TLR signaling controls lethal encephalitis in WNV-infected brain

Sabouri, Amir H.; Marcondes, Maria Cecília Garibaldi; Flynn, Claudia T.; Berger, Michael; Xiao, Nengming; Fox, Howard S.; Sarvetnick, Nora

doi:10.1016/j.brainres.2014.05.049

Cited by 31 publications

(28 citation statements)

References 44 publications

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“…In microglia, there are constitutively expression of TLR3, TLR7 and TLR9 [12]. Although the basal level of these membrane protein is relatively low, their expression is strongly upregulated after viral infection [39,45].…”

Section: Toll Like Receptors In Microglia Mediated Neuroinflammationmentioning

confidence: 99%

Viral infection and neurological disorders—potential role of extracellular nucleotides in neuroinflammation

Mao

Wang

et al. 2019

ExRNA

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Neuroinflammation can be induced under several conditions including pathogen infection such as virus. As the main immune cells in brain, microglia activation plays a pivotal role in neuroinflammation by responding to the invading pathogens (viral DNA/RNA) through toll-like receptors. Chronic activation of microglia caused by sustained viral infection will lead to persistent release of pro-inflammatory molecules, which is different from their beneficial functions under physiological conditions. Sustained exposure of neurons to the inflammatory condition can result in neuronal dysfunction as well as cell degeneration that contribute to the pathogenesis of several neurological disorders. This review proposed that during sustained infection, viral DNA/RNA activated microglia through TLRs, inducing persistent inflammatory response that causes long term, mild but irreversible changes, which ultimately contribute to the neuronal dysfunction or cell degeneration.

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Section: Toll Like Receptors In Microglia Mediated Neuroinflammationmentioning

confidence: 99%

Viral infection and neurological disorders—potential role of extracellular nucleotides in neuroinflammation

Mao

Wang

et al. 2019

ExRNA

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“…encephalitis upon TBEV infection(59). In contrast, mouse studies with other Flaviviruses such as WNV and ZIKV revealed a protective role of TLR-signaling(60,61).Taken together, upon in vitro TBEV infection of mouse-derived brain resident cell subsets, astrocytes are the main IFN-β producers. Early after infection, astrocytes are stimulated in a MAVS-dependent manner, presumably via RLR signaling, whereas at later time points MyD88/TRIF-signaling was needed.…”

mentioning

confidence: 99%

Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes

Ghita

Breitkopf

Mulenge

et al. 2020

Preprint

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AbstractTick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV infected mice, mitochondrial antiviral signaling protein (MAVS), the downstream adaptor of retinoic acid inducible gene I-like receptor (RLR)-signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To identify the brain resident cell subset that produces protective IFN-β in TBEV infected mice, we isolated neurons, astrocytes and microglia and exposed these cells to TBEV in vitro. Under such conditions, neurons showed the highest percentage of infected cells, whereas astrocytes and microglia were infected to a lesser extent. In the supernatant (SN) of infected neurons, IFN-β was not detectable, while infected astrocytes showed very high and microglia low IFN-β production. Transcriptome analyses of astrocytes implied that MAVS-signaling was needed early after TBEV infection. Accordingly, MAVS-deficient astrocytes showed enhanced TBEV infection and significantly reduced early IFN-β responses. At later time points, moderate amounts of IFN-β were detected in the SN of infected MAVS-deficient astrocytes. Transcriptome analyses indicated that MAVS-deficiency negatively affected the induction of early anti-viral responses, which resulted in significantly increased TBEV replication. Treatment with MyD88 and TRIF inhibiting peptides reduced late IFN-β responses of TBEV infected WT astrocytes and entirely blocked IFN-β responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-β producers that show biphasic IFN-β induction that initially depends on MAVS- and later on MyD88/TRIF-signaling.

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“…Alternatively, a systemic inflammatory response may be induced by early haematogenous circulation of virus (viraemia), stimulating viral sensors, such as Toll-like receptors, at the blood-tissue interphase [327][328][329].…”

Section: Discussionmentioning

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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TLR signaling controls lethal encephalitis in WNV-infected brain

Cited by 31 publications

References 44 publications

Viral infection and neurological disorders—potential role of extracellular nucleotides in neuroinflammation

Viral infection and neurological disorders—potential role of extracellular nucleotides in neuroinflammation

Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes

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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