PMID- 36142395 OWN - NLM STAT- MEDLINE DCOM- 20220926 LR - 20230217 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 18 DP - 2022 Sep 9 TI - Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background. LID - 10.3390/ijms231810482 [doi] LID - 10482 AB - 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. FAU - Lawley, Koedi S AU - Lawley KS AUID- ORCID: 0000-0002-2734-6728 AD - Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. FAU - Rech, Raquel R AU - Rech RR AD - Department of Veterinary Pathobiology, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. FAU - Perez Gomez, Aracely A AU - Perez Gomez AA AUID- ORCID: 0000-0002-1047-7246 AD - Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. FAU - Hopkins, Laura AU - Hopkins L AD - Department of Epidemiology and Biostatistics, School of Public Health, Texas A&M University, College Station, TX 77843, USA. FAU - Han, Gang AU - Han G AD - Department of Epidemiology and Biostatistics, School of Public Health, Texas A&M University, College Station, TX 77843, USA. FAU - Amstalden, Katia AU - Amstalden K AD - Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. FAU - Welsh, C Jane AU - Welsh CJ AUID- ORCID: 0000-0001-9659-8032 AD - Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. AD - Department of Veterinary Pathobiology, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. AD - Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843, USA. FAU - Young, Colin R AU - Young CR AD - Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. FAU - Jones-Hall, Yava AU - Jones-Hall Y AUID- ORCID: 0000-0003-4030-9830 AD - Department of Veterinary Pathobiology, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. FAU - Threadgill, David W AU - Threadgill DW AD - Department of Molecular and Cellular Medicine, School of Medicine, Texas A&M University, College Station, TX 77843, USA. FAU - Brinkmeyer-Langford, Candice L AU - Brinkmeyer-Langford CL AUID- ORCID: 0000-0001-6423-8585 AD - Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. AD - Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843, USA. 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 GR - DGE 1746932/National Science Foundation/ PT - Journal Article DEP - 20220909 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (RNA, Messenger) RN - 63231-63-0 (RNA) SB - IM MH - Animals MH - Genetic Background MH - Mice MH - Neuroinflammatory Diseases MH - RNA MH - RNA, Messenger MH - *Theilovirus/genetics PMC - PMC9501595 OTO - NOTNLM OT - Iba-1 OT - RNA in situ hybridization OT - TMEV OT - acute infection OT - collaborative cross OT - hippocampal formation OT - neurological disease COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. EDAT- 2022/09/24 06:00 MHDA- 2022/09/28 06:00 PMCR- 2022/09/09 CRDT- 2022/09/23 01:23 PHST- 2022/08/09 00:00 [received] PHST- 2022/08/30 00:00 [revised] PHST- 2022/08/30 00:00 [accepted] PHST- 2022/09/23 01:23 [entrez] PHST- 2022/09/24 06:00 [pubmed] PHST- 2022/09/28 06:00 [medline] PHST- 2022/09/09 00:00 [pmc-release] AID - ijms231810482 [pii] AID - ijms-23-10482 [pii] AID - 10.3390/ijms231810482 [doi] PST - epublish SO - Int J Mol Sci. 2022 Sep 9;23(18):10482. doi: 10.3390/ijms231810482.