Mechanisms of Central Nervous System Viral Persistence: the Critical Role of Antibody and B Cells

Abstract

Contributions of humoral and cellular immunity in controlling neurotropic mouse hepatitis virus persistence within the CNS were determined in B cell-deficient JHD and syngeneic H-2d B cell+ Ab-deficient mice. Virus clearance followed similar kinetics in all mice, confirming initial control of virus replication by cellular immunity. Nevertheless, virus reemerged within the CNS of all Ab-deficient mice. In contrast to diminished T cell responses in H-2b B cell-deficient μMT mice, the absence of B cells or Ab in the H-2d mice did not compromise expansion, recruitment into the CNS, or function of virus-specific CD4+ and CD8+ T cells. The lack of B cells and lymphoid architecture thus appears to manifest itself on T cell responses in a genetically biased manner. Increasing viral load did not enhance frequencies or effector function of virus-specific T cells within the CNS, indicating down-regulation of T cell responses. Although an Ab-independent antiviral function of B cells was not evident during acute infection, the presence of B cells altered CNS cellular tropism during viral recrudescence. Reemerging virus localized almost exclusively to oligodendroglia in B cell+ Ab-deficient mice, whereas it also replicated in astrocytes in B cell-deficient mice. Altered tropism coincided with distinct regulation of CNS virus-specific CD4+ T cells. These data conclusively demonstrate that the Ab component of humoral immunity is critical in preventing virus reactivation within CNS glial cells. B cells themselves may also play a subtle role in modulating pathogenesis by influencing tropism.

Type I IFN-Mediated Protection of Macrophages and Dendritic Cells Secures Control of Murine Coronavirus Infection

“…MHV can enter the CNS via the olfactory nerve system (40) and spreads transneuronally, leading to infection of distinct parts of the brain and the spinal cord. CTLs control viral replication within the CNS but cannot completely eliminate the virus (21), whereas neutralizing Abs are essential to prevent viral recrudescence (24). Thus, MHV is well adapted to use the CNS as an immunoprivileged site to escape complete clearance from the system.…”

“…This natural mouse pathogen is one of the most extensively studied coronaviruses (20). A strong CTL response mediates clearance of the virus between days 6 and 8 postinfection (21,22), and neutralizing Abs appear to be required to prevent re-emergence of persistent CNS infection (23,24). Nonetheless, before effective adaptive immune responses are elicited, type I IFN-mediated innate immune responses are essential for the survival of the host in the early phase of infection.…”

CD4 T Cell-Mediated Protection from Lethal Influenza: Perforin and Antibody-Mediated Mechanisms Give a One-Two Punch

“…In some experiments, CD8 TCR Tg mice (a gift from Dr. L. Sherman, The Scripps Research Institute) specific for peptide 518 -526 of PR8 HA and OVA 323-339-specific (DO11.10) TCR Tg mice were used as controls. WT TCR Tg, IFN-␥ Ϫ/Ϫ TCR Tg, BALB/c/Thy1.1, and B cell-deficient mice homozygous for a disruption at the J H locus (J H D) (20), backcrossed to BALB/c mice were all maintained at Trudeau Institute. BALB/c By and BALB/c nu/nu mice were purchased from The Jackson Laboratory.…”

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

“…IgG therapy (53)(54)(55)(56). Especially in the case of neurotropic viruses, Abs have been shown to limit or prevent virus spread to the CNS system or restrict virus expression (57)(58)(59)(60). Other viruses infecting epithelia such as pulmonary influenza virus can be cleared by application of Abs after establishment of infection (61).…”