A novel variant of Sindbis virus is both neurovirulent and neuroinvasive in adult mice

Lustig, Shlomo; Halevy, M.; Ben‐Nathan, D.; Akov, Y.

doi:10.1007/bf01317186

Cited by 31 publications

(38 citation statements)

References 14 publications

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“…3B). At 48 h postinfection, when the virus is expected to move to the central nervous system (8), serum viral titers were below the detection limit (data not shown). Comparison of the serum viral titers in the knockout and wild-type mice revealed that at 12 h and 24 h postinfection, the viral titers in the knockout mice were about 10-fold higher than those in the wildtype mice, but at 36 h postinfection the titers were not significantly different (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, age affects the outcome; some strains spread from the periphery and cause fatal encephalomyelitis in suckling mice but not in weanling mice (6). A strain of Sindbis virus that is both neuroinvasive and neurovirulent (SVNI), adapted from extensive passaging in mouse brains, can reach the brain and cause lethal encephalitis in weanling mice after peripheral inoculation (7,8).…”

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confidence: 99%

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Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance

Wang

Zhao

et al. 2016

J Virol

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Viral infection induces production of type I interferons (IFNs), which stimulate the expression of a variety of antiviral factors to inhibit viral replication. To establish effective infection, viruses need to develop strategies to evade the immune responses. A neurovirulent Sindbis virus strain with neuroinvasive properties (SVNI) causes lethal encephalitis in mice, and its replication in cultured cells is inhibited by the zinc finger antiviral protein (ZAP), a host factor that specifically inhibits the replication of certain viruses by binding to the viral mRNAs, repressing the translation of target mRNA, and promoting the degradation of target mRNA. We report here that murine embryonic fibroblast cells from ZAP knockout mice supported more efficient SVNI replication than wild-type cells. SVNI infection of 10-day-old suckling mice led to reduced survival in the knockout mice. Unexpectedly, however, SVNI infection of 23-day-old weanling mice, whose immune system is more developed than that of the suckling mice, resulted in significantly improved survival in ZAP knockout mice. Further analyses revealed that in the weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of IFN production, which restricted viral spread to the central nervous system. Blocking IFN activity through the use of receptor-neutralizing antibodies rendered knockout mice more sensitive to SVNI infection than wild-type mice. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance. IMPORTANCESindbis virus, a prototypic member of the Alphavirus genus, has been used to study the pathogenesis of acute viral encephalitis in mice for many years. How the virus evades immune surveillance to establish effective infection is largely unknown. ZAP is a host antiviral factor that potently inhibits Sindbis virus replication in cell culture. We show here that infection of ZAP knockout suckling mice with an SVNI led to faster disease progression. However, SVNI infection of weanling mice led to slower disease progression in knockout mice. Further analyses revealed that in weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of interferon production, which restricted viral spread to the central nervous system. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance and allow enhanced neuroinvasion.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance

Wang

Zhao

et al. 2016

J Virol

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“…21,22 We show that the apoptosis triggered by SVNI infection can be inhibited by the expression of vFLIP protein and that TNF-a plays a role in the apoptotic process.…”

Section: Introductionmentioning

confidence: 99%

“…21 Briefly, the neurovirulent strain SVNI was isolated by serial passages of a SV strain in brains of suckling and weanling mice.…”

Section: Virusesmentioning

confidence: 99%

vFLIP protects PC-12 cells from apoptosis induced by Sindbis virus: implications for the role of TNF-α

et al. 2001

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Sindbis virus (SV) is an alphavirus used as a model for studying the pathogenesis of viral encephalitis. In this study we examined the effects and the mechanisms involved in the apoptosis induced by SV in PC-12 cells, and the role of a vFLIP in this process. Infection of PC-12 cells with a neurovirulent strain of SV, SVNI, induced cell apoptosis. Overexpression of vFLIP encoded by the HHV-8 or treatment with a caspase-8 inhibitor inhibited cell apoptosis. SVNI induced an increase in the expression of tumor necrosis factor a (TNF-a), and pretreatment of the cells with an anti-TNF-a blocking antibody or with soluble TNF-a receptor abrogated the apoptotic effect of SVNI. Moreover, TNF-aR1 knockout mice were more resistant to the cytopathic effects of the virus as compared to control animals. Our results indicate that the apoptosis induced by SVNI is mediated by activation of caspase-8, and that TNF-a plays an important role in the apoptotic response. Cell Death and Differentiation (2001) 8, 1224 ± 1231.

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“…Sindbis virus (SINV), the prototype alphavirus, is an Old World alphavirus responsible for cases of self-limited arthralgia in humans. Infection of mice with SINV has also provided an excellent model of alphavirus-induced encephalomyelitis (14,31,33,40,41).…”

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confidence: 99%

A Determinant of Sindbis Virus Neurovirulence Enables Efficient Disruption of Jak/STAT Signaling

Simmons

Wollish

Heise

2010

J Virol

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Previous studies with Venezuelan equine encephalitis virus and Sindbis virus (SINV) indicate that alphaviruses are capable of suppressing the cellular response to type I and type II interferons (IFNs) by disrupting Jak/STAT signaling; however, the relevance of this signaling inhibition toward pathogenesis has not been investigated. The relative abilities of neurovirulent and nonneurovirulent SINV strains to downregulate Jak/STAT signaling were compared to determine whether the ability to inhibit IFN signaling correlates with virulence potential. The adult mouse neurovirulent strain AR86 was found to rapidly and robustly inhibit tyrosine phosphorylation of STAT1 and STAT2 in response to IFN-␥ and/or IFN-␤. In contrast, the closely related SINV strains Girdwood and TR339, which do not cause detectable disease in adult mice, were relatively inefficient inhibitors of STAT1/2 activation. Decreased STAT activation in AR86-infected cells was associated with decreased activation of the IFN receptor-associated tyrosine kinases Tyk2, Jak1, and Jak2. To identify the viral factor(s) involved, we infected cells with several panels of AR86/Girdwood chimeric viruses. Surprisingly, we found that a single amino acid determinant, threonine at nsP1 position 538, which is required for AR86 virulence, was also required for efficient disruption of STAT1 activation, and this determinant fully restored STAT1 inhibition when it was introduced into the avirulent Girdwood background. These data indicate that a key virulence determinant plays a critical role in downregulating the response to type I and type II IFNs, which suggests that the ability of alphaviruses to inhibit Jak/STAT signaling relates to their in vivo virulence potential.

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A novel variant of Sindbis virus is both neurovirulent and neuroinvasive in adult mice

Cited by 31 publications

References 14 publications

Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance

Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance

vFLIP protects PC-12 cells from apoptosis induced by Sindbis virus: implications for the role of TNF-α

A Determinant of Sindbis Virus Neurovirulence Enables Efficient Disruption of Jak/STAT Signaling

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