Protection Against Japanese Encephalitis Virus in Mice and Hamsters by Treatment with Carboxymethylacridanone, a Potent Interferon Inducer

Abstract

A low-molecular-weight chemical inducer of interferon, 10-carboxymethyl-9-acridanone (CMA), effectively prevented death caused by Japanese encephalitis virus (JEV) injected peripherally into weanling mice and baby hamsters. Marked reductions in mortality were seen in mice when a single dose of CMA was administered intraperitoneally, subcutaneously, or intramuscularly to animals challenged intraperitoneally with JEV. The degree of protection was dependent on dose and time of administration of CMA in relation to virus challenge: all hamsters given CMA on the same day as JEV survived, with lesser although still significant protection when CMA was given one or two days after JEV. Viremia, an important characteristic of the pathogenesis of natural JEV infection, was reduced nearly 10,000-fold in hamsters treated with CMA. Thus, in the experimental animal models developed for these studies, CMA provided marked therapeutic and prophylactic effect against JEV.

Delayed Cytosolic Exposure of Japanese Encephalitis Virus Double-Stranded RNA Impedes Interferon Activation and Enhances Viral Dissemination in Porcine Cells

“…Accordingly, late IFN treatment implies more difficulty in inhibiting viral replication. This principle is reiterated in the in vitro and in vivo studies of Harinasuta et al (11) and Taylor et al (42), respectively. However, when Diamond and his group (4) performed a similar experiment on DENV, IFN treatment postinfection did not inhibit viral replication and dissemination, although IFN treatment prior to infection did.…”

“…Indeed, IFN has been noted to be a potent antiviral agent against JEV in vitro and in vivo (7,11,42,45). However, in the IFN-producing porcine PS, PK, and ESK cell lines, JEV manages to propagate well, as indicated by its plaque-foming foci and high-titer replication (Fig.…”

The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response

“…This inhibition of IFN expression is supported by a complimentary in vitro study, which revealed by ribonuclease protection assay that IFN-α2 expression was depressed in vesicular stomatitis virus (VSV)-infected L929 cultures supplemented with SGE (Limesand et al 2003). The contribution of type I IFN towards recovery from infection and defence against arboviruses has been demonstrated in vivo by the therapeutic and prophylactic effects of administration of IFN-inducers or IFN (Haahr 1971, Taylor et al 1980, Vargin et al 1977. After a low-dose infection with the flavivirus Murray Valley encephalitis virus, mice deficient in IFN-α receptor succumb to infection, in contrast to a 70% survival rate in wild-type mice (Lobigs et al 2003).…”

Immunobiology of Japanese Encephalitis Virus

“…IFN production after JEV infection was initially documented in mice (Rokutanda, 1969) and later in humans (Burke & Morill, 1987). Early in vitro and in vivo animal studies depicting its significance as an antiviral compound against JEV employed the use of IFN inducers (Ghosh et al, 1990;Taylor et al, 1980) and recombinant IFN- (Crance et al, 2003). Furthermore, mice deficient in IFN-receptor infected with JEV show sustained high viremia and fulminant disease Lobigs et al, 2009), demonstrating that type I IFN is a key tropism determinant of JEV.…”