Defining the role of antibodies and innate immunity in herpes simplex virus 1 (HSV1) brain infection and autoimmunity


Background: Herpes simplex virus 1 (HSV1) infects up to 90% of the population worldwide and establishes latency in peripheral nerves. Reactivations can occur and cause benign recurrent cold sores (recHSV), but also serious disease such as HSV1 encephalitis (HE), which can be complicated by a severe autoimmune encephalitis (AE post-HE). It remains unclear why some HSV1-infected patients only develop recHSV, whereas others develop HE, or why some are at risk to develop AE post-HE. My preliminary data suggest that host’s defense, and in particular the antibody response, accounts for such different effects. Aims: This study aims to determine the role of HSV1-specific antibody response in controlling HSV1 infection of the peripheral nerve (recHSV) versus the brain (HE) and in driving pathologic autoimmune anti-neuronal response (AE post-HE), by focusing in particular on the antibody-mediated innate immunity functions. Also, this study aims to identify prognostic factors for good/bad outcome and for development of post-HE AE. Finally, this study will define the functional role of HSV1 antibodies in neuronal death. Methods: This study will use cutting edge system biology techniques to profile antibody signatures in 3 groups of HSV1 infected patients: recHSV, HE and AE post-HE. These signatures will include determination of specific antibody targets, antibody classes, IgG subclasses, binding to Fc receptors (FcR), Fc-glycosilation, and capacity to mediate innate immunity functions (such as phagocytosis by monocytes or neutrophils, complement deposition and NK cells activation). These antibody signatures will identify prognostic factors of good outcome using univariate and multivariate regression models. Also, this project will explore the mechanisms of antibody-induced neuronal death (necrosis versus apoptosis) through an in vitro model of HSV1 infection of hippocampal neurons treated with patients’ HSV1 antibodies and challenged with different innate immune cells.