Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality

Li, Hao; Zhang, Leike; Li, Shufen; Zhang, Shao‐Fei; Wan, Weiwei; Zhang, Yulan; Xin, Qilin; Dai, Ke; Hu, Yuanyuan; Wang, Zhibo; Zhu, Xiaoxian; Fang, Yujie; Cui, Ning; Zhang, Pan-He; Yuan, Chun; Lu, Qing‐Bin; Bai, Jing; Deng, Fei; Xiao, Gengfu; Liu, Wei; Peng, Ke

doi:10.1038/s41422-019-0214-z

Cited by 89 publications

(100 citation statements)

References 65 publications

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“…Therefore, Ca V 1.2 may serve as a host cell surface receptor that binds IAV and is critical for IAV entry (Figure 2A). New world hemorrhagic fever arenaviruses (NWA) are another virus that is reportedly sensitive to the VGCC blocker club member [12,13]. An siRNA screen with Junín virus glycoprotein-pseudotyped viruses identified that VGCCs are involved in NWA entry.…”

Section: Viruses Control Host Voltage-gated Calcium Channels (Vgccs)mentioning

confidence: 99%

“…These drugs were subsequently validated for their antiviral activities against other flavivirus, such as Zika virus (ZIKV), dengue virus (DENV), and West Nile virus (WNV). Similarly, another research group screened the FDA-approved drug library and found that nifedipine and benidipine hydrochloride inhibited severe fever with thrombocytopenia syndrome virus (SFTSV) replication in vitro [12]. Moreover, the retrospective clinical investigation on SFTS patients showed that nifedipine can significantly inhibit SFTSV infection.…”

Section: Viruses Control Host Voltage-gated Calcium Channels (Vgccs)mentioning

confidence: 99%

“…Benidipine hydrochloride, VGCC blocker, inhibits SFTSV infection via impairing virus internalization and genome replication [12].…”

Section: Sftsvmentioning

confidence: 99%

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Host Calcium Channels and Pumps in Viral Infections

Chen

Cao²,

Zhong³

2019

Cells

120

115

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Ca2+ is essential for virus entry, viral gene replication, virion maturation, and release. The alteration of host cells Ca2+ homeostasis is one of the strategies that viruses use to modulate host cells signal transduction mechanisms in their favor. Host calcium-permeable channels and pumps (including voltage-gated calcium channels, store-operated channels, receptor-operated channels, transient receptor potential ion channels, and Ca2+-ATPase) mediate Ca2+ across the plasma membrane or subcellular organelles, modulating intracellular free Ca2+. Therefore, these Ca2+ channels or pumps present important aspects of viral pathogenesis and virus–host interaction. It has been reported that viruses hijack host calcium channels or pumps, disturbing the cellular homeostatic balance of Ca2+. Such a disturbance benefits virus lifecycles while inducing host cells’ morbidity. Evidence has emerged that pharmacologically targeting the calcium channel or calcium release from the endoplasmic reticulum (ER) can obstruct virus lifecycles. Impeding virus-induced abnormal intracellular Ca2+ homeostasis is becoming a useful strategy in the development of potent antiviral drugs. In this present review, the recent identified cellular calcium channels and pumps as targets for virus attack are emphasized.

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Section: Viruses Control Host Voltage-gated Calcium Channels (Vgccs)mentioning

confidence: 99%

Section: Viruses Control Host Voltage-gated Calcium Channels (Vgccs)mentioning

confidence: 99%

See 1 more Smart Citation

Host Calcium Channels and Pumps in Viral Infections

Chen

Cao²,

Zhong³

2019

Cells

120

115

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“…Notably, nifedipine is one of the most widely used drugs for treating hypertension and atherosclerosis in China. Thus, Li et al (2019) performed a retrospective clinical investigation on a large cohort of 2087 patients with SFTS comprising 83 nifedipinetreated, who received nifedipine before admission and during hospitalization, 48 non-nifedipine-treated ones who received nifedipine before admission but not during hospitalization, and 249 general SFTS patients who did not receive nifedipine at all. The case fatality rate was decreased by >5-fold in the nifedipine-treated group (3.6%) compared with the general SFTS group (19.7%) or non-nifedipine treated group (20.8%) .…”

Section: Calcium Channel Blockersmentioning

confidence: 99%

Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

Takayama-Ito

Saijo

2020

Front. Microbiol.

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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by SFTS virus (SFTSV), which is a novel bunyavirus. SFTSV was first isolated from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction in China. Subsequently, it was found to be widely distributed in Southeast Asia (Korea, Japan, and Vietnam). SFTSV can be transmitted not only from ticks but also from domestic animals, companion animals, and humans. Because the case fatality rate of SFTS is high (6-30%), development of specific and effective treatment for SFTS is required. Studies of potential antiviral drugs for SFTS-specific therapy have been conducted on existing or newly discovered agents in vitro and in vivo, with ribavirin and favipiravir being the most promising candidates. While animal experiments and retrospective studies have demonstrated the limited efficacy of ribavirin, it was also speculated that ribavirin would be effective in patients with a viral load <1 × 10 6 copies/mL. Favipiravir showed higher efficacy than ribavirin against SFTSV in in vitro assays and greater efficacy in animal models, even administrated 3 days after the virus inoculation. Although clinical trials evaluating the efficacy of favipiravir in SFTS patients in Japan are underway, this has yet to be confirmed. Other drugs, including hexachlorophene, calcium channel blockers, 2 ′ -fluoro-2 ′ -deoxycytidine, caffeic acid, amodiaquine, and interferons, have also been evaluated for their inhibitory efficacy against SFTSV. Among them, calcium channel blockers are promising because in addition to their efficacy in vitro and in vivo, retrospective clinical data have indicated that nifedipine, one of the calcium channel blockers, reduced the case fatality rate by >5-fold. Although further research is necessary to develop SFTS-specific therapy, considerable progress has been achieved in this area. Here we summarize and discuss recent advances in antiviral drugs against SFTSV.Keywords: severe fever with thrombocytopenia syndrome, severe fever with thrombocytopenia syndrome virus, antiviral, ribavirin, favipiravir Frontiers in Microbiology | www.frontiersin.org

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“…with mortality rates ranging from 12 to 50% (5)(6)(7)(8). Although several vaccines and drugs have been shown to be effective in cell or animal models, to date none have been used for clinical prevention or treatment in humans (9)(10)(11)(12), as little is known about how the virus interacts with host cells.…”

mentioning

confidence: 99%

The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G ₂ Cell Cycle Arrest and Positively Regulate Viral Replication

Liu

Kang

et al. 2020

J Virol

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Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. While many viruses subvert the host cell cycle to promote viral growth, it is unknown whether this is a strategy employed by SFTSV. In this study, we investigated how SFTSV manipulates the cell cycle and the effect of the host cell cycle on SFTSV replication. Our results suggest that cells arrest at the G2/M transition following infection with SFTSV. The accumulation of cells at the G2/M transition did not affect virus adsorption and entry but did facilitate viral replication. In addition, we found that SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells and promotes virulence by modulating the interferon response, induces a large number of cells to arrest at the G2/M transition by interacting with CDK1. The interaction between NSs and CDK1, which is inclusion body dependent, inhibits formation and nuclear import of the cyclin B1-CDK1 complex, thereby leading to cell cycle arrest. Expression of a CDK1 loss-of-function mutant reversed the inhibitive effect of NSs on the cell cycle, suggesting that this protein is a potential antiviral target. Our study provides new insight into the role of a specific viral protein in SFTSV replication, indicating that NSs induces G2/M arrest of SFTSV-infected cells, which promotes viral replication. IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne pathogen that causes severe hemorrhagic fever. Although SFTSV poses a serious threat to public health and was recently isolated, its pathogenesis remains unclear. In particular, the relationship between SFTSV infection and the host cell cycle has not been described. Here, we show for the first time that both asynchronized and synchronized SFTSV-susceptible cells arrest at the G2/M checkpoint following SFTSV infection and that the accumulation of cells at this checkpoint facilitates viral replication. We also identify a key mechanism underlying SFTSV-induced G2/M arrest, in which SFTSV NSs interacts with CDK1 to inhibit formation and nuclear import of the cyclin B1-CDK1 complex, thus preventing it from regulating cell cycle progression. Our study highlights the key role that NSs plays in SFTSV-induced G2/M arrest.

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Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality

Cited by 89 publications

References 65 publications

Host Calcium Channels and Pumps in Viral Infections

Host Calcium Channels and Pumps in Viral Infections

Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G ₂ Cell Cycle Arrest and Positively Regulate Viral Replication

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Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality

Cited by 89 publications

References 65 publications

Host Calcium Channels and Pumps in Viral Infections

Host Calcium Channels and Pumps in Viral Infections

Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G 2 Cell Cycle Arrest and Positively Regulate Viral Replication

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Product

Resources

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The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G ₂ Cell Cycle Arrest and Positively Regulate Viral Replication