Whole Exome Sequencing of patients with recurrent HSV-2 lymphocytic Mollaret's meningitis.

Recurrent lymphocytic meningitis (RLM), also referred to as Mollaret's meningitis is a rare neuro-disease characterized mainly by reactivation of herpes simplex virus (HSV)-2 from sensory ganglia. However, the underlying host immune determinants and viral factors rendering some individuals unable to maintain HSV-2 latency are largely unknown. We collected a cohort of fifteen patients diagnosed with Mollaret's meningitis. By whole exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in i) ubiquitin-proteasome pathways, ii) the autophagy machinery, and iii) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived dsDNA ligands revealed reduced antiviral interferon (IFN) responses in most patients. These findings may contribute to a better understanding of disease pathogenesis and protective immunity to HSV in the central nervous system (CNS), and may ultimately be of importance for identification of therapeutic targets for development of improved prophylaxis and treatment of this disease.