Flaviviridae virus nonstructural proteins 5 and 5A mediate viral immune evasion and are promising targets in drug development

Chen, Shun; Yang, Chao; Zhang, Wei; Mahalingam, Suresh; Wang, Mingshu; Cheng, Anchun

doi:10.1016/j.pharmthera.2018.05.004

Cited by 10 publications

(8 citation statements)

References 115 publications

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“…The ability of pathogenic viral proteins to interfere with the innate and adaptive immune response in the form of altered gene expression conferring tolerance or other forms of immune evasion has been observed. 120,121 For the coronaviruses, several structural and non-structural proteins which play a role in pathways leading to IFN-I and III expression have been identified, 122 including nsp16, 123 membrane, 124,125 nucleocapsid, 126 amongst others. Some of these immune evasive proteins have a high homology with SARS-CoV-2 proteins.…”

Section: Covid-19 Vaccine Should Induce Protective and Durable Immunitymentioning

confidence: 99%

SARS-CoV-2 reinfection and implications for vaccine development

Nainu

Abidin

Bahar

et al. 2020

Human Vaccines & Immunotherapeutics

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Coronavirus disease 2019 (COVID-19) pandemic continues to constitute a public health emergency of international concern. Multiple vaccine candidates for COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have entered clinical trials. However, some evidence suggests that patients who have recovered from COVID-19 can be reinfected. For example, in China, two discharged COVID-19 patients who had recovered and fulfilled the discharge criteria for COVID-19 were retested positive to a reverse transcription polymerase chain reaction (RT-PCR) assay for the virus. This finding is critical and could hamper COVID-19 vaccine development. This review offers literature-based evidence of reinfection with SARS-CoV-2, provides explanation for the possibility of SARS-CoV-2 reinfection both from the agent and host points of view, and discusses its implication for COVID-19 vaccine development.

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Section: Covid-19 Vaccine Should Induce Protective and Durable Immunitymentioning

confidence: 99%

SARS-CoV-2 reinfection and implications for vaccine development

Nainu

Abidin

Bahar

et al. 2020

Human Vaccines & Immunotherapeutics

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“…Flaviviral NS5 interacts with different host proteins in an infected cell. Some of these interactions are relevant to the process of viral RNA genome synthesis, while in some other cases the interaction of NS5 with other host factors can interfere with or modulate cellular functions [19].…”

Section: Introductionmentioning

confidence: 99%

Akt Interacts with Usutu Virus Polymerase, and Its Activity Modulates Viral Replication

et al. 2021

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Usutu virus (USUV) is a flavivirus that mainly infects wild birds through the bite of Culex mosquitoes. Recent outbreaks have been associated with an increased number of cases in humans. Despite being a growing source of public health concerns, there is yet insufficient data on the virus or host cell targets for infection control. In this work we have investigated whether the cellular kinase Akt and USUV polymerase NS5 interact and co-localize in a cell. To this aim, we performed co-immunoprecipitation (Co-IP) assays, followed by confocal microscopy analyses. We further tested whether NS5 is a phosphorylation substrate of Akt in vitro. Finally, to examine its role in viral replication, we chemically silenced Akt with three inhibitors (MK-2206, honokiol and ipatasertib). We found that both proteins are localized (confocal) and pulled down (Co-IP) together when expressed in different cell lines, supporting the fact that they are interacting partners. This possibility was further sustained by data showing that NS5 is phosphorylated by Akt. Treatment of USUV-infected cells with Akt-specific inhibitors led to decreases in virus titers (>10-fold). Our results suggest an important role for Akt in virus replication and stimulate further investigations to examine the PI3K/Akt/mTOR pathway as an antiviral target.

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“…Unlike DENV, YFV NS4B has also been shown to block RIG-I stimulation through an interaction with STING (32). Moreover, NS5 is known to establish a common mode of IFNa/b signaling antagonist for some flaviviruses by inhibiting the JAK/STAT pathway (33,34).…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Beta Interferon Inhibition by NS4B Contributes to Attenuating Tembusu Virus Virulence in Ducks

et al. 2021

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Our previous studies reported that duck Tembusu virus nonstructural protein 2A (NS2A) is a major inhibitor of the IFNβ signaling pathway through competitively binding to STING with TBK1, leading to a reduction in TBK1 phosphorylation. Duck TMUV NS2B3 could cleave and bind STING to subvert the IFNβ signaling pathway. Here, we found that overexpression of duck TMUV NS4B could compete with TBK1 in binding to STING, reducing TBK1 phosphorylation and inhibiting the IFNβ signaling pathway by using the Dual-Glo® Luciferase Assay System and the NanoBiT protein-protein interaction (PPI) assay. We further identified the E2, M3, G4, W5, K10 and D34 residues in NS4B that were important for its interaction with STING and its inhibition of IFNβ induction, which were subsequently introduced into a duck TMUV replicon and an infectious cDNA clone. We found that the NS4B M3A mutant enhanced RNA replication and exhibited significantly higher titer levels than WT at 48-72 hpi but significantly decreased mortality (80%) in duck embryos compared to WT (100%); the NS4B G4A and R36A mutants slightly reduced RNA replication but exhibited the same titer levels as WT. However, the NS4B R36A mutant did not attenuate the virulence in duck embryos, whereas the G4A mutant significantly decreased the mortality (70%) of duck embryos. In addition, the NS4B W5A mutant did not affect viral replication, whereas the D34A mutant slightly reduced RNA replication, and both mutants exhibited significantly lower titer levels than the WT and significantly decreased mortality (90% and 70%, respectively) in duck embryos. Hence, our findings provide new insight into the development of attenuated flaviviruses by targeting the disabling viral strategies used to evade the innate defense mechanisms.

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Flaviviridae virus nonstructural proteins 5 and 5A mediate viral immune evasion and are promising targets in drug development

Cited by 10 publications

References 115 publications

SARS-CoV-2 reinfection and implications for vaccine development

SARS-CoV-2 reinfection and implications for vaccine development

Akt Interacts with Usutu Virus Polymerase, and Its Activity Modulates Viral Replication

Amelioration of Beta Interferon Inhibition by NS4B Contributes to Attenuating Tembusu Virus Virulence in Ducks

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