MyD88 signalling in B cells and antibody responses during Oropouche virus-induced neurological disease in mice

Abstract

Background: Oropouche virus (OROV) is a neglected insect-borne orthobunyavirus that causes a febrile illness, neurological disease, and pregnancy complications in humans across an endemic area spanning South and Central America. The host factors associated with disease pathogenesis have nonetheless remained obscure, and little is known about the immune determinants of protection against OROV.

Methods: We tracked morbidity, mortality, viral loads, and serum neutralisation in wild-type (WT), Rag1^-/-, CD19-Cre⁺Ifnar^fl, and CD19-Cre⁺MyD88^fl mice and performed immunophenotyping experiments, passive serum transfers, and adoptive cell transfers to determine how early antibody responses and B cell subsets control viral replication and dissemination to the central nervous system after infection with OROV.

Findings: In line with a protective role for B cells, WT mice efficiently produced OROV-specific antibodies within 6 days of infection. Serum transfer containing neutralising IgM from WT to Rag1^-/- mice prevented neurological disease in OROV-challenged mice. CD19-Cre⁺MyD88^fl mice but not CD19-Cre⁺Ifnar^fl mice were vulnerable to neurological disease and produced lower titres of OROV-specific antibodies that exhibited suboptimal neutralisation and potency compared with MyD88-sufficient mice. CD19-Cre⁺MyD88^fl mice also presented with reduced numbers of marginal zone B (MZB) cells and plasmablasts after infection, which were associated with high viral burdens and lethality. Adoptive transfer of MZB cells from WT mice protected CD19-Cre⁺MyD88^fl mice and partially protected Rag1^-/- mice from lethal infection with OROV.

Interpretation: Early MyD88 signalling in B cells is required for optimal antibody responses that limit viral replication and neurological disease in mice infected with OROV.

Funding: São Paulo Research Foundation (FAPESP), National Council for Scientific and Technological Development (CNPq), Coordination for the Improvement of Higher Education Personnel (CAPES), Unicamp Research Affairs Office, PIPAE University of São Paulo, Wellcome Trust, and National Institute of Science and Technology on Photonics Applied to Cell Biology (INFABIC, Unicamp).

Keywords: Emerging viruses; IgM; Innate immune response; Marginal zone B cells; Oropouche virus; Vector-borne diseases.