Crosstalk Between Glucocorticoid Receptor and Mineralocorticoid Receptor Regulates Herpes Simplex Virus 1 Reactivation from Latency

Following herpes simplex virus-1 (HSV-1) acute infection, sensory neurons in trigeminal ganglia (TG) are important sites for life-long latency. Acute or chronic stress increases the incidence of HSV-1 reactivation from latency, in part because the glucocorticoid receptor (GR) is activated. GR antagonists impair HSV-1 replication and explant-induced reactivation from latency. A mouse strain expressing GR with a serine 229 mutated to alanine (GRS229A) previously revealed that female GRS229A mice latently infected with HSV-1 shed significantly lower virus in TG during explant-induced reactivation when compared to male GRS229A mice and wild-type (wt) C57BL/6J mice regardless of sex. A new study demonstrated that heat-stress-induced HSV-1 reactivation from latency is significantly reduced in female GRS229A mice but not male GRS229A mice or wt C57BL/6J mice. A mineralocorticoid receptor (MR)-specific antagonist (Esaxerenone) increased explant-induced or heat-stress-increased reactivation from latency in female GRS229A mice but not male GRS229A mice or wt C57BL/6J mice regardless of sex. Additional studies revealed Esaxerenone increased virus shedding in primary kidney cells prepared from GRS229A males or females and neuroblastoma cells (Neuro-2A). In conclusion, this study revealed virus shedding was reduced in the TG of GRS229A female mice when reactivation from latency was induced by explant or heat stress; but, Esaxerenone rescued reactivation in GRS229A female mice.