•USUV nonstructural proteins including NS4A suppress interferon production.•NS4A inhibits interferon production by counteracting MAVS signaling.•NS4A blocks the interaction between MDA5 and ...MAVS.•NS4A proteins from various flaviviruses suppress MAVS signaling.
Usutu virus (USUV) is an emerging flavivirus that can infect birds and mammals. In humans, in severe cases, it may cause neuroinvasive disease. The innate immune system, and in particular the interferon response, functions as the important first line of defense against invading pathogens such as USUV. Many, if not all, viruses have developed mechanisms to suppress and/or evade the interferon response in order to facilitate their replication. The ability of USUV to antagonize the interferon response has so far remained largely unexplored. Using dual-luciferase reporter assays we observed that multiple of the USUV nonstructural (NS) proteins were involved in suppressing IFN-β production and signaling. In particular NS4A was very effective at suppressing IFN-β production. We found that NS4A interacted with the mitochondrial antiviral signaling protein (MAVS) and thereby blocked its interaction with melanoma differentiation-associated protein 5 (MDA5), resulting in reduced IFN-β production. The TM1 domain of NS4A was found to be essential for binding to MAVS. By screening a panel of flavivirus NS4A proteins we found that the interaction of NS4A with MAVS is conserved among flaviviruses. The increased understanding of the role of NS4A in flavivirus immune evasion could aid the development of vaccines and therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Infection with Usutu virus (USUV) has been recently associated with neurologic disorders, such as encephalitis or meningoencephalitis, in humans. These findings indicate that USUV is a potential ...health threat. We report an acute human infection with USUV in France putatively associated with a clinical diagnosis of idiopathic facial paralysis.
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Usutu virus (USUV) is an emerging mosquitoborne flavivirus with an increasing number of reports from several countries in Europe, where USUV infection has caused high avian mortality rates. However, ...20 years after the first observed outbreak of USUV in Europe, there is still no reliable assessment of the large-scale impact of USUV outbreaks on bird populations. In this study, we identified the areas suitable for USUV circulation in Germany and analyzed the effects of USUV on breeding bird populations. We calculated the USUV-associated additional decline of common blackbird (Turdus merula) populations as 15.7% inside USUV-suitable areas but found no significant effect for the other 14 common bird species investigated. Our results show that the emergence of USUV is a further threat for birds in Europe and that the large-scale impact on population levels, at least for common blackbirds, must be considered.
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West Nile virus (WNV) and Usutu virus (USUV) circulate in several European Union (EU) countries. The risk of transfusion-transmitted West Nile virus (TT-WNV) has been recognized, and preventive blood ...safety measures have been implemented. We summarized the applied interventions in the EU countries and assessed the safety of the blood supply by compiling data on WNV positivity among blood donors and on reported TT-WNV cases. The paucity of reported TT-WNV infections and the screening results suggest that blood safety interventions are effective. However, limited circulation of WNV in the EU and presumed underrecognition or underreporting of TT-WNV cases contribute to the present situation. Because of cross-reactivity between genetically related flaviviruses in the automated nucleic acid test systems, USUV-positive blood donations are found during routine WNV screening. The clinical relevance of USUV infection in humans and the risk of USUV to blood safety are unknown.
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We detected Usutu virus in a dead Eurasian blackbird (Turdus merula) in Luxembourg in September 2020. The strain clustered within the Africa 3.1 lineage identified in Western Europe since 2016. Our ...results suggest maintenance of the virus in Europe despite little reporting during 2019-2020, rather than a new introduction.
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We identified Usutu virus (USUV) RNA in 6 pools of mosquitoes trapped in northern Israel during 2014-2015. These Israeli strains were most similar to strains identified in Senegal and Germany, which ...further elucidates common ancestry and evolutionary dynamics of USUV. Our findings suggest that human infection with USUV might occur in Israel.
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Usutu virus (USUV) is an emerging flavivirus that causes Usutu disease mainly in birds, but infection of mammals such as rodents, bats and horses has also been demonstrated. In addition, human cases ...(both in immunocompromised and -competent individuals) were also reported. Large outbreaks with other flaviviruses, such as West Nile virus and Zika virus, indicate that one should be vigilant for yet other outbreaks. To allow the identification of inhibitors of USUV replication, we established in vitro antiviral assays, which were validated using a small selection of known flavivirus inhibitors, including the broad-spectrum viral RNA polymerase inhibitor favipiravir (T-705). Next, an USUV infection model in AG129 (IFN-α/β and IFN-γ receptor knockout) mice was established. AG129 mice proved highly susceptible to USUV; an inoculum as low as 102 PFU (1.3 × 105 TCID50) resulted in the development of symptoms as early as 3 days post infection with viral RNA being detectable in various tissues. Treatment of mice with favipiravir (150 mg/kg/dose, BID, oral gavage) significantly reduced viral load in blood and tissues and significantly delayed virus-induced disease. This USUV mouse model is thus amenable for assessing the potential in vivo efficacy of (novel) USUV/flavivirus inhibitors.
•Usutu virus (USUV) is a potential health concern considering the recent upsurge in USUV infections, including in humans.•In vitro assays as well as a mouse infection model were established.•The in vitro antiviral assays and the mouse infection model were validated for use in antiviral studies.•Favipiravir, although not very potent in inhibiting in vitro USUV replication, significantly delayed virus-induced disease.
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This reprint covers different aspects of the West Nile virus (WNV), a mosquito-borne pathogen that belongs to the Flavivirus genus (family Flaviviridae). The virus is maintained in nature in a rural ...cycle between mosquito vectors, mainly Culex species, and avian hosts. Spillover from this cycle occasionally results in outbreaks in horses and humans. In severe cases, the infection can induce neurological signs, such as meningitis and encephalitis, and in some cases, it can lead to death. The virus has spread across the world in this century, including its expansion in the Americas since 1999, and an increase in the number of outbreaks and its severity has been observed in Europe in recent years. Considering all these aspects, an approach including public, animal and environmental health is the best option to increase the knowledge of this problem, making this disease an excellent example of a “One Health” issue. Bearing in mind this multidisciplinary aspect, the volume includes contributions related to the pathogenesis, vaccines, diagnosis and epidemiology of the virus both in humans and animals.
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