The IKKepsilon serine/threonine protein kinase in herpes simplex virus type 2 meningitis

The overarching goal of the present project is to explore the role of the serine/threonine protein kinase IKKe in HSV2 infection and to delineate the physiologic role of this protein enzyme in antiviral defense in the central nervous system (CNS).

We have, through exome sequencing, identified a HSV2 meningitis patient with severely impaired type I IFN responses to HSV2 who has a heterozygote point mutation in the IKBKE gene encoding IKKe. The mutation leads to a frameshift in the amino acid sequence and a truncated IKKe protein.

We will characterize the molecular pathways affected by this mutation using patient blood lymphocytes, fibroblasts and iPSC-generated microglia and state-of-the art techniques such as siRNA-knockdown, lentiviral transduction, western blot, FACS sorting and qPCR We have also introduced the patient IKBKE mutation in mice via CRISPR/Cas9 editing and we will infect these mice with HSV2 to prove that the truncated IKKe predisposes to HSV2 meningitis.

The acquired knowledge from our research will help to identify fundamental mechanisms that control viral infection and reactivation in the CNS and create opportunities for the development of prophylactic treatments and antiviral therapies.