Herpes simplex encephalitis in adult patients with MASP-2 deficiency

Abstract

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 summaryHuman 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 PLOS Pathogens | https://doi.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.Herpes simplex encephalitis and MASP-2 deficiency PLOS Pathogens | https://doi.

Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis

“…Recently, two cases of HSE have been reported in adult patients harboring mutations in mannan-binding lectin serine protease 2 (MASP-2), the central activator of the lectin pathway of the complement system (153). The lectin pathway is involved in the recognition of mannan and carbohydrate structures present on the surface of pathogens by PRRs such as mannose-binding lectin, collectins, and ficolins (154).…”

“…MASP-2 has the ability to form complexes with these PRRs and initiates the cleavage of C4 and C2, which are involved in opsonization, inflammation, and lysis of infected cells. The first identified mutation was shown to reduce the secretion of the protein, whereas the second one resulted in an abolished protein secretion associated with an inability to cleave MASP-2 precursor into its active form, which led to decreased antiviral activity (153).…”

Novel Cationic Meso-Arylporphyrins and Their Antiviral Activity against HSV-1

“…Reactivation of the infection leads to relapse, and, in older people, the local inflammatory process, with viral latency in the neurons, can lead to the development of neurodegenerative diseases [ 7 ]. Herpetic infection also causes severe complications in immunocompromised patients, pregnant women and newborns [ 8 , 9 ]. According to the cryoelectron tomography, HSV-1 is an enveloped virus, with a sphere diameter of 186 nm and, including glycoprotein protrusions, a diameter of 225 nm [ 10 ].…”

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

“…MASP deficiencies are rare ( Degn et al, 2011 ). MASP-2 deficiency was the first MASP deficiency to be described and has been associated with recurrent infections and chronic inflammatory diseases ( Stengaard-Pedersen et al, 2003 ; Bibert et al, 2019 ). However, it appears not to be indispensable since deficiencies are observed in healthy individuals and blood donors ( García-Laorden et al, 2020 ).…”