mAb therapy controls CNS-resident lyssavirus infection via a CD4 T cell-dependent mechanism

Kate E. Mastraccio, Celeste Huaman, Si'Ana A. Coggins, Caitlyn Clouse, Madeline Rader, Lianying Yan, Pratyusha Mandal, Imran Hussain, Anwar E. Ahmed, Trung Ho, Austin Feasley, Bang K. Vu, Ina L. Smith, Wanda Markotter, Dawn L. Weir, Eric D. Laing, Christopher C. Broder*, Brian C. Schaefer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre-symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti-lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11-dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell-dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ-binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization-independent T cell-mediated effects, even against an established CNS infection by a lethal neurotropic virus.

Original languageEnglish
Article numbere16394
JournalEMBO Molecular Medicine
Volume15
Issue number10
DOIs
StatePublished - 11 Oct 2023

Keywords

  • adaptive immunity
  • Australian bat lyssavirus
  • Fc function
  • monoclonal antibody
  • rabies

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