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

Abstract

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.

Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models

“…Mice from each strain were then randomly sorted into exposure groups-PBS-injected or TMEV-infected (Table 1). Mice at four weeks of age were anesthetized by isoflurane inhalation (MWI, Meridian, ID, USA) and inoculated into the right mid-parietal cortex at a depth of ~1.5 mm with 20 µL of 1 × Phosphate Buffer Solution (PBS) (PBS-injected/control mice), or with 5.0 × 10 4 plaque-forming units (PFU) of BeAn strain of TMEV (TMEV-injected/infected mice) (American Type Culture Collection [ATCC] VR 995, Manassas, VA, USA), as previously used in [25,[37][38][39][40]. Mice were housed separately by exposure groups.…”

“…We focused on five CC strains we had found to represent maximum phenotypic divergence (e.g., mild to severe disease) based on their phenotypic responses to TMEV during the chronic phase of infection, described in detail [25,38,39,47]. In the current study, TMEV significantly induced various clinical symptoms such as a decreased righting response, hunching, and limb paralysis in those strains most severely affected by TMEV, allowing for strain categorization based on acute phenotypes.…”

C57BL/6J mice exposed to perfluorooctanoic acid demonstrate altered immune responses and increased seizures after Theiler’s murine encephalomyelitis virus infection

“…A variety of neurological phenotypes resulting from TMEV exposure have been characterized in different mouse strains ( 29 , 45 , 47 ). B6 mice, considered a TMEV-resistant strain, were used in this study to determine whether PFOA exposure resulted in an increased incidence and/or severity in neurological clinical symptoms.…”

“…At PND 25 – 26, blood was collected from the submandibular vein via puncture with a lancet at a depth of ~1 mm. At the end of study (PND 42), mice were euthanized by intraperitoneal (IP) injection of Beuthansia at 150 mg/kg (Merck & Co., Kenilworth, NJ, USA) as described previously ( 45 , 47 , 48 ). Thereafter, blood was collected from the right atrium and was refrigerated at 4°C for an hour.…”

Brain-Derived Neurotrophic Factor Inhibits the Function of Cation-Chloride Cotransporter in a Mouse Model of Viral Infection-Induced Epilepsy

“…Furthermore, high mortality rate and low rate of epilepsy development in majority of these models curtail their utility (Patel and Wilcox, 2017;Löscher and Howe, 2022). In contrast, TMEV-infected C57BL/6J mice exhibit acute seizures during active infection, survive the initial infection, exhibit hippocampal neuropathology and gliotic scar, develop behavioral comorbidities such as anxiety and cognitive impairment, and develop epilepsy after about 2-3 months post-infection (Libbey et al, 2008;Stewart et al, 2010a;Umpierre et al, 2014;Broer et al, 2016;Lawley et al, 2021). This model recapitulates many pathological and behavioral sequelae of human TLE patients, and therefore, offers a unique opportunity to study the molecular mechanism(s) underlying seizure generation and epileptogenesis.…”