Monoclonal antibody therapy promotes survival by recalibrating neuroinflammation during Australian Bat Lyssavirus Infection 2308563

Abstract Introduction Australian Bat Lyssavirus (ABLV), a neurotropic relative of Rabies virus, causes fatal encephalitis. Effective treatment for symptomatic infections remains elusive. Our prior work showed that an anti-ABLV monoclonal antibody (mAb) F11 or A6 can prevent disease even after the establishment of central nervous system (CNS) infection. Survival requires CD4 T cell-dependent immunity. mAb therapy alters CNS leukocyte composition, suggesting mAb-driven immune restructuring. The precise mechanism of protection is unclear; specifically, whether mAb protection results from enhancing overall immunity or from moderating inflammation. We hypothesized that F11 or A6 therapy promotes survival by recalibrating, rather than enhancing, CNS immune activation. Methods Mice were infected with a lethal dose of ABLV in the rear footpad. On day 5 post-infection, mice received mAb (F11 or A6), an isotype control mAb, or mock treatment. Brain tissue was analyzed on day 13 or 14 post-infection using multiplex cytokine assays, bulk RNA sequencing, and flow cytometry to compare immune signatures across treatment groups. Results Mock-treated mice showed elevated levels of inflammatory cytokines, type I/II interferons, and chemokines associated with myeloid, NK, and T cell recruitment, with transcriptomic enrichment for neuroinflammation and interferon/STAT pathways. In contrast, F11 or A6 therapy produced distinct transcriptional signatures marked by coordinated downregulation of inflammatory pathways and reduced cytokine and chemokine expression. Despite reduced inflammation, treated mice displayed increased numbers of CD11b+MHCII+ myeloid cells and a higher CD4:CD8 T cell ratio. Conclusion Therapy with F11 or A6 dampens interferon-driven inflammation while promoting balanced immunity in the CNS. Survival correlates with reduced pro-inflammatory cytokine expression and altered phenotypes of infiltrating immune cells, suggesting that excessive inflammation is detrimental to survival during ABLV infection. Funding Source US Department of Defense Topic Categories Vaccines and Immunotherapy (VAC)