Viral Load Increases in SJL/J Mice Persistently Infected by Theiler's Virus after Inactivation of the β₂mGene

Abstract

We show that inactivating the ␤ 2 m gene increases the viral load of SJL/J mice persistently infected by Theiler's virus. Together with previous results, this shows that the characteristics of Tmevp1, a locus which controls the amount of viral RNA that persists in the central nervous system, are those of an H-2 class I gene.The DA strain of Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, is responsible for a biphasic neurological disease of mice. The first phase is an acute encephalomyelitis which takes place during the first 2 weeks that follow intracerebral inoculation. During the second phase, which occurs only in susceptible animals and is lifelong, persistent infection of the white matter of the spinal cord causes chronic inflammation and primary demyelination (14,15). This natural disease is considered one of the best models for multiple sclerosis (13,20).The extent of demyelination and the amount of viral RNA that persists in the central nervous system (CNS) vary greatly among inbred mouse strains (8). A locus with a major effect on both phenotypes has been mapped by several groups to the H-2D region of the major histocompatibility complex (MHC) (10,12,17,21,23). This locus has been named Tmevp1 for Theiler's murine encephalomyelitis virus persistence locus 1. Three phenotypes have been defined for the amount of viral RNA that persists in the CNS. Resistant strains clear the infection, and their F 1 crosses with the SJL/J strain clear the infection as well. Strains of intermediate susceptibility clear the infection, but their F 1 crosses with the SJL/J strain do not and are infected at high levels. Finally, susceptible strains remain persistently infected at high levels. In 15 of 16 mouse strains examined in one study, the viral RNA load was determined by the Tmevp1 haplotype. The H-2 b haplotype was associated with resistance, the H-2 q haplotype was associated with susceptibility, and the H-2 d , H-2 k , and H-2 s haplotypes were associated with intermediate levels of susceptibility (10). The SJL/J strain was the only strain which was more susceptible than predicted by its H-2 s haplotype. In subsequent work, its susceptibility was explained by non-H-2 loci, which have been mapped, on the mouse genome (9). Two of these loci are located close to each other on the telomeric part of chromosome 10 (6). Interestingly, multiple susceptibility loci located in the same region have also been reported for other phenotypes induced by Theiler's virus infection and for other diseases. ) were inoculated intracerebrally with 10 4 PFU of the DA1 strain of TMEV and studied during the acute (6 days postinoculation [p.i.]) and the chronic phase (21 and 45 days p.i.) of the infection. DA1 is a molecularly cloned TMEV DA strain produced from the infectious pTMDA1 plasmid (18,19). The amount of viral RNA in the CNS was measured by using a dot blot assay (1, 10). Briefly, for each mouse, fivefold dilutions of total RNA were dotted onto a filter and hybridized with either a viral cDNA probe or a control ␤-acti...

Transition from Acute to Persistent Theiler's Virus Infection Requires Active Viral Replication That Drives Proinflammatory Cytokine Expression and Chronic Demyelinating Disease

“…Consistent with this hypothesis, Aubagnac et al (1) found by Northern hybridization that DA virus-infected SJL/J mice with an inactivated ␤2m gene (SJL/J ␤2m Ϫ/Ϫ ) had significantly increased amounts of spinal cord viral RNA on day 45 p.i. compared to wild-type mice (SJL/J ␤2m ϩ/ϩ ).…”

Neuropathogenesis of Theiler’s Murine Encephalomyelitis Virus Infection, An Animal Model for Multiple Sclerosis

“…However, in mice that normally do not develop demyelination, elimination ofMHC class I through genetic knockout of β 2 -microglobulin makes them susceptible to demyelination. TMEV infection in β 2 -microglobulin-deficient mice on SJL (Aubagnac et al 2001; Begolka et al 2001) and B6 × 129 (Fiette et al 1993) backgrounds results in exacerbation of neuropathology with an increase in viral persistence, while preservation of neurological function correlates with axonal preservation in mice with a B6 × 129 background (Ure and Rodriguez 2002). In addition, during the chronic phase, MHC class I-restricted CD8 + T cells have been suggested to play a role in the development of axonal damage (Rivera-Quiñones et al 1998).…”

Interleukin 22 Is a Candidate Gene forTmevp3, a Locus Controlling Theiler's Virus-Induced Neurological Diseases

“…During persistence there is a great variability of viral load, measured as the quantity of viral genomes present in the spinal cord, among strains of laboratory mice (Bureau et al 1992). A major locus controlling viral load, the H2-D class I gene, has been characterized on chromosome 17 (Azoulay et al 1994;Azoulay-Cayla et al 2000;Aubagnac et al 2001;Mendez-Fernandez et al 2005). However during persistence, the SJL strain is infected at a higher level than the B10.S strain, although both bear the same H2 s haplotype.…”