Recovery from viral encephalomyelitis: immune-mediated noncytolytic virus clearance from neurons

Abstract

Viral encephalomyelitis is caused by virus infections of neurons in the brain and spinal cord. Recovery is dependent on immune-mediated control and clearance of virus from these terminally differentiated essential cells. Preservation of neuronal function is essential for prevention of neurologic sequelae such as paralysis, seizures and cognitive deficits. Using the model system of Sindbis virus-induced encephalomyelitis in mice, we have shown that immune-mediated clearance of infectious virus from neurons is a noncytolytic process. The major effectors are antibody to the E2 surface glycoprotein produced by B cells, and interferon-gamma produced by T cells. These effectors work in synergy, but neuronal populations differ in their responses to each. Virus is least likely to be cleared from brain neurons and most likely to be cleared from motor neurons in the cervical and thoracic regions of the spinal cord. Because the infected neurons are not eliminated, viral RNA persists and long-term control is needed to prevent virus reactivation. Virus-specific antibody-secreting cells residing in the nervous system after recovery from infection are likely to be important for long-term control.

Fig. 1

Effect of passive transfer of antibody or T cells to SCID mice persistently infected with SINV. a Passive transfer of SINV-specific hyperimmune serum (HIS) on infectious virus in the brain (pfu/gram) and on levels of viral RNA (in situ hybridization/RT–PCR). Transfer of T cells had no effect. b Recrudescence of infectious virus in the brain after passive transfer of hyperimmune serum (200 μg IgG) or anti-E2 monoclonal antibody at two different doses (50 μg and 200 μg). Data from (21, 53, 56)

Fig. 2

Numbers of total B cells secreting immunoglobulin in the CNS after intracerebral infection of BALB/c mice with SINV and percent of those antibody-secreting cells (ASC) producing antibody specific for SINV (53)

Fig. 3

Clearance of infectious SINV from the brains of wild type (WT), IFN-β-/- (BKO), IFN-γ-/- (GKO), antibody-deficient (μMT), antibody and INF-γ-deficient (GKO/μMT) and severe combinded immunodeficiency (SCID) C57BL/6 (B6) mice. Dashed line indicates the limit of detection. Data from (52)