CD8+ T cells require perforin to clear West Nile virus from infected neurons.
Injury to neurons after West Nile virus (WNV) infection is believed to occur because of viral and host immune-mediated effects. Previously, we demonstrated that CD8+ T cells are required for the resolution of WNV infection in the central nervous system (CNS). CD8+ T cells can control infection by producing antiviral cytokines (e.g., gamma interferon or tumor necrosis factor alpha) or by triggering death of infected cells through perforin- or Fas ligand-dependent pathways. Here, we directly evaluated the role of perforin in controlling infection of a lineage I New York isolate of WNV in mice. A genetic deficiency of perforin molecules resulted in higher viral burden in the CNS and increased mortality after WNV infection. In the few perforin-deficient mice that survived initial challenge, viral persistence was observed in the CNS for several weeks. CD8+ T cells required perforin to control WNV infection as adoptive transfer of WNV-primed wild-type but not perforin-deficient CD8+ T cells greatly reduced infection in the brain and spinal cord and enhanced survival of CD8-deficient mice. Analogous results were obtained when wild-type or perforin-deficient CD8+ T cells were added to congenic primary cortical neuron cultures. Taken together, our data suggest that despite the risk of immunopathogenesis, CD8+ T cells use a perforin-dependent mechanism to clear WNV from infected neurons.
Shrestha
Bimmi
B
Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110, USA.
Samuel
Melanie A
MA
Diamond
Michael S
MS
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000821:virology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000494:pharmacology*; D014901:West Nile Fever / Q000276:immunology; D014902:West Nile virus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin