Cyclophilin A: a possible host modulator in Chandipura virus infection

Abstract

Chandipura virus (CHPV), belonging to the genus Vesiculovirus of the family Rhabdoviridae, has been identified as one of the causes of pediatric encephalitis in India. Currently, neither vaccines nor therapeutic drugs are available against this agent. Considering that the disease progresses very fast with a high mortality rate, working towards the development of potential therapeutics against it will have a public health impact. Although the use of viral inhibitors as antiviral agents is the most common way to curb virus replication, the mutation-prone nature of viruses results in the development of resistance to antiviral agents. The recent development of proteomic platforms for analysis of purified viral agents has allowed certain upregulated host proteins that are involved in the morphogenesis and replication of viruses to be identified. Thus, the alternative approach of inhibition of host proteins involved in the regulation of virus replication could be explored for their therapeutic effectiveness. In the current study, we have evaluated the effect of inhibition of cyclophilin A (CypA), an immunophilin with peptidyl-prolyl cis/trans-isomerase activity, on the replication of CHPV. Treatment with cyclosporin A, used in vitro for the inhibition of CypA, resulted in a 3-log reduction in CHPV titer and an undetectable level of CypA in comparison to an untreated control. An in silico analysis of the interaction of the CHPV nucleoprotein with the human CypA protein showed stable interaction in molecular docking and molecular dynamics simulations. Overall, the results of this study suggest a possible role of CypA in facilitating CHPV replication, thus making it one of the potential host factors to be explored in future antiviral studies.

In vitro and in vivo testing of the antiviral effect of favipiravir (T705) against the neurotropic Chandipura virus

“…In the current JMV study, 1 the authors showed 70% plaque reduction of CHPV at 20 ug/mL and complete inhibition at 50 and 100 ug/mL of favipiravir in Vero cells. They calculated an EC 50 (concentration at which half of the virus is dead/neutralized) of 92.26 uM, which falls below the predicted cytotoxicity range (CC 50 ) of 4774 uM (750 ug/mL).…”

“…They calculated an EC 50 (concentration at which half of the virus is dead/neutralized) of 92.26 uM, which falls below the predicted cytotoxicity range (CC 50 ) of 4774 uM (750 ug/mL). 1 The selectivity index, the toxic concentration compared to active concentration of favipiravir against CHPV, was 51.24, which suggests a reasonably good range of concentrations of favipiravir needed to control CHPV infection that would not be toxic to the patients.…”

“…As part of this study, 1 the authors optimized a mouse model for CHPV infection, using 10-day old CD1 mice inoculated with 10 000 PFU of CPHV through an intraperitoneal route of injection, which resulted in 100% mortality. The authors showed 75% and 100% survival rates when the animals were treated orally with 100 and 300 mg/kg/day of favipiravir, respectively.…”

“…To the Editor, Chandipura virus (CHPV) is a negative-sense single-stranded RNA virus known to cause fatal encephalitis in the pediatric population. 1 It is a vector-borne virus in the family Rhabdoviridae that is transmitted by the sand fly species Phlebotomus sp., Sergentomyia sp., and the mosquito Aedes aegypti. 2 CHPV primarily replicates in neurons, which can lead to neuroinflammation and neuronal cell death.…”

“…3 Though it has been demonstrated that the probability of favipiravir-resistant influenza viruses developed during treatment appears low, which is an attractive feature of favipiravir, 12 it is important to determine whether drug-resistant CHPV can be developed, which has not been done in the JMV study. 1 It is also important to recognize the potential teratogenic and embryotoxic effects of favipiravir. 12…”