Usutu virus growth in human cell lines: induction of and sensitivity to type I and III interferons

Scagnolari, Carolina; Caputo, Beniamino; Trombetti, Simona; Cacciotti, Giulia; Soldà, A. M.; Spanò, Lucia; Villari, Paolo; Torre, Alessandra della; Nowotny, Norbert; Antonelli, Guido

doi:10.1099/vir.0.046433-0

Cited by 16 publications

(18 citation statements)

References 33 publications

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“…Interestingly, this strong IFN-β induction did not prevent USUV replication. These findings further support the hypothesis that USUV do not possess mechanisms that interfere with IFN induction as previously suggested in other studies on dendritic and epithelial cell [ 33 , 34 ]. The type I IFN response can limit viral dissemination by different mechanisms: restricting the spread of progeny viruses to neighboring cells or/and reducing overall viral replication.…”

Section: Discussionsupporting

confidence: 92%

“…Although USUV is an emerging pathogen and dispersed quickly in Europe, very little is known about its pathogenesis, biologic features and host spectrum. It is nonetheless described that USUV infection upregulates the cellular autophagic pathway [ 32 ] and can induce type 1 IFN production [ 33 , 34 ]. Susceptibility of adult wild type (WT) mice to USUV is limited [ 35 ], whereas mice lacking the interferon type 1 receptor ( Ifnar1 -/- ) are susceptible, as described for other flaviviruses such as ZIKV [ 36 – 39 ].…”

Section: Introductionmentioning

confidence: 99%

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Deleterious effect of Usutu virus on human neural cells

et al. 2017

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In the last decade, the number of emerging Flaviviruses described worldwide has increased considerably. Among them Zika virus (ZIKV) and Usutu virus (USUV) are African mosquito-borne viruses that recently emerged. Recently, ZIKV has been intensely studied due to major outbreaks associated with neonatal death and birth defects, as well as neurological symptoms. USUV pathogenesis remains largely unexplored, despite significant human and veterinary associated disorders. Circulation of USUV in Africa was documented more than 50 years ago, and it emerged in Europe two decades ago, causing massive bird mortality. More recently, USUV has been described to be associated with neurological disorders in humans such as encephalitis and meningoencephalitis, highlighting USUV as a potential health threat. The aim of this study was to evaluate the ability of USUV to infect neuronal cells. Our results indicate that USUV efficiently infects neurons, astrocytes, microglia and IPSc-derived human neuronal stem cells. When compared to ZIKV, USUV led to a higher infection rate, viral production, as well as stronger cell death and anti-viral response. Our results highlight the need to better characterize the physiopathology related to USUV infection in order to anticipate the potential threat of USUV emergence.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Deleterious effect of Usutu virus on human neural cells

et al. 2017

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“…In response to USUV infection, this inflammatory context is associated with strong antiviral-response induction, as shown by up regulation of IFNβ and ISGs in the brain and spinal cord. These observations confirm previous studies showing induction of anti-viral response despite USUV replication, supporting the hypothesis that USUV does not possess mechanisms that interfere efficiently with IFN induction [45,64]. Mechanisms used by USUV to overcome this IFN response, while establishing a productive (B) BBB model was infected with USUV at MOI 0.1.…”

Section: Discussionsupporting

confidence: 89%

Study of Usutu virus neuropathogenicity in mice and human cellular models

et al. 2020

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Usutu virus (USUV), an African mosquito-borne flavivirus closely related to West Nile virus, was first isolated in South Africa in 1959. USUV emerged in Europe two decades ago, causing notably massive mortality in Eurasian blackbirds. USUV is attracting increasing attention due to its potential for emergence and its rapid spread in Europe in recent years. Although mainly asymptomatic or responsible for mild clinical signs, USUV was recently described as being associated with neurological disorders in humans such as encephalitis and meningoencephalitis, highlighting the potential health threat posed by the virus. Despite this, USUV pathogenesis remains largely unexplored. The aim of this study was to evaluate USUV neuropathogenicity using in vivo and in vitro approaches. Our results indicate that USUV efficiently replicates in the murine central nervous system. Replication in the spinal cord and brain is associated with recruitment of inflammatory cells and the release of inflammatory molecules as well as induction of antiviral-responses without major modulation of bloodbrain barrier integrity. Endothelial cells integrity is also maintained in a human model of the blood-brain barrier despite USUV replication and release of pro-inflammatory cytokines. Furthermore, USUV-inoculated mice developed major ocular defects associated with inflammation. Moreover, USUV efficiently replicates in human retinal pigment epithelium. Our results will help to better characterize the physiopathology related to USUV infection in order to anticipate the potential threat of USUV emergence.

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“…Having in mind that different PI3Ks are under strict consideration as cellular targets for treatment of human disorders [52], the results here presented set a starting point for antiviral development to combat USUV based on inhibition of these cellular enzymes. Other previously identified cellular pathways as regulators of USUV infection have been the synthesis of fatty acids [32], the innate immune response induced in infected cells [53], and preliminary data also point to the induction of apoptosis in infected cells [32]. In fact, connections between autophagy and these other metabolic pathways involved on USUV infection have been also documented for other members of the Flaviviridae family [21], [24], [54].…”

Section: Discussionmentioning

confidence: 85%

Infection with Usutu Virus Induces an Autophagic Response in Mammalian Cells

et al. 2013

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Usutu virus (USUV) is an African mosquito-borne flavivirus closely related to West Nile virus and Japanese encephalitis virus, which host range includes mainly mosquitoes and birds, although infections in humans have been also documented, thus warning about USUV as a potential health threat. Circulation of USUV in Africa was documented more than 50 years ago, but it was not until the last decade that it emerged in Europe causing episodes of avian mortality and some human severe cases. Since autophagy is a cellular pathway that can play important roles on different aspects of viral infections and pathogenesis, the possible implication of this pathway in USUV infection has been examined using Vero cells and two viral strains of different origin. USUV infection induced the unfolded protein response, revealed by the splicing of Xbp-1 mRNA. Infection with USUV also stimulated the autophagic process, which was demonstrated by an increase in the cytoplasmic aggregation of microtubule-associated protein 1 light chain 3 (LC3), a marker of autophagosome formation. In addition to this, an increase in the lipidated form of LC3, that is associated with autophagosome formation, was noticed following infection. Pharmacological modulation of the autophagic pathway with the inductor of autophagy rapamycin resulted in an increase in virus yield. On the other hand, treatment with 3-methyladenine or wortmannin, two distinct inhibitors of phosphatidylinositol 3-kinases involved in autophagy, resulted in a decrease in virus yield. These results indicate that USUV virus infection upregulates the cellular autophagic pathway and that drugs that target this pathway can modulate the infection of this virus, thus identifying a potential druggable pathway in USUV-infection.

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Usutu virus growth in human cell lines: induction of and sensitivity to type I and III interferons

Cited by 16 publications

References 33 publications

Deleterious effect of Usutu virus on human neural cells

Deleterious effect of Usutu virus on human neural cells

Study of Usutu virus neuropathogenicity in mice and human cellular models

Infection with Usutu Virus Induces an Autophagic Response in Mammalian Cells

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