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Herpes simplex virus (HSV-1), which is extremely common on earth but mostly benign, can nevertheless cause lethal viral encephalitis in 2-4 people per million people each year if left untreated. These forms of encephalitis (HSE) occur most frequently between the ages of 6 months and 3 years, and may be followed by recurrences in adulthood. The virus accumulates in the central nervous system, where it causes significant neurological damage.
Since 2006, spontaneous mutations in the TLR3 and IFNAR1 pathways have been identified as contributing to susceptibility to this disease, due to deficits in type I interferon (IFN-I)-mediated antiviral immunity in intrinsic cells of the central nervous system. On the other hand, mutations in the SNORA31 and DBR1 genes have been identified in other children with HSE, due to alterations in novel antiviral mechanisms not yet fully established.
More recently, the team at Institut Imagine accompanied a young French girl, generally healthy, who suffered two attacks of HSE very early in her life. The sequencing of her genome made it possible to target the RIPK3 candidate gene, which allows the synthesis of a ubiquitous kinase regulating cell death (in particular apoptosis and necroptosis), and which had two different mutations in the patient, each of which had the effect of altering the RIPK3 protein. It has already been established that the regulation of cell death allows the body to defend itself against herpes viruses, notably by limiting the "spaces" in which the viruses can reproduce and accumulate, thus increasing the viral load.
To confirm that these mutations were linked to the emergence of HSE in the girl, the team measured the level of RIPK3 protein expressed in the patient's cells. They were unable to detect RIPK3 in the patient's fibroblasts, which were also found to be particularly susceptible to HSV-1 infection. Similarly, a very low rate of programmed cell death, accompanied by a very high rate of HSV-1 replication, could be measured in neurons derived from the girl's hPSC (human pluripotent stem cells).
These data confirm that antiviral immunity of neurons is dependent on RIPK3-regulated apoptosis and necroptosis. If this cellular mechanism fails, neurons are much more susceptible to HSV-1 infection; the progression of this infection is itself potentially dependent on pathways involving TLR3, ZBP1/DAI and/or other factors, which have long been suspected to be involved in cell death, and which are thought to be controlled by, among other things, RIPK3. Recessive RIPK3 deficiency is the 15th genetic cause of HSE identified to date.