TMEV persistence and clinical disease. However, non-H2 genes also contribute to the pathogenic heterogeneity. A major objective of this project is to identify non-H2 determinants of viral pathologies.
The study of TMEV-induced pathologies using conventional inbred mouse strains with limited genetic diversity has revealed little about non-H2 genes involved in TMEV pathogenesis, and these strains may not sufficiently represent the disease diversity seen in humans. The Collaborative Cross (CC), developed by intercrossing eight genetically diverse mouse strains, is a powerful translational tool for systems genetic analyses of complex phenotypes including diseases elicited by viruses.
In this study, we have evaluated different CC strains for outcomes of TMEV infection using neurological/behavioral phenotyping tests and histology. We correlated phenotypic observations with haplotypes of genomic regions previously linked to TMEV susceptibility to test the hypothesis that genomic diversity within CC mice results in variable disease phenotypes in response to TMEV. Our findings to date demonstrate the value of the CC resource for studying how viral infection can cause different neurological outcomes depending on host genetic background.
 
 
References: Brinkmeyer-Langford CL, Rech R, Amstalden K, Hillhouse A, Kochan K, Young C, Welsh CJ, Threadgill DW. Host genetic background influences diverse responses to viral infection in mice. 2017. Sci Rep. 7(1):12194. PMCID: PMC5610195
 
Funding: NIH NINDS R01 NS103934-01