Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.

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) elicit...

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Autores principales:	Koedi S Lawley, Raquel R Rech, Faith Elenwa, Gang Han, Aracely A Perez Gomez, Katia Amstalden, C Jane Welsh, Colin R Young, David W Threadgill, Candice L Brinkmeyer-Langford
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/07223f1805384c1fae1ab5708c93dae4
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spelling	oai:doaj.org-article:07223f1805384c1fae1ab5708c93dae42021-12-02T20:04:45ZHost genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.1932-620310.1371/journal.pone.0256370https://doaj.org/article/07223f1805384c1fae1ab5708c93dae42021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0256370https://doaj.org/toc/1932-6203Host 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.Koedi S LawleyRaquel R RechFaith ElenwaGang HanAracely A Perez GomezKatia AmstaldenC Jane WelshColin R YoungDavid W ThreadgillCandice L Brinkmeyer-LangfordPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0256370 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Koedi S Lawley Raquel R Rech Faith Elenwa Gang Han Aracely A Perez Gomez Katia Amstalden C Jane Welsh Colin R Young David W Threadgill Candice L Brinkmeyer-Langford Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.
description	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.
format	article
author	Koedi S Lawley Raquel R Rech Faith Elenwa Gang Han Aracely A Perez Gomez Katia Amstalden C Jane Welsh Colin R Young David W Threadgill Candice L Brinkmeyer-Langford
author_facet	Koedi S Lawley Raquel R Rech Faith Elenwa Gang Han Aracely A Perez Gomez Katia Amstalden C Jane Welsh Colin R Young David W Threadgill Candice L Brinkmeyer-Langford
author_sort	Koedi S Lawley
title	Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.
title_short	Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.
title_full	Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.
title_fullStr	Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.
title_full_unstemmed	Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.
title_sort	host genetic diversity drives variable central nervous system lesion distribution in chronic phase of theiler's murine encephalomyelitis virus (tmev) infection.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/07223f1805384c1fae1ab5708c93dae4
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Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.

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