Immune evasion by silver-haired bat rabies virus and implications for treatment
Infection of central nervous system (CNS) tissues with pathogenic rabies virus (RV) strains is most often lethal to the host if the conventional post-exposure treatment is missed or administered after the appearance of the clinical signs of rabies. Over the last decade, RV associated with the silver-haired bat (SHBRV) have emerged as the leading cause of human deaths from rabies in the United States, as a consequence of exposure to the virus being unnoticed. The need to treat SHBRV-infected individuals following the development of clinical rabies has led us to investigate why the anti-viral immune response fails to protect in the later stage of infection. Towards this end, we have established that anti-viral immunity is indistinguishable between mice infected with SHBRV and an attenuated RV strain. However, the blood-brain barrier (BBB) fails to open and immune effectors are not delivered to the CNS tissues of the SHBRV-infected animals, and consequently the virus is not cleared. Conceivably, when immune access to the infected CNS tissues is limited, either the provision or development of anti-viral immunity will be ineffective. We have demonstrated that mice with SJL background have a greater capacity to open the BBB and develop CNS inflammation in response to SHBRV infection, and are resultantly more resistant to lethal disease. The therapeutic induction of more extensive BBB permeability and CNS inflammation in these animals results in greater virus clearance and improved survival. We conclude that BBB permeability changes and delivery of immune effectors across the BBB is critical to surviving an RV infection, and SHBRV evades immune clearance by inhibiting these processes. We have also demonstrated that the immune evasion strategy of SHBRV is common to a variety of pathogenic RV strains including dog rabies viruses. Peroxynitrite is known to enhance BBB permeability. Our findings indicate that the failure to enhance BBB permeability during SHBRV infection is caused by a reduction in IFN-γ induced production of peroxynitrite in brain microvessels. Evidence suggests that the insufficient IFN-γ signaling in the BBB of SHBRV infected animals is a result of inadequate viral antigen-specific activation of CD4 T-cells in the brain capillaries. This work identifies a novel immune evasion strategy of pathogenic RV strains that contributes to the lethality of the infection, and suggests a possible approach to subvert the evasion process and clear the virus from the brain.
Roy, Anirban, "Immune evasion by silver-haired bat rabies virus and implications for treatment" (2008). ETD Collection for Thomas Jefferson University. AAI3480612.