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Characterization of the Neuropathological Effects of Theiler’s Murine Encephalomyelitis Virus in a Genetically Diverse Mouse Panel
Abstract
A wide range of viruses cause immediate or delayed 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 on a myriad of
factors including host genetic background. The interaction between host genetic background,
neurological response to viral infection and subsequent clinical manifestations remains poorly
understood, despite ramifications on health between different populations infected by the same
virus. In the present study, we used the genetically diverse Collaborative Cross (CC) mouse
resource to better understand how differences in genetic background drive the clinical signs and
neuropathological manifestations of acute Theiler’s murine encephalomyelitis virus (TMEV)
infection. For the first time, we characterized how TMEV viral tropism and load varies based on
host genetic background and correlated viral load with microglial/macrophage activation. In five
CC strains (CC002, CC023, CC027, CC057, and CC078) infected with TMEV, we described the
clinical signs, lesion distribution, microglial/macrophage response, expression, and distribution
of TMEV mRNA, and the related genetic determinants during the over the course of a 90 day
infection period. We confirmed how TMEV elicits clinical signs which vary in type as well as
severity, depending on the CC strain. Additionally, we examined the brain and spinal cord
pathology to determine possible causes of these differences in clinical signs and found that the
hippocampal formation, namely field CA1 and field CA2, and the lumbar spinal cord segment
were especially targeted by TMEV across all strains. We identified and characterized strain- and
timepoint-specific variation in microglial/macrophage reactivity using Iba-1 immunolabeling. As
viral clearance can influence disease outcome, we used RNA in situ hybridization to quantify viral load and TMEV mRNA distribution. 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 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 investigations which may lead to more
effective intervention strategies and treatment regimens.
Citation
Lawley, Koedi Savannah (2022). Characterization of the Neuropathological Effects of Theiler’s Murine Encephalomyelitis Virus in a Genetically Diverse Mouse Panel. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /198159.