Mechanism of West Nile Virus Neuroinvasion:  A Critical Appraisal

Suen, Willy W.; Prow, Natalie A.; Hall, Roy A.; Bielefeldt‐Ohmann, Helle

doi:10.3390/v6072796

Cited by 109 publications

(98 citation statements)

References 139 publications

(224 reference statements)

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“…Virus may enter via either direct infection of BMECs, passive diffusion through the BBB, transcellular transport through BMECs, or by paracellular migration between endothelial TJs after BBB disruption. Although BMECs have been shown to be infected by several encephalitic arboviruses in vitro [150][151][152], there is no strong evidence of arboviral infection of BMECs in vivo, indicating that BMEC infection is not necessary for entry to the CNS [153,154]. Passive diffusion of virus across the BBB has been proposed previously; yet, convincing evidence to support this hypothesis has still to be demonstrated.…”

Section: Entry Of Arboviruses Into the Cnsmentioning

confidence: 68%

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

2016

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Arboviruses are arthropod-borne viruses that exhibit worldwide distribution, contributing to systemic and neurologic infections in a variety of geographical locations. Arboviruses are transmitted to vertebral hosts during blood feedings by mosquitoes, ticks, biting flies, mites, and nits. While the majority of arboviral infections do not lead to neuroinvasive forms of disease, they are among the most severe infectious risks to the health of the human central nervous system. The neurologic diseases caused by arboviruses include meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and myositis in which virus-and immune-mediated injury may lead to severe, persisting neurologic deficits or death. Here we will review the major families of emerging arboviruses that cause neurologic infections, their neuropathogenesis and host neuroimmunologic responses, and current strategies for treatment and prevention of neurologic infections they cause.

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Section: Entry Of Arboviruses Into the Cnsmentioning

confidence: 68%

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

2016

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“…A large proportion of the content of this literature review chapter has been included in my published review [1]. An introduction to the immune mechanisms associated with the control of WNV infections and a short review of WNV epidemiology in the Australian context have also been included in this chapter.…”

Section: Manuscript Informationmentioning

confidence: 99%

“…While these rodent models typically produce severe encephalitis after virulent WNV infection, the level of central nervous system (CNS) infection in these small animal models often is too severe to be reflective of most human and equine disease [31,197]. Minimal levels of virus replication take place in the CNS of most human and equine infection, unless the individuals are immunocompromised [1,49,87,198]. This important difference suggests that the neuropathogenesis of WNV in immunocompetent…”

Section: Introductionmentioning

confidence: 98%

“…Despite ample neuronal infection (red stain, arrowhead), the endothelial cells are not infected (arrow). (Antibody binding was visualised using AEC substrate and the section counterstained with Mayer's haematoxylin; magnification at 400x) [1].…”

Section: Transendothelial Viral Entrymentioning

confidence: 99%

“…These cytokines/chemokine have also been reported to be important determinants of the disease outcomes after WNV infections in humans [151,314], horses [23,315] and the mouse [40,276,316,317]. Since the existing mouse models do not consistently recapitulate non-lethal disease associated with virulent WNV infections in humans and horses, as already discussed in length in [1,263], we were interested in the relevance of these genes in the phenotypically resistant rabbit model. Via this investigation, we also aimed to characterise the association between cytokine/chemokine response in the brain and non-lethal neuropathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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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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Intraosseous administration into the skull: Potential blood–brain barrier bypassing route for brain drug delivery

Kang

2022

Bioengineering & Transla Med

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Progress in treating central nervous system (CNS) disorders is retarded owing to a limited understanding of brain disease pathology. Additionally, the blood-brain barrier (BBB) limits molecular entry into the brain. Many approaches for brain drug delivery to overcome the BBB, such as BBB permeability enhancement, transient BBB disruption, and direct surgical administration have been explored with limited success. Recent research has shown that direct vascular channels exist between the skull bone marrow and the meninges, allowing myeloid and lymphoid cells to migrate. We hypothesized that these direct channels may also allow brain drug delivery from the skull bone marrow to the brain. In this study, for the first time we propose intraosseous administration of drugs into the skull (intracalvariosseous [ICO]) as a novel approach for brain drug delivery via BBB bypassing routes. We tested the feasibility of the approach by applying nine representative compounds over thinned mouse skulls to simulate ICO and measuring the compound entry level in the brain compared to that after systemic administration. Surprisingly, we found that the skull is not completely impermeable to drug penetration into the brain and the tested compounds reached the brain tissue several tens-to-hundred times higher by ICO than systemic application. These findings suggest a role for the BBB bypassing route from skull to brain, apart from the systemic route, in the drug entry into the brain after ICO. This approach should be applicable to other CNS drugs and even BBB impermeable drugs. Overall ICO provides an innovative and advantageous pathway for effective treatment of brain diseases.

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Mechanism of West Nile Virus Neuroinvasion: A Critical Appraisal

Cited by 109 publications

References 139 publications

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

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

Intraosseous administration into the skull: Potential blood–brain barrier bypassing route for brain drug delivery

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