Dataset Information

Favipiravir treatment prolongs the survival in a lethal mouse model intracerebrally inoculated with Jamestown Canyon virus.

ABSTRACT:

Background

Jamestown Canyon virus (JCV) is a mosquito-borne orthobunyavirus that causes acute febrile illness, meningitis, and meningoencephalitis, primarily in North American adults. Currently, there are no available vaccines or specific treatments against JCV infections.

Methodology/principal findings

The antiviral efficacy of favipiravir (FPV) against JCV infection was evaluated in vitro and in vivo in comparison with that of ribavirin (RBV) and 2'-fluoro-2'-deoxycytidine (2'-FdC). The in vitro inhibitory effect of these drugs on JCV replication was evaluated in Vero and Neuro-2a (N2A) cells. The efficacy of FPV in the treatment of JCV infection in vivo was evaluated in C57BL/6J mice inoculated intracerebrally with JCV, as per the survival, viral titers in the brain, and viral RNA load in the blood. The 90% inhibitory concentrations (IC90) of FPV, RBV, and 2'-FdC were 41.0, 61.8, and 13.6 μM in Vero cells and 20.7, 25.8, and 8.8 μM in N2A cells, respectively. All mice infected with 1.0×104 TCID50 died or were sacrificed within 10 days post-infection (dpi) without treatment. However, mice treated with FPV for 5 days [initiated either 2 days prior to infection (-2 dpi-2 dpi) or on the day of infection (0 dpi-4 dpi)] survived significantly longer than control mice, administered with PBS (p = 0.025 and 0.011, respectively). Moreover, at 1 and 3 dpi, the virus titers in the brain were significantly lower in FPV-treated mice (0 dpi-4 dpi) versus PBS-treated mice (p = 0.002 for both 1 and 3 dpi).

Conclusions/significance

Although the intracerebral inoculation route is thought to be a challenging way to evaluate drug efficacy, FPV inhibits the in vitro replication of JCV and prolongs the survival of mice intracerebrally inoculated with JCV. These results will enable the development of a specific antiviral treatment against JCV infections and establishment of an effective animal model.

SUBMITTER: Kato H

PROVIDER: S-EPMC8281987 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Jamestown Canyon virus (JCV), a negative-sense arbovirus, is increasingly common in the upper Midwest of the USA. Transmitted by a range of mosquito genera, JCV's primary amplifying host is white-tailed deer. Aedes aegypti is responsible for transmitting various positive-sense viruses globally including dengue (DENV), Zika, chikungunya, and Yellow Fever. Ae. aegypti's distribution, once confined to the tropics, is expanding, in part due to climate change. Wolbachia, an insect endosymbiont, limits the replication of co-infecting viruses inside insects. The release and spread of the symbiont into Ae. aegypti populations have been effective in reducing transmission of DENV to humans, although the mechanism of Wolbachia-mediated viral blocking is still poorly understood. Here we explored JCV infection potential in Ae. aegypti, the nature of the vector's immune response, and interactions with Wolbachia infection. We show that Ae. aegypti is highly competent for JCV, which grows to high loads and rapidly reaches the saliva after an infectious blood meal. The mosquito immune system responds with strong induction of RNAi and JAK/STAT. Neither the direct effect of viral infection nor the energetic investment in immunity appears to affect mosquito longevity. Wolbachia infection blocked JCV only in the early stages of infection. Wolbachia-induced immunity was small compared to that of JCV, suggesting innate immune priming does not likely explain blocking. We propose two models to explain why Wolbachia's blocking of negative-sense viruses like JCV may be less than that of positive-sense viruses, relating to the slowdown of host protein synthesis and the triggering of interferon-like factors like Vago. In conclusion, we highlight the risk for increased human disease with the predicted future overlap of Ae. aegypti and JCV ranges. We suggest that with moderate Wolbachia-mediated blocking and distinct biology, negative-sense viruses represent a fruitful comparator model to other viruses for understanding blocking mechanisms in mosquitoes.

Project description:During the summers of 2017-2019, 60 human cases of Jamestown Canyon virus-associated disease were reported in the State of Wisconsin, U.S.A; by comparison, there were 28 cases in the 5 years prior. Jamestown Canyon virus (JCV, Peribunyaviridae: Orthobunyavirus) is a zoonotic, mosquito-borne virus that is endemic throughout North America. The proposed transmission cycle for JCV involves horizontal transmission by a variety of mammal-feeding mosquito species and deer hosts, and transseasonal maintenance by vertical transmission in Aedes mosquito species. Although some of the earliest work on JCV transmission and disease was done in Wisconsin (WI), little is known about the spectrum of mosquitoes that are currently involved in transmission and maintenance of JCV, which is key to inform the approach to control and prevent JCV transmission, and to understand why case numbers have increased dramatically in recent years. Therefore, we undertook an intensive surveillance effort in Sawyer and Washburn counties, WI between April and August of 2018 and 2019, in an area with a concentration of JCV human cases. Larval and adult stages of mosquitoes were surveyed using larval dippers and emergence traps, light traps, resting boxes, a Shannon-style trap, and backpack aspirator. In total, 14,949 mosquitoes were collected in 2018, and 28,056 in 2019; these specimens represent 26 species in 7 genera. Suspect vector species were tested for JCV by polymerase chain reaction (PCR); of 23 species that were tested, only Aedes provocans yielded JCV positive results. In 2018, a single pool of Ae. provocans tested positive. In 2019, with more focused early season surveillance, we detected JCV in 4 pools of adult mosquitoes, and one pool that consisted of lab-raised adults that were collected as larvae. Material from all of these PCR-positive samples also yielded infectious virus in cell culture. Overall, these data provide new insight into the seasonality and habitat preferences for 26 mosquito species in Northern WI, which will be useful to inform future surveillance efforts for JCV. The results underscore the importance of Ae. provocans as a vector species involved in transseasonal maintenance of JCV in this region.