Herpes simplex encephalitis in adult patients with MASP-2 deficiency

We report here two cases of Herpes simplex virus encephalitis (HSE) in adult patients with very rare, previously uncharacterized, non synonymous heterozygous G634R and R203W substitution in mannan-binding lectin serine protease 2 (MASP2), a gene encoding a key protease of the lectin pathway of the complement system. None of the 2 patients had variants in genes involved in the TLR3-interferon signaling pathway. Both MASP2 variants induced functional defects in vitro, including a reduced (R203W) or abolished (G634R) protein secretion, a lost capability to cleave MASP-2 precursor into its active form (G634R) and an in vivo reduced antiviral activity (G634R). In a murine model of HSE, animals deficient in mannose binding lectins (MBL, the main pattern recognition molecule associated with MASP-2) had a decreased survival rate and an increased brain burden of HSV-1 compared to WT C57BL/6J mice. Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE. Author summary Human herpes virus type 1 (HSV-1) infects a large number of individuals during their life, with manifestations usually limited to mild and self-limiting inflammation of the oral mucosa (cold sore). However, HSV-1 can cause a very severe disease of the brain called Herpes simplex encephalitis (HSE) in 1 out of 250'000-500'000 individuals per year. The reasons why HSV-1 can cause such a devastating disease in a very limited number of individuals are unknown. Increasing evidence suggests that susceptibility to HSE in children can results from genetic variations in the immune system, in particular in a viral detection pathway called the Toll-like receptor 3 (TLR3)-interferon (IFN) axis. Fewer data are available to explain HSE in adult patients. Here, we describe two adult patients with HSE who carry mutations in a gene called mannan-binding lectin serine protease 2 (MASP2), which is part of an immune pathway different from the TLR3-IFN axis, called the lectin pathway of the complement system. We demonstrate that MASP2 mutations induce functional defects in immune defense against HSV-1 that prevent viral replication. Mice deficient in the lectin pathway have higher mortality compared to wild-type mice after HSV-1 infection. Altogether, our study suggests that susceptibility to HSE in adults relies of immune deficiencies that are different from those causing HSE in children.