Abstract
The immune competence of an individual is a major determinant of morbidity in West Nile virus (WNV)-infection. Previously, we showed that immunocompetent New Zealand White rabbits (NZWRs; Oryctolagus cuniculus) are phenotypically resistant to WNV-induced disease, thus presenting a suitable model for study of virus-control mechanisms. The current study used corticosteroid-treated NZWRs to model acute “stress”-related immunosuppression. Maximal effects on immune parameters were observed on day 3 post dexamethasone-treatment (pdt). However, contrary to our hypothesis, intradermal WNV challenge at this time pdt produced significantly lower viremia 1 day post-infection (dpi) compared to untreated controls, suggestive of changes to antiviral control mechanisms. To examine this further, RNAseq was performed on RNA extracted from draining lymph node—the first site of virus replication and immune detection. Unaffected by dexamethasone-treatment, an early antiviral response, primarily via interferon (IFN)-I, and induction of a range of known and novel IFN-stimulated genes, was observed. However, treatment was associated with expression of a different repertoire of IFN-α-21-like and IFN-ω-1-like subtypes on 1 dpi, which may have driven the different chemokine response on 3 dpi. Ongoing expression of Toll-like receptor-3 and transmembrane protein-173/STING likely contributed to signaling of the treatment-independent IFN-I response. Two novel genes (putative HERC6 and IFIT1B genes), and the SLC16A5 gene were also highlighted as important component of the transcriptomic response. Therefore, the current study shows that rabbits are capable of restricting WNV replication and dissemination by known and novel robust antiviral mechanisms despite environmental challenges such as stress.
Highlights
West Nile virus (WNV) is a mosquito-borne flavivirus that has the potential to cause fatal encephalitis in humans, horses, birds and several other animals
As a pilot study to validate the changes in immune responses associated with dexamethasone treatment and to investigate the optimal time post-dexamethasone treatment for WNV inoculation in the subsequent study, four New Zealand White rabbits (NZWRs) of approximately 4–5 weeks of age were injected with 6.5 mg/kg of dexamethasone intramuscularly and bled once prior to treatment and daily thereafter for 7 days
We have presented data for our studies examining the effect of acute “stress”, in the form of a single systemic injection of the synthetic corticosteroid drug dexamethasone, on viral replication and the antiviral innate immune response following intradermal WNV infection in young rabbits
Summary
West Nile virus (WNV) is a mosquito-borne flavivirus that has the potential to cause fatal encephalitis in humans, horses, birds and several other animals. Pathogens 2019, 8, 195 significance with disease outbreaks occurring in Europe, Africa, the Middle East and the Americas. Highly virulent strains of WNV have been exotic to Australia, a strain of low virulence (Kunjin-KUNV) has circulated here for more than 50 years, causing only rare cases of mild clinical disease in humans and horses [2,3]. This scenario changed dramatically in 2011 when an unprecedented outbreak of equine WNV encephalitis occurred in south eastern Australia. More than 1000 horses were affected, with a mortality rate of 10–15% [4]
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