Monoclonal antibody therapy augments production of virus-specific CD4 T cells during Australian bat lyssavirus infection of the CNS 2309800

Abstract

Abstract Introduction Developing therapeutic countermeasures that can target pathogens within the central nervous system (CNS) remains a challenging task. Rabies virus and other lyssaviruses are well-known examples of neurotropic pathogens that can efficiently evade both the host immune response and current therapeutic strategies. Australian bat lyssavirus (ABLV) is a member of the lyssavirus genus and is known to causes disease that is indistinguishable from rabies. Rabies is uniformly fatal once the infection has entered the CNS, and there is currently no effective treatment post-CNS involvement. Previously, our group demonstrated that a single dose of monoclonal antibody (mAb) treatment can prevent mortality even in mice with established CNS infections, and mAb-mediated survival was CD4 T-cell dependent. To investigate the mechanism of enhancement of the host adaptive immune response, we have developed tools to assess the dynamics of virus-specific CD4 T-cells produced in ABLV-infected mice. Methods Using a novel anti-lyssavirus MHC II tetramer, we quantified virus-specific CD4 T-cell responses in the spleens and brains of infected mice that received mock- or mAb-treatment. Results We found evidence of anti-lyssavirus CD4 T-cells in the spleen as early as day 8 post-infection in infected animals, and this population increased until ≥28 days post-infection in infected mAb-treated mice. We also found a higher frequency of anti-lyssavirus CD4 T-cells in the brains of infected mAb-treated mice on day 14 post-infection, when compared to infected, mock-treated mice. Interestingly, although there were fewer ABLV-specific T-cells in the mock-treated animals, these T-cells produced much more IFN-γ than the T-cells isolated from mAb-treated mice. Conclusion Collectively, our data suggests that mAb treatment can alter the T-cell response by augmenting the generation of virus-specific CD4 T-cells and by modulating effector cytokine production by these T-cells. Funding Source U.S. Department of Defense Topic Categories Vaccines and Immunotherapy (VAC)