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

Fig 1. Cumulative frequency and progression scores of clinical phenotypes. a) Cumulative frequency of neurological and sickness phenotypes, based on observations over a 90-day period, varied by strain. Phenotypic observation frequencies for righting reflex, paresis, paralysis, seizures, limb clasping, encephalitis, and ruffling were recorded over the 90 day infection period. Data shown here are mean ± SEM of the average clinical phenotype frequency across 90 dpi for each strain. b) Clinical progression of neurological and sickness phenotypes varied by strain. Phenotypic observation frequencies for righting reflex, paresis, paralysis, seizures, limb clasping, encephalitis, and ruffling were calculated at 14dpi and 90 dpi and the differences from 14 to 90dpi were compared to generate a progression score to understand the effect of the virus during the chronic phase of infection. For each phenotype, positive progression scores indicate that severity increased over time. Data shown here are mean ± SEM of the progression score for each strain.

Fig 2. Relationship between 90 dpi cumulative phenotype frequency, progression score and lesion location. a.) Statistically significant associations and suggestive associations between lesion location and 90 dpi phenotypes. b.) Statistically significant associations and suggestive associations between lesion locations and clinical progression scores. The values presented are the Spearman correlation coefficients. The values shown in gray are for strain-specific associations.

Fig 3. Cross-sections of the cerebrum at level B of CC mice infected with Theiler’s Murine Encephalomyelitis Virus (TMEV) and euthanized ~90 dpi. A. Strain CC002, B. Strain CC012xCC032, and C. Strain CC023: Linear neuroparenchymal necrosis and mineralization of the dorsal hippocampal commissure (black arrows). Hematoxylin and eosin stain; bar = 200 μm. D. Strain CC027: Locally extensive neuroparenchymal necrosis and loss of the hippocampal neurons of the pyramidal layer of CA1 with gliosis of the stratum oriens and stratum radiatum (black rectangle); Hematoxylin and eosin stain; bar = 100 μm. E. CC057 strain: Locally extensive neuroparenchymal necrosis and mineralization of the pyramidal layer of CA1 field with gliosis of the stratum oriens, stratum radiatum and stratum lacunosum-moleculare (black rectangle); Hematoxylin and eosin stain; bar = 100 μm. F. Strain CC078: Focal areas of neuroparenchymal necrosis and mineralization with neuronal loss of the hippocampal CA1 and CA2 pyramidal layer (arrows) and gliosis and mineralization of the superjacent stratum oriens and subjacent stratum radiatum. Hematoxylin and eosin stain; bar = 100 μm. G. Schematic representations of the TMEV-induced…

Fig 4. Cross-sections of the lumbosacral spinal cord of CC mice strains infected with Theiler’s Murine Encephalomyelitis Virus (TMEV) and euthanized at ~90 dpi. A. Strain CC002: Bilateral radiculoneuropathy of the ventral nerve roots. Hematoxylin and eosin stain; bar = 200 μm. B. Detail of the lesion shown in A: Chronic axonal degeneration and loss with vacuolation of the myelin sheaths. Hematoxylin and eosin stain; bar = 50 μm. C. Strain CC023: Bilateral radiculoneuropathy of the ventral nerve roots. Hematoxylin and eosin stain; bar = 200 μm. D. Detail of the lesion shown in C: Chronic axonal degeneration loss of myelin sheaths and infiltration of macrophages. Hematoxylin and eosin stain; bar = 50 μm.