ABSTRACT
Resistance to lethal encephalitis in mice infected with HSV-1 via the oral mucosa is mouse strain dependent. In susceptible BALB/c, HSV-1 spreads throughout the CNS but in resistant BL/6 mice, virus is restricted to the brainstem. To examine the contribution of cellular immunity in restricting viral spread, we used a combination of antibody depleted and KO mice. Individually, NK/NKT, iNKT, CD4(+), CD8(+), and gammadelta T-cells do not restrict HSV-1 spread. In contrast, virus spreads throughout the CNS of BL/6 CL I KO mice and BL/6 mice treated with either anti-asialoGM1 Ab or both anti-CD8 and anti-NK1.1 mAbs. The results highlight the importance of redundancy in the immune system in restricting viral spread in the CNS, argue for a role of NK/NKT and CD8(+) T-cells in mediating the restriction, and provide a hierarchical order of the individual elements in controlling virus in BL/6 mice infected with HSV-1 via the oral mucosa.
Subject(s)
Central Nervous System/immunology , Central Nervous System/virology , Herpes Simplex/immunology , Herpesvirus 1, Human/immunology , Immunity, Innate , Animals , Brain/virology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Killer Cells, Natural/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocyte Subsets/immunology , Viral LoadABSTRACT
CD8+ T-cell persistence can be seen in ganglia harboring latent herpes simplex virus (HSV) infection. While there is some evidence that these cells suppress virus reactivation, this view remains controversial. Given that maintenance of latency by CD8+ T cells would necessitate ongoing exposure to antigen within this site, we sought evidence for such chronic stimulation. Initial experiments showed infiltration by activated but not naïve CD8+ T cells into ganglia harboring latent HSV infection. While such infiltration was independent of T-cell specificity, once recruited, only virus-specific T cells expressed high levels of preformed granzyme B, a marker of ongoing activation. Moreover, bone marrow replacement chimeras showed that these elevated granzyme levels were totally dependent on presentation by parenchymal cells within the ganglia. Overall, this study argues that activated CD8+ T cells are nonspecifically recruited into latently infected ganglia, and in this site they are exposed to ongoing antigen stimulation, most likely by infected neuronal cells.
