PMID- 34415947 OWN - NLM STAT- MEDLINE DCOM- 20211216 LR - 20230205 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 16 IP - 8 DP - 2021 TI - Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection. PG - e0256370 LID - 10.1371/journal.pone.0256370 [doi] LID - e0256370 AB - Host genetic background is a significant driver of the variability in neurological responses to viral infection. Here, we leverage the genetically diverse Collaborative Cross (CC) mouse resource to better understand how chronic infection by Theiler's Murine Encephalomyelitis Virus (TMEV) elicits diverse clinical and morphologic changes in the central nervous system (CNS). We characterized the TMEV-induced clinical phenotype responses, and associated lesion distributions in the CNS, in six CC mouse strains over a 90 day infection period. We observed varying degrees of motor impairment in these strains, as measured by delayed righting reflex, paresis, paralysis, seizures, limb clasping, ruffling, and encephalitis phenotypes. All strains developed neuroparenchymal necrosis and mineralization in the brain, primarily localized to the hippocampal regions. Two of the six strains presented with axonal degeneration with myelin loss of the nerve roots in the lumbar spinal cord. Moreover, we statistically correlated lesion distribution with overall frequencies of clinical phenotypes and phenotype progression to better understand how and where TMEV targets the CNS, based on genetic background. Specifically, we assessed lesion distribution in relation to the clinical progression of these phenotypes from early to late TMEV disease, finding significant relationships between progression and lesion distribution. Finally, we identified quantitative trait loci associated with frequency of lesions in a particular brain region, revealing several loci of interest for future study: lysosomal trafficking regulator (Lyst) and nidogen 1 (Nid1). Together, these results indicate that the genetic background influences the type and severity of clinical phenotypes, phenotypic resilience to TMEV, and the lesion distribution across strains. FAU - Lawley, Koedi S AU - Lawley KS AUID- ORCID: 0000-0002-2734-6728 AD - Department of Veterinary Integrative Biosciences, College Station, TX, United States of America. AD - College of Veterinary Medicine and Biomedical Sciences, College Station, TX, United States of America. AD - Texas A&M University, College Station, TX, United States of America. FAU - Rech, Raquel R AU - Rech RR AD - College of Veterinary Medicine and Biomedical Sciences, College Station, TX, United States of America. AD - Texas A&M University, College Station, TX, United States of America. AD - Department of Veterinary Pathobiology, College Station, TX, United States of America. FAU - Elenwa, Faith AU - Elenwa F AD - Texas A&M University, College Station, TX, United States of America. AD - Department of Epidemiology and Biostatistics, College Station, TX, United States of America. AD - School of Public Health, College Station, TX, United States of America. FAU - Han, Gang AU - Han G AD - Texas A&M University, College Station, TX, United States of America. AD - Department of Epidemiology and Biostatistics, College Station, TX, United States of America. AD - School of Public Health, College Station, TX, United States of America. FAU - Perez Gomez, Aracely A AU - Perez Gomez AA AD - Department of Veterinary Integrative Biosciences, College Station, TX, United States of America. AD - College of Veterinary Medicine and Biomedical Sciences, College Station, TX, United States of America. AD - Texas A&M University, College Station, TX, United States of America. FAU - Amstalden, Katia AU - Amstalden K AD - Department of Veterinary Integrative Biosciences, College Station, TX, United States of America. AD - College of Veterinary Medicine and Biomedical Sciences, College Station, TX, United States of America. AD - Texas A&M University, College Station, TX, United States of America. FAU - Welsh, C Jane AU - Welsh CJ AD - Department of Veterinary Integrative Biosciences, College Station, TX, United States of America. AD - College of Veterinary Medicine and Biomedical Sciences, College Station, TX, United States of America. AD - Texas A&M University, College Station, TX, United States of America. AD - Department of Veterinary Pathobiology, College Station, TX, United States of America. AD - Texas A&M Institute for Neuroscience, College Station, TX, United States of America. FAU - Young, Colin R AU - Young CR AD - Department of Veterinary Integrative Biosciences, College Station, TX, United States of America. AD - College of Veterinary Medicine and Biomedical Sciences, College Station, TX, United States of America. AD - Texas A&M University, College Station, TX, United States of America. FAU - Threadgill, David W AU - Threadgill DW AD - Texas A&M University, College Station, TX, United States of America. AD - Department of Molecular and Cellular Medicine, College Station, TX, United States of America. FAU - Brinkmeyer-Langford, Candice L AU - Brinkmeyer-Langford CL AD - Department of Veterinary Integrative Biosciences, College Station, TX, United States of America. AD - College of Veterinary Medicine and Biomedical Sciences, College Station, TX, United States of America. AD - Texas A&M University, College Station, TX, United States of America. AD - Texas A&M Institute for Neuroscience, College Station, TX, United States of America. LA - eng GR - P30 ES029067/ES/NIEHS NIH HHS/United States GR - R01 NS103934/NS/NINDS NIH HHS/United States GR - T32 ES026568/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20210820 PL - United States TA - PLoS One JT - PloS one JID - 101285081 SB - IM MH - Animals MH - Demyelinating Diseases MH - Enterovirus Infections MH - Lymphocyte Activation MH - Mice MH - Persistent Infection MH - *Theilovirus PMC - PMC8378701 COIS- The authors have declared that no competing interests exist. EDAT- 2021/08/21 06:00 MHDA- 2021/12/17 06:00 PMCR- 2021/08/20 CRDT- 2021/08/20 17:20 PHST- 2021/05/07 00:00 [received] PHST- 2021/08/04 00:00 [accepted] PHST- 2021/08/20 17:20 [entrez] PHST- 2021/08/21 06:00 [pubmed] PHST- 2021/12/17 06:00 [medline] PHST- 2021/08/20 00:00 [pmc-release] AID - PONE-D-21-13003 [pii] AID - 10.1371/journal.pone.0256370 [doi] PST - epublish SO - PLoS One. 2021 Aug 20;16(8):e0256370. doi: 10.1371/journal.pone.0256370. eCollection 2021.