Antibody mediated induction of type 1 interferon responses in the central nervous system (360G-Wellcome-202417_Z_16_Z)

Intrathecal synthesis of lipid-specific IgM antibodies in patients with multiple sclerosis (MS) is associated with a decreased risk of developing progressive multifocal leukoencephalopathy (PML), a potentially fatal opportunistic virus infection of the central nervous system (CNS). Exciting preliminary studies suggest this reflects induction of an interferon-alpha/beta receptor (IFNAR1)-dependent anti-viral response by an IgM response directed against sulphatide, a glycosphingolipid is highly enriched in CNS myelin. This project will build on these observations using a sulphatide-reactive IgM monoclonal antibody (mAb) O4 to explore how this suppresses replication of Semliki Forest Virus (SFV; a model neurotropic virus) in myelinating cultures derived from in wild type and IFNAR1-/- mice. Specifically we will: (1) Map the time course of infection to determine its cellular tropism, how this is effected by mAb O4 and dependency of these effects on IFNAR1 (2) Determine the time frame in which the mAb O4 mediates it protective effect, in particular whether we can exploit this therapeutically, as well as prophylactically Effects on viral replication will followed and quantified using a combination of immune fluorescence microscopy (to identify and quantify SFV infected cells) and qPCR to determine changes in copy numbers of viral transcripts.