Tissue-specific transcription profile of cytokine and chemokine genes associated with flavivirus control and non-lethal neuropathogenesis in rabbits

Suen, Willy W.; Uddin, Muhammad Jasim; Prow, Natalie A.; Bowen, Richard A.; Hall, Roy A.; Bielefeldt‐Ohmann, Helle

doi:10.1016/j.virol.2016.03.026

Cited by 9 publications

(11 citation statements)

References 49 publications

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“…Both of these chemokines bind to the chemokine receptor CXCR3, the signaling through which has been shown to be very important in many viral infections [54][55][56][57]. We previously demonstrated upregulation of CXCL10 in brain and draining lymph node following WNV infection in rabbits [20,21] and this was validated for the draining lymph node in this study in both dexamethasone treated and untreated rabbits. We also demonstrated equally potent upregulation of CXCL9 in a similar time-and treatment-independent manner (Figure 6B, Table 4).…”

Section: • Ifn-signalingsupporting

confidence: 71%

“…In our previous studies, we demonstrated the draining popliteal lymph node was the first tissue site with detectable tissue viral load [20,21], and thus, a suitable site for study of early antiviral responses. Therefore, RNA was extracted from the draining lymph node and RNAseq was performed in order to examine potential differences in the early immune response between dexamethasone and mock-treated rabbits.…”

Section: Differential Gene Expression Analyses Of Rna Extracted From Fraining Lymph Nodesmentioning

confidence: 99%

“…The much-exaggerated level of morbidity and mortality in mice following WNV-infection suggests a potentially different pathogenesis of disease in this species compared to humans and horses [10,[15][16][17], and call into question the utility of the mouse models for study of human [18,19] and equine [17] WNV infections. We have developed a rabbit model of non-lethal WNV infection, which mimics the course of the majority of human and equine WNV-infections, including low, transient viremia, and no or negligible morbidity despite histopathological evidence of infection-induced neuro-inflammation and virus replication in peripheral tissues [17,20,21].…”

Section: Introductionmentioning

confidence: 99%

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An Acute Stress Model in New Zealand White Rabbits Exhibits Altered Immune Response to Infection with West Nile Virus

et al. 2019

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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.

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Section: • Ifn-signalingsupporting

confidence: 71%

Section: Differential Gene Expression Analyses Of Rna Extracted From Fraining Lymph Nodesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Acute Stress Model in New Zealand White Rabbits Exhibits Altered Immune Response to Infection with West Nile Virus

et al. 2019

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“…Subjects with severe WNV infection have downregulated IL-4, IL-1β (peripheral blood cells), and CXCL1 (myeloid dendritic cells) [ 417 , 418 ]. There is other evidence of upregulation of IFN γ, TNFα an IL-6 in the CNS during the acute phase of neuroinvasive WNV infection [ 419 ]. Likewise, it was demonstrated that IL-10 gene expression is upregulated in plasma during the acute phase of infection with WNV [ 420 ].…”

Section: Biomarkers Of Wnv Infectionmentioning

confidence: 99%

West Nile Virus: An Update on Pathobiology, Epidemiology, Diagnostics, Control and “One Health” Implications

et al. 2020

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West Nile virus (WNV) is an important zoonotic flavivirus responsible for mild fever to severe, lethal neuroinvasive disease in humans, horses, birds, and other wildlife species. Since its discovery, WNV has caused multiple human and animal disease outbreaks in all continents, except Antarctica. Infections are associated with economic losses, mainly due to the cost of treatment of infected patients, control programmes, and loss of animals and animal products. The pathogenesis of WNV has been extensively investigated in natural hosts as well as in several animal models, including rodents, lagomorphs, birds, and reptiles. However, most of the proposed pathogenesis hypotheses remain contentious, and much remains to be elucidated. At the same time, the unavailability of specific antiviral treatment or effective and safe vaccines contribute to the perpetuation of the disease and regular occurrence of outbreaks in both endemic and non-endemic areas. Moreover, globalisation and climate change are also important drivers of the emergence and re-emergence of the virus and disease. Here, we give an update of the pathobiology, epidemiology, diagnostics, control, and “One Health” implications of WNV infection and disease.

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“…Firstly, a Swiss white CD1 mouse model, typically producing high mortality rate when infected with the virulent Australian strain, WNV NSW2011 , was used to explore WNV neuropathogenesis [100,219,246] (Chapter 3 and 4). The second half of this thesis established a phenotypically resistant animal model in rabbits for studying the clinical, virological, pathological and immunological features of non-lethal WNV infections with equine-virulent strains, which are the predominant presentation of human and equine WNV infections [263,311] (Chapter 5 and 6).…”

Section: Chapter 7 General Discussion and Conclusionmentioning

confidence: 99%

Investigation of neuropathogenesis and control of an equine-pathogenic Australian West Nile virus isolate in an established CD1 Swiss white mouse and a novel rabbit model

Suen¹

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West Nile virus (WNV) is a globally significant mosquito-borne neurotropic virus. In 2011, a large-scale arboviral encephalitis outbreak occurred in Australia, involving close to 1000 horses. A virulent WNV strain, WNV NSW2011 , was isolated from the brain of an encephalitic horse during this outbreak. Preliminary assessment showed that this strain is intermediate in virulence and belongs in the same lineage as the highly virulent North American strains. However, the pathogenesis of WNV in general, let alone this novel Australian strain, remains largely unclear.The first part of the project aimed to investigate the pathogenesis of lethal WNV NSW2011 infection in the established young adult Swiss white (CD1) mouse model, since previous survival challenge experiments demonstrated high lethality (~70%) of WNV NSW2011 in this animal model. I conducted a pilot time-course experiment, which demonstrated only benign pathological and virological outcomes in sacrificed mice on day 3 and 7 post-infection (pi), despite the relatively high lethality seen in previous survival trials. In a subsequent experiment, I characterised the disease phenotype in moribund/dead and surviving mice after WNV NSW2011 infection. Notably, I detected a high degree of intra-group variability in the neuropathology, neural infection and glial cell activation. Even cases with neuroinvasion are typically not fatal, unless underlying co-morbidities or immunosuppressive disease exist.I chose rabbits as a candidate for a novel animal model, due to the ease of performing intra-vital sampling and monitoring, as well as the possibility for tissue sharing in different assays, given the larger size of rabbits than mice. Rabbits are also hind-gut fermenters, and thus may be a better representation of a horse than a mouse. New Zealand White (NZWRs; Oryctolagus cuniculus) and iii North American cottontail rabbits (CTRs; Sylvilagus sp.) were challenged with WNV strains of different virulence (WNV NSW2011 and WNV TX8667 ), and the prototype Murray Valley encephalitis virus strain (MVE 1-51 ), by the footpad route. The rabbits were consistently resistant to developing severe disease after virulent WNV and MVEV infection, regardless of age, gender and species, despite productive virus replication in the draining popliteal lymph node (PLN). The resultant viraemia for all rabbits was also of low magnitude and transient. Furthermore, establishment of virus infection in the brain was not a feature of the disease, despite mild to moderate neuropathology in a subset of rabbits. This capacity to control flavivirus infection may be explained by the rapid antiviral innate immune response detectable by day 3 pi, as well as a fast anti-WNV neutralising antibody response detectable from day 7 pi.Comparisons of the tissue-specific transcriptional profile of important cytokine and chemokine genes suggested that virus control in rabbits was achieved differently depending on the virus, as well as the rabbit species. However, common transcriptional upregulation of IFNγ in...

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Tissue-specific transcription profile of cytokine and chemokine genes associated with flavivirus control and non-lethal neuropathogenesis in rabbits

Cited by 9 publications

References 49 publications

An Acute Stress Model in New Zealand White Rabbits Exhibits Altered Immune Response to Infection with West Nile Virus

An Acute Stress Model in New Zealand White Rabbits Exhibits Altered Immune Response to Infection with West Nile Virus

West Nile Virus: An Update on Pathobiology, Epidemiology, Diagnostics, Control and “One Health” Implications

Investigation of neuropathogenesis and control of an equine-pathogenic Australian West Nile virus isolate in an established CD1 Swiss white mouse and a novel rabbit model

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