The Effect Of IFI16 Inflammasome Inhibitors Against Feline Herpesvirus-1 Inflammation

Feline viral rhinotracheitis(FVR)is a widespread infectious disease caused by feline herpesvirus-1(FHV-1)worldwide,and the main cause of upper respiratory tract infections.FHV-1 poses a serious threat to the life and health of cats and felines,so it has received a lot of clinical attention.The clinical manifestations of cats infected with FHV-1 are usually fever,depression,loss of appetite,increased eye and nasal secretions,facial or nasal dermatitis,conjunctivitis,frequent sneezing,excessive salivation,ulcerative keratitis,etc.The disease also causes the death of kittens,which are mainly caused by symptoms such as loss of appetite and dehydration caused by increased secretions from the eyes and nose.Therefore,inhibiting the inflammatory response caused by FHV-1 infection can be symptomatic treatment for the clinical symptoms of feline infectious rhinotracheitis,and can also inhibit the death caused by "inflammatory factor storm" and other reasons.At present,anti-herpes virus drugs such as lysine,interferon and famciclovir have been developed at home and abroad for the treatment of FVR,but the therapeutic effects are controversial and are rarely used in clinical practice.Our laboratory found in previous studies that infection with FHV-1 can activate the assembly of the IFI16 inflammasome in inflammatory cells,induce the activation of Caspase-1 and the secretion of IL-1β,and then induce the secretion of other pro-inflammatory cytokines,causing an inflammatory response.However,IFI16 inflammasome inhibitors can inhibit the secretion of IL-1β,so IFI16 inflammasome inhibitors can be considered for the anti-inflammatory treatment of FHV-1 infection.In this study,the inhibitors Z-VAD-FMK and Shikonin were first verified to have lower cytotoxicity at certain concentrations in in vitro experiments.In the process of studying the anti-FHV-1 effect of the inhibitor,through the detection of virus titer and virus gene expression level,it was found that the inhibitor would not affect the replication of the virus.However,in the study of the effect of inhibitors on inflammasome activation,it was found that they can inhibit IL-1β and TNF-α secreted by inflammatory cells stimulated by FHV-1,inhibit the activation of Caspase-1,and then inhibit other pro-inflammatory cytokines secretion.In conclusion,IFI16 inflammasome inhibitors can be considered for the anti-inflammatory treatment of FHV-1 infection.After that,considering various factors,the inhibitor Shikonin was selected to continue to explore its anti-FHV-1 effect in vivo.First,Shikonin was formulated into a working solution that could be used for in vivo experiments.After 24 hours of challenge,different doses of Shikonin were administered to experimental cats by nasal drop to evaluate its anti-FHV-1 effect.After administration of the inhibitor,the clinical symptoms of the infected cats were relieved,and the mortality rate was lower than that of the challenge group.Administration of the inhibitor Shikonin can inhibit the secretion of inflammatory factors IL-1β,IL-6 and TNF-α in cats,and reduce the inflammatory response caused by infection with FHV-1.Through blood routine and biochemical analysis,it was further found that Shikonin did not negatively affect the cat’s body.It can be seen that the inflammasome IFI16 inhibitor Shikonin can be considered as one of the clinical anti-inflammatory treatment candidates for FHV-1 infection,providing new ideas for the treatment of FHV-1.