Cargando…

Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background

A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the brain, depending in part on host genetic background. The interaction...

Descripción completa

Detalles Bibliográficos
Autores principales: Lawley, Koedi S., Rech, Raquel R., Perez Gomez, Aracely A., Hopkins, Laura, Han, Gang, Amstalden, Katia, Welsh, C. Jane, Young, Colin R., Jones-Hall, Yava, Threadgill, David W., Brinkmeyer-Langford, Candice L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9501595/
https://www.ncbi.nlm.nih.gov/pubmed/36142395
http://dx.doi.org/10.3390/ijms231810482
_version_ 1784795513598509056
author Lawley, Koedi S.
Rech, Raquel R.
Perez Gomez, Aracely A.
Hopkins, Laura
Han, Gang
Amstalden, Katia
Welsh, C. Jane
Young, Colin R.
Jones-Hall, Yava
Threadgill, David W.
Brinkmeyer-Langford, Candice L.
author_facet Lawley, Koedi S.
Rech, Raquel R.
Perez Gomez, Aracely A.
Hopkins, Laura
Han, Gang
Amstalden, Katia
Welsh, C. Jane
Young, Colin R.
Jones-Hall, Yava
Threadgill, David W.
Brinkmeyer-Langford, Candice L.
author_sort Lawley, Koedi S.
collection PubMed
description A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the brain, depending in part on host genetic background. The interaction between host genetic background, neurological response to viral infection, and subsequent clinical manifestations remains poorly understood. In the present study, we used the genetically diverse Collaborative Cross (CC) mouse resource to better understand how differences in genetic background drive clinical signs and neuropathological manifestations of acute Theiler’s murine encephalomyelitis virus (TMEV) infection. For the first time, we characterized variations of TMEV viral tropism and load based on host genetic background, and correlated viral load with microglial/macrophage activation. For five CC strains (CC002, CC023, CC027, CC057, and CC078) infected with TMEV, we compared clinical signs, lesion distribution, microglial/macrophage response, expression, and distribution of TMEV mRNA, and identified genetic loci relevant to the early acute (4 days post-infection [dpi]) and late acute (14 dpi) timepoints. We examined brain pathology to determine possible causes of strain-specific differences in clinical signs, and found that fields CA1 and CA2 of the hippocampal formation were especially targeted by TMEV across all strains. Using Iba-1 immunolabeling, we identified and characterized strain- and timepoint-specific variation in microglial/macrophage reactivity in the hippocampal formation. Because viral clearance can influence disease outcome, we used RNA in situ hybridization to quantify viral load and TMEV mRNA distribution at both timepoints. TMEV mRNA expression was broadly distributed in the hippocampal formation at 4 dpi in all strains but varied between radiating and clustered distribution depending on the CC strain. We found a positive correlation between microglial/macrophage reactivity and TMEV mRNA expression at 4 dpi. At 14 dpi, we observed a dramatic reduction in TMEV mRNA expression, and localization to the medial portion of field CA1 and field CA2. To better understand how host genetic background can influence pathological outcomes, we identified quantitative trait loci associated with frequency of lesions in a particular brain region and with microglial/macrophage reactivity. These QTL were located near several loci of interest: lysosomal trafficking regulator (Lyst) and nidogen 1 (Nid1), and transmembrane protein 106 B (Tmem106b). Together, these results provide a novel understanding about the influences of genetic variation on the acute neuropathological and immunopathological environment and viral load, which collectively lead to variable disease outcomes. Our findings reveal possible avenues for future investigation which may lead to more effective intervention strategies and treatment regimens.
format Online
Article
Text
id pubmed-9501595
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-95015952022-09-24 Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background Lawley, Koedi S. Rech, Raquel R. Perez Gomez, Aracely A. Hopkins, Laura Han, Gang Amstalden, Katia Welsh, C. Jane Young, Colin R. Jones-Hall, Yava Threadgill, David W. Brinkmeyer-Langford, Candice L. Int J Mol Sci Article A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the brain, depending in part on host genetic background. The interaction between host genetic background, neurological response to viral infection, and subsequent clinical manifestations remains poorly understood. In the present study, we used the genetically diverse Collaborative Cross (CC) mouse resource to better understand how differences in genetic background drive clinical signs and neuropathological manifestations of acute Theiler’s murine encephalomyelitis virus (TMEV) infection. For the first time, we characterized variations of TMEV viral tropism and load based on host genetic background, and correlated viral load with microglial/macrophage activation. For five CC strains (CC002, CC023, CC027, CC057, and CC078) infected with TMEV, we compared clinical signs, lesion distribution, microglial/macrophage response, expression, and distribution of TMEV mRNA, and identified genetic loci relevant to the early acute (4 days post-infection [dpi]) and late acute (14 dpi) timepoints. We examined brain pathology to determine possible causes of strain-specific differences in clinical signs, and found that fields CA1 and CA2 of the hippocampal formation were especially targeted by TMEV across all strains. Using Iba-1 immunolabeling, we identified and characterized strain- and timepoint-specific variation in microglial/macrophage reactivity in the hippocampal formation. Because viral clearance can influence disease outcome, we used RNA in situ hybridization to quantify viral load and TMEV mRNA distribution at both timepoints. TMEV mRNA expression was broadly distributed in the hippocampal formation at 4 dpi in all strains but varied between radiating and clustered distribution depending on the CC strain. We found a positive correlation between microglial/macrophage reactivity and TMEV mRNA expression at 4 dpi. At 14 dpi, we observed a dramatic reduction in TMEV mRNA expression, and localization to the medial portion of field CA1 and field CA2. To better understand how host genetic background can influence pathological outcomes, we identified quantitative trait loci associated with frequency of lesions in a particular brain region and with microglial/macrophage reactivity. These QTL were located near several loci of interest: lysosomal trafficking regulator (Lyst) and nidogen 1 (Nid1), and transmembrane protein 106 B (Tmem106b). Together, these results provide a novel understanding about the influences of genetic variation on the acute neuropathological and immunopathological environment and viral load, which collectively lead to variable disease outcomes. Our findings reveal possible avenues for future investigation which may lead to more effective intervention strategies and treatment regimens. MDPI 2022-09-09 /pmc/articles/PMC9501595/ /pubmed/36142395 http://dx.doi.org/10.3390/ijms231810482 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lawley, Koedi S.
Rech, Raquel R.
Perez Gomez, Aracely A.
Hopkins, Laura
Han, Gang
Amstalden, Katia
Welsh, C. Jane
Young, Colin R.
Jones-Hall, Yava
Threadgill, David W.
Brinkmeyer-Langford, Candice L.
Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background
title Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background
title_full Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background
title_fullStr Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background
title_full_unstemmed Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background
title_short Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background
title_sort viral clearance and neuroinflammation in acute tmev infection vary by host genetic background
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9501595/
https://www.ncbi.nlm.nih.gov/pubmed/36142395
http://dx.doi.org/10.3390/ijms231810482
work_keys_str_mv AT lawleykoedis viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT rechraquelr viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT perezgomezaracelya viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT hopkinslaura viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT hangang viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT amstaldenkatia viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT welshcjane viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT youngcolinr viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT joneshallyava viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT threadgilldavidw viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground
AT brinkmeyerlangfordcandicel viralclearanceandneuroinflammationinacutetmevinfectionvarybyhostgeneticbackground