Whole-Exome Sequencing of Patients With Recurrent HSV-2 Lymphocytic Mollaret Meningitis.

Recurrent lymphocytic meningitis, also referred to as Mollaret meningitis, is a rare neurological disease characterized mainly by reactivation of herpes simplex virus 2 (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 15 patients diagnosed with Mollaret meningitis. By whole-exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in (1) ubiquitin-proteasome pathways, (2) the autophagy machinery, and (3) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived double-stranded DNA ligands revealed reduced antiviral interferon 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, and may ultimately be of importance for identification of targets for development of improved prophylaxis and treatment of this disease.

Host Genetics, Innate Immune Responses, and Cellular Death Pathways in Poliomyelitis Patients.

PURPOSE: Poliovirus (PV) is one of the most studied viruses. Despite efforts to understand PV infection within the host, fundamental questions remain unanswered. These include the mechanisms determining the progression to viremia, the pathogenesis of neuronal infection and paralysis in only a minority of patients. Because of the rare disease phenotype of paralytic poliomyelitis (PPM), we hypothesize that a genetic etiology may contribute to the disease course and outcome. METHODS: We used whole-exome sequencing (WES) to investigate the genetic profile of 18 patients with PPM. Functional analyses were performed on peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MdMs). RESULTS: We identified rare variants in host genes involved in interferon signaling, viral replication, apoptosis, and autophagy. Upon PV infection of MdMs, we observed a tendency toward increased viral burden in patients compared to controls, suggesting reduced control of PV infection. In MdMs from patients, the IFNß response correlated with the viral burden. CONCLUSION: We suggest that genetic variants in innate immune defenses and cell death pathways contribute to the clinical presentation of PV infection. Importantly, this study is the first to uncover the genetic profile in patients with PPM combined with investigations of immune responses and viral burden in primary cells.