Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis

Abstract

STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3’ untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING’s antiviral action.

Osteopontin contributes to virus resistance associated with type I IFN expression, activation of downstream ifn-inducible effector genes, and CCR2+CD115+CD206+ macrophage infiltration following ocular HSV-1 infection of mice

“…Such results correlated well with the expression of IFN-α1 which has been found to elicit robust resistance to HSV-1 replication ( 51 ). However, STING was not found to be elevated in the cornea of WT compared to OPN KO mice even though previously published data indicate the STING pathway is an integral defense against HSV-1 replication including the cornea and for which the virus attempts to counter through induction of cellular microRNA-24 ( 20 , 58 , 110 – 112 ). Likewise, the STING-inducible molecule, tetherin ( Bst2 ) did not display differential expression in the cornea comparing WT to OPN KO mice.…”

Development of a Multi-Epitope Vaccine for Mycoplasma hyopneumoniae and Evaluation of Its Immune Responses in Mice and Piglets

“…In the co-evolution of pathogens and host immune systems, pathogens with immune evasion mechanisms have been reported, including influenza A virus (IAV) [ 23 ], SARS-CoV-2 [ 24 ], Streptococcus pneumoniae [ 25 ], and herpes simplex virus 1 [ 26 ]. We proposed earlier that genomic variability and post-translational protein modification enhance the immune evasion of Mhp [ 5 ], which limits the general applicability of commercial vaccines.…”

Function and regulation of cGAS-STING signaling in infectious diseases

“…Moreover, besides affecting type I IFN induction, HSV-1 UL24 selectively restricts NF-κB promoter activation through binding NF-κB subunits p65 and p50 ( 148 ). Of note, besides HSV-1 encoded proteins, microRNA-24, which is induced by HSV-1 infection, targets the 3’ untranslated region of STING mRNA and impairs its translation ( 149 ).…”