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

Abstract

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.

CD28-signaling can be partially compensated in CD28-knockout mice but is essential for virus elimination in a murine model of multiple sclerosis

“…The intracerebral inoculation with Theiler’s murine encephalomyelitis virus (TMEV) is a widely used, infectious model for neuro-inflammatory and -degenerative diseases like multiple sclerosis (MS) or epilepsy in humans ( 1 ). Susceptibility and outcome of a TMEV-infection in mice is genetically defined by the host ( 2 ). Infection of the central nervous system (CNS) is also influenced by the virus strain and as importantly, disease progression and virus spread within the nervous tissue from the cerebrum to the spinal cord is associated with changes in cell tropism ( 2 – 5 ).…”

“…Susceptibility and outcome of a TMEV-infection in mice is genetically defined by the host ( 2 ). Infection of the central nervous system (CNS) is also influenced by the virus strain and as importantly, disease progression and virus spread within the nervous tissue from the cerebrum to the spinal cord is associated with changes in cell tropism ( 2 – 5 ). TMEV shows a strong tropism to neurons during the acute phase, which is followed by a predominant infection of glial cells and macrophages in the chronic phase of infection after three to four weeks ( 2 – 8 ).…”

“…Infection of the central nervous system (CNS) is also influenced by the virus strain and as importantly, disease progression and virus spread within the nervous tissue from the cerebrum to the spinal cord is associated with changes in cell tropism ( 2 – 5 ). TMEV shows a strong tropism to neurons during the acute phase, which is followed by a predominant infection of glial cells and macrophages in the chronic phase of infection after three to four weeks ( 2 – 8 ). Briefly, the acute phase of the TMEV-infection is related to a direct virus-mediated effect predominantly on neurons and characterized by a transient encephalitis that lasts about two to three weeks after intracerebral infection in most mouse strains ( 1 , 9 ).…”

“…In susceptible mouse strains with an insufficient anti-viral immune response, like SJL mice, the acute phase is followed by a chronic phase, characterized by virus spread into the spinal cord and persistent TMEV-infection with concomitant development of a progressive demyelinating disease (TMEV-IDD), resembling progressive MS ( 1 , 9 ). The alterations seen in the chronic phase are caused by immune-mediated tissue damage and infection of glial cells and macrophages ( 2 – 8 ). Thus, the division into an acute and chronic phase is not only based on the pathomorphological changes in the CNS, but also characterized by a changing cell tropism of the virus and underlying pathogenetic mechanisms ( 2 – 5 ).The clearance of a pathogen is critically dependent on a functioning immune system.…”

“…The alterations seen in the chronic phase are caused by immune-mediated tissue damage and infection of glial cells and macrophages ( 2 – 8 ). Thus, the division into an acute and chronic phase is not only based on the pathomorphological changes in the CNS, but also characterized by a changing cell tropism of the virus and underlying pathogenetic mechanisms ( 2 – 5 ).The clearance of a pathogen is critically dependent on a functioning immune system. For a virus infection, especially cytotoxic CD8 + T cells and NK cells are significantly involved, but the function of these cells is also embedded in the general context of a healthy immune system, involving antigen-presenting cells of the myeloid lineage as important cells for T cell activation and also T-helper cells for assisting the CD8 + cytotoxic response.…”