Role Of IL-34 In Japanese Encephalitis Virus Infection

Japanese encephalitis virus(JEV)infection is a mosquito-borne meningitis,which is most predominant in Southeast Asian countries.JEV infection is directly related to the perturbation of the microenvironment in the brain.This microenvironment system consists mainly of the cytokines that are released by the immune cells like microglia.In normal physiological condition,microglia is at rest.In contrast,after stimulation like an infection,microglia is activated to act as phagocyte and secretes inflammatory cytokines,which are necessary to fight against pathogen attack.But at the same time,uncontrolled secretion of these cytokines causes several detrimental effects.One of the damaging effects of robust inflammation is that it may cause the disruption of the bloodbrain barrier(BBB).The BBB is known to act as a physical layer that resists microbe dissemination into the central nervous system(CNS).Several studies have been conducted to understand the exact pathogenesis and the mechanisms involved in the virus spread to the CNS.However,the phenomenon and mechanism involved in this process are not clear to date.In our study,we exploit the role of IL-34 in JEV disease pathogenesis and progression.IL-34 is one of the novel cytokines,which has gained focus recently due to its role in the development of microglial cells.Earlier studies have reported that deletion of IL-34 leads to impaired microglial development.It is reported in west-nile virus infection that IL-34 deleted mice lacked microglia and thus showed lesser antiviral activity against viral attack in the CNS.However,whether JEV infection modulates the expression of IL-34,or whether or not IL-34 is involved in JEV disease pathogenesis,is not known.Our preliminary data showed the induction of IL-34 post-JEV infection.This result paved our current research study to understand the role of this induction.The goal of this study was to understand the extensive role of IL-34 in JEV disease pathogenesis,including its part in the microglial activity.We set up IL-34 knockout models and infected them with intraperitoneal injections using virulent JEV strains to get insights into the role of the cytokine post JEV infection.Our study demonstrated an interesting improved trend in survival in the IL-34 knockout mice compared to the wild type mice post JEV encounter.We also found that viral infection was not the key for this improved survival trend.Furthermore,our results demonstrated that the IL-34 knockout mice had significantly dampened inflammatory responses post JEV infection,which was the reason behind their improved survival trend.Previous data also exhibits the importance of inflammation in BBB disruption;we found through our data that IL-34 deletion leads to improved survival in mice along with a significant reduction in inflammatory cytokine expression.Therefore,to know exactly how IL-34 effects the disease progression we studied the effect of IL-34 in relation with BBB permeability using mice model.We infected mice of both the genotypes with JEV and physically broke the BBB by brain punch.Our data demonstrated that BBB is crucial for viral dissemination into the brain.In addition,IL-34 induction post-JEV infection causes the robust expression of pro-inflammatory and inflammatory cytokines,which in turn act on the BBB,and makes it more permeable.BBB permeability aids in rapid virus entry to the brain and thus causes more infection in the brain.Hence,the robust inflammatory responses and the rapid viral entry into the brain together lead to encephalitis and neuronal death.Taken together,our study elucidates that IL-34 induction has a key role in expanding the JEV infection in the brain by influencing the BBB integrity.