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

Abstract

The dynamics of Theiler's murine encephalomyelitis virus (TMEV) RNA replication in the central nervous systems of susceptible and resistant strains of mice were examined by quantitative real-time reverse transcription-PCR and were found to correlate with host immune responses. During the acute phase of infection in both susceptible and resistant mice, levels of viral replication were high in the brain and brain stem, while levels of viral genome equivalents were 10-to 100-fold lower in the spinal cord. In the brain, viral RNA replication decreased after a peak at 5 days postinfection (p.i.), in parallel with the appearance of virus-specific antibody responses; however, by 15 days p.i., viral RNA levels began to increase in the spinal cords of susceptible mice. During the transition to and the persistent phase of infection, the numbers of viral genome equivalents in the spinal cord varied substantially for individual mice, but high levels were consistently associated with high levels of proinflammatory Th1 cytokine and chemokine mRNAs. Moreover, a large number of viral genome equivalents and high proinflammatory cytokine mRNA levels in spinal cords were only observed for susceptible SJL/J mice who developed demyelinating disease. These results suggest that TMEV persistence requires active viral replication beginning about day 11 p.i. and that active viral replication with high viral genome loads leads to increased levels of Th1 cytokines that drive disease progression in infected mice.Theiler's murine encephalomyelitis virus (TMEV) is a naturally occurring enteric pathogen of mice that belongs to the Cardiovirus genus in the Picornaviridae family (39, 41). Lowneurovirulence strains, such as BeAn and DA, produce persistent infections in the central nervous systems (CNS) of susceptible strains of mice that result in mononuclear cell inflammation and largely immune system-mediated demyelination, providing an experimental analog for multiple sclerosis (MS) in humans (6,13,19,44). While only small amounts of infectious virus (100 to 1,000 PFU/spinal cord) are recovered during the persistent phase of infection (11, 29), very high levels of viral genome equivalents have been reported (49), suggesting that widespread and persistent TMEV infection involves continuous viral replication with restricted infectious virus production. Viral antigens and RNA are largely found in neurons in the brain and spinal cord during the acute phase of infection (2, 16), whereas macrophages or microglia containing viral antigen(s) and RNA predominate in the spinal cord during chronic infection (3, 30). The spread of infection to oligodendrocytes and astrocytes is also seen (3,9,44,47,51). TMEV replication in macrophages is highly restricted at the levels of RNA replication and virion assembly, consistent with mechanisms of persistence of cytolytic RNA viruses (23, 49). The mechanism(s) underlying TMEV transition from an acute neuronal infection in the gray matter to a chronic macrophagic and glial infection in the white matter is not well u...

Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

“…Interestingly, both of these viruses cause severe, acute encephalitis similar to that observed with VSV. In contrast, studies with lymphocytic choriomeningitis virus (LCMV) and the BeAn strain of TMEV have shown a lack IFN production after early viral replication in the brain (Sandberg et al, 1994;Trottier et al, 2004). Similar to our findings, LCMV induced peripheral, but not CNS, production of IFN (Sandberg et al, 1994).…”

Modeling the Acute and Chronic Phases of Theiler Murine Encephalomyelitis Virus Infection

“…The factor (t), where 0 Յ (t) Յ 1, describes the reduction of the infection rate due to virus-specific antibodies (equations 7 and 8), which are detected as early as day 5 p.i. (9).…”

“…During the acute phase of infection in both susceptible and resistant mice, levels of viral replication peak and then decrease at approximately 5 days postinfection (p.i.) in parallel with the appearance of virus-specific antibodies (9) and CD8 ϩ T cells (10)(11)(12). However, after about 2 weeks p.i., viral RNA numbers begin to increase again only in the spinal cords of susceptible mice.…”

“…Unlike viral infections with agents such as human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), and hepatitis C virus (HCV), the unique feature of TMEV infection is that the dominant cell type of infection changes during the transition from the acute to the chronic phase of infection. The temporal dynamics of TMEV RNA replication in the CNS of susceptible and resistant strains of mice has been examined by quantitative RT-PCR and correlated with host immune responses (9). During the acute phase of infection in both susceptible and resistant mice, levels of viral replication peak and then decrease at approximately 5 days postinfection (p.i.)…”

“…However, after about 2 weeks p.i., viral RNA numbers begin to increase again only in the spinal cords of susceptible mice. High-viral-genome equivalents in spinal cords are observed only in susceptible strains of mice, such as SJL/J mice developing demyelinating disease (9,13).…”