Host-Specific NS5 Ubiquitination Determines Yellow Fever Virus Tropism

Miorin, Lisa; Laurent-Rolle, Maudry; Pisanelli, Giuseppe; Co, Pierre Hendrick; Albrecht, Randy A.; Garcı́a-Sastre, Adolfo; Morrison, Juliet

doi:10.1128/jvi.00151-19

Cited by 24 publications

(23 citation statements)

References 23 publications

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“…In addition to that, NS5 uses its MTase domain to bind to STAT2 preparing it for degradation but requires the full length NS5 to complete the process [26,27]. Finally, ZIKV NS5 only interacts with human and other non-human primate STAT2 and while wild type mice are immune, IFN deficient mice were susceptible to ZIKV infection, thus showing the importance of this signalling pathway in fighting infection [26,46].…”

Section: Ns5 Causes the Degradation Of Stat2mentioning

confidence: 99%

Importance of Zika Virus NS5 Protein for Viral Replication

2019

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Zika virus is the latest addition to an ever-growing list of arboviruses that are causing outbreaks with serious consequences. A few mild cases were recorded between 1960 and 1980 until the first major outbreak in 2007 on Yap Island. This was followed by more severe outbreaks in French Polynesia (2013) and Brazil (2015), which significantly increased both Guillain-Barre syndrome and microcephaly cases. No current vaccines or treatments are available, however, recent studies have taken interest in the NS5 protein which encodes both the viral methyltransferase and RNA-dependent RNA polymerase. This makes it important for viral replication alongside other important functions such as inhibiting the innate immune system thus ensuring virus survival and replication. Structural studies can help design inhibitors, while biochemical studies can help understand the various mechanisms utilized by NS5 thus counteracting them might inhibit or abolish the viral infection. Drug repurposing targeting the NS5 protein has also proven to be an effective tool since hundreds of thousands of compounds can be screened therefore saving time and resources, moreover information on these compounds might already be available especially if they are used to treat other ailments.

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Section: Ns5 Causes the Degradation Of Stat2mentioning

confidence: 99%

Importance of Zika Virus NS5 Protein for Viral Replication

2019

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“…For this, we developed a unique YFV infection model in fumarylacetoacetate hydrolase [ F ah] −/− , R ag2 −/− , and Il2r ɣ −/− (FRG) chimeric mice. Wild-type (WT) mice are naturally resistant to hepatic YFV infection via peripheral routes of inoculation and do not develop YF-induced hepatic disease or coagulopathy ( 26 – 30 ). However, FRG mice have three genetic lesions ( F ah −/− , R ag2 −/− , and Il2r ɣ −/− on a C57BL/6J background), which, together with specifically timed dietary modifications, facilitate the durable replacement of murine hepatocytes with transplanted human hepatocytes ( 31 ).…”

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confidence: 99%

Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury

Bailey

Kang

Zanella

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Yellow fever (YF) is a mosquito-transmitted viral disease that causes tens of thousands of deaths each year despite the long-standing deployment of an effective vaccine. In its most severe form, YF manifests as a hemorrhagic fever that causes severe damage to visceral organs. Although coagulopathy is a defining feature of severe YF in humans, the mechanism by which it develops remains uncertain. Hepatocytes are a major target of yellow fever virus (YFV) infection, and the coagulopathy in severe YF has long been attributed to massive hepatocyte infection and destruction that results in a defect in clotting factor synthesis. However, when we analyzed blood from Brazilian patients with severe YF, we found high concentrations of plasma D-dimer, a fibrin split product, suggestive of a concurrent consumptive process. To define the relationship between coagulopathy and hepatocellular tropism, we compared infection and disease in Fah−/−, Rag2−/−, and Il2rɣ−/− mice engrafted with human hepatocytes (hFRG mice) and rhesus macaques using a highly pathogenic African YFV strain. YFV infection of macaques and hFRG mice caused substantial hepatocyte infection, liver damage, and coagulopathy as defined by virological, clinical, and pathological criteria. However, only macaques developed a consumptive coagulopathy whereas YFV-infected hFRG mice did not. Thus, infection of cell types other than hepatocytes likely contributes to the consumptive coagulopathy associated with severe YF in primates and humans. These findings expand our understanding of viral hemorrhagic disease and associated coagulopathy and suggest directions for clinical management of severe YF cases.

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“…Several prior studies have described species-specific differences in STAT2 inhibition by the flaviviruses Dengue, Zika, and Yellow Fever viruses [ 50 , 51 , 52 ]. Consequently, hSTAT2 KI mice infected with mouse-adapted Zika virus exhibited increased viral replication, broader tissue spread, and enhanced transplacental spread [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

STAT2 Limits Host Species Specificity of Human Metapneumovirus

Rogers

Miranda-Katz

Oury

et al. 2020

Viruses

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The host tropism of viral infection is determined by a variety of factors, from cell surface receptors to innate immune signaling. Many viruses encode proteins that interfere with host innate immune recognition in order to promote infection. STAT2 is divergent between species and therefore has a role in species restriction of some viruses. To understand the role of STAT2 in human metapneumovirus (HMPV) infection of human and murine tissues, we first infected STAT2−/− mice and found that HMPV could be serially passaged in STAT2−/−, but not WT, mice. We then used in vitro methods to show that HMPV inhibits expression of both STAT1 and STAT2 in human and primate cells, but not in mouse cells. Transfection of the murine form of STAT2 into STAT2-deficient human cells conferred resistance to STAT2 inhibition. Finally, we sought to understand the in vivo role of STAT2 by infecting hSTAT2 knock-in mice with HMPV, and found that mice had increased weight loss, inhibition of type I interferon signaling, and a Th2-polarized cytokine profile compared to WT mice. These results indicate that STAT2 is a target of HMPV in human infection, while the murine version of STAT2 restricts tropism of HMPV for murine cells and tissue.

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Host-Specific NS5 Ubiquitination Determines Yellow Fever Virus Tropism

Cited by 24 publications

References 23 publications

Importance of Zika Virus NS5 Protein for Viral Replication

Importance of Zika Virus NS5 Protein for Viral Replication

Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury

STAT2 Limits Host Species Specificity of Human Metapneumovirus

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