Manassantin B shows antiviral activity against coxsackievirus B3 infection by activation of the STING/TBK-1/IRF3 signalling pathway

Song, Jae-Hyoung; Ahn, Jae-Hee; Kim, Seong-Ryeol; Cho, Sungchan; Hong, Eock Kee; Kwon, Bo-Eun; Kim, Dongeun; Choi, Min; Choi, Hwa-Jung; Cha, Younggil; Chang, Shau‐Jin; Ko, Hyun‐Jeong

doi:10.1038/s41598-019-45868-8

Cited by 23 publications

(17 citation statements)

References 54 publications

(60 reference statements)

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“…To further interrogate this, we treated HeLa cells with the specific TBK1 agonist Manassantin B (ManB) to test effects on CVB infection and viral EV shedding. ManB is a neolignan isolated from Saururus chinensis that exhibits antiviral and anti-inflammatory effects via activation of the STING-TBK1 pathway [ 25 ]. After infecting with eGFP-CVB for 24 h, we saw a marked reduction in eGFP cells following ManB treatment (14% decrease; *, p < 0.05) ( Fig 6A ) and plaque assays revealed a substantial reduction in EV-associated viral titers but interestingly, free viral titers were not significantly different ( Fig 6B ).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, these EVs showed increased viral infection efficacy as revealed by plaque assay. Consistent with these findings, direct activation of TBK1 by Manassantin B (ManB) significantly reduced viral infection and viral dissemination via EVs [ 25 ]. We hypothesize that in addition to its canonical role in antiviral cytokine activation, TBK1 reduces viral production by increasing delivery of virus-laden autophagosomes to lysosomes for degradation.…”

Section: Introductionmentioning

confidence: 82%

“…Though TBK1 has been implicated in suppression of CVB infection via interferon signaling, our findings demonstrate an additional critical antiviral role for TBK1 in the suppression of viral replication and vesicle-based viral egress through autophagy [ 25 , 66 ]. We hypothesize that TBK1 facilitates autophagic degradation of virus-laden autophagosomes before they can be released from the cell as EVs ( Fig 10 ).…”

Section: Discussionmentioning

confidence: 99%

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TBK1 and GABARAP family members suppress Coxsackievirus B infection by limiting viral production and promoting autophagic degradation of viral extracellular vesicles

et al. 2022

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Host-pathogen dynamics are constantly at play during enteroviral infection. Coxsackievirus B (CVB) is a common juvenile enterovirus that infects multiple organs and drives inflammatory diseases including acute pancreatitis and myocarditis. Much like other enteroviruses, CVB is capable of manipulating host machinery to hijack and subvert autophagy for its benefit. We have previously reported that CVB triggers the release of infectious extracellular vesicles (EVs) which originate from autophagosomes. These EVs facilitate efficient dissemination of infectious virus. Here, we report that TBK1 (Tank-binding kinase 1) suppresses release of CVB-induced EVs. TBK1 is a multimeric kinase that directly activates autophagy adaptors for efficient cargo recruitment and induces type-1 interferons during viral-mediated STING recruitment. Positioning itself at the nexus of pathogen elimination, we hypothesized that loss of TBK1 could exacerbate CVB infection due to its specific role in autophagosome trafficking. Here we report that infection with CVB during genetic TBK1 knockdown significantly increases viral load and potentiates the bulk release of viral EVs. Similarly, suppressing TBK1 with small interfering RNA (siRNA) caused a marked increase in intracellular virus and EV release, while treatment in vivo with the TBK1-inhibitor Amlexanox exacerbated viral pancreatitis and EV spread. We further demonstrated that viral EV release is mediated by the autophagy modifier proteins GABARAPL1 and GABARAPL2 which facilitate autophagic flux. We observe that CVB infection stimulates autophagy and increases the release of GABARAPL1/2-positive EVs. We conclude that TBK1 plays additional antiviral roles by inducing autophagic flux during CVB infection independent of interferon signaling, and the loss of TBK1 better allows CVB-laden autophagosomes to circumvent lysosomal degradation, increasing the release of virus-laden EVs. This discovery sheds new light on the mechanisms involved in viral spread and EV propagation during acute enteroviral infection and highlights novel intracellular trafficking protein targets for antiviral therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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TBK1 and GABARAP family members suppress Coxsackievirus B infection by limiting viral production and promoting autophagic degradation of viral extracellular vesicles

et al. 2022

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“…It was shown, that oroxylin increased phosphorylation of eIF2α, which takes part in ER stress response [21]. Manassantin B (ManB), a lignan isolated from Saururus sp., displayed significant antiviral activity against group B coxsackieviruses in vitro during early steps of infection [36]. In mouse model of pancreatic CVB3 infection ManB treatment prevented body weight loss and decreased proinflammatory cytokines levels.…”

Section: Current Therapeutic Approaches For Cvb3 Infectionmentioning

confidence: 99%

Development of antiviral therapeutics combating coxsackievirus type B3 infection

Volobueva

Zarubaev

Lantseva

2021

Russian Journal of Infection and Immunity

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Enteroviruses are highly diverse group of single-stranded positive RNA viruses belonging to Enterovirus genus from Picornaviridae family. They are the most prevalent viruses in the world. Enteroviruses normally cause seasonal self-limiting infections but they are also known as causative infectious agents of encephalitis, myocarditis, poliomyelitis, acute heart failure and sepsis. Genetic plasticity of enteroviruses allows for widespread epidemics and sporadic outbreaks to occur (for example, outbreaks of Enterovirus D68 and Enterovirus 71). Type B Coxsackieviruses of Enterovirus B species is one of commonly identified infectious agents associated predominantly with mild upper respiratory and gastrointestinal illnesses. Nevertheless, Coxsackieviruses B3 infection can result in severe myocarditis leading ultimately to heart failure. The pathogenesis of Coxsackieviruses B3 induced myocarditis is well studied, and it is mediated by both direct injury mediated by viral proteases and indirect damage secondary to host immune responses. There are no approved direct antiviral medications for the treatment of enteroviral infection in particular Coxsackieviruses B3 myocardial infection to date. Neither are there ongoing clinical trials in the field of Coxsackieviruses B3 infection treatment or prophylaxis. Available treatment strategies are mainly supportive to stabilize the patient condition and to relieve discomforts. Possibly, the relatively small market for anti-enteroviral drugs prevents pharma industry from new drug development. The lifecycle of Coxsackieviruses B3 have been extensively studied and attractive targets for drug design are known. The aim of the present review is to describe the current state of the field of antiviral drug design against Coxsackieviruses B3 infection with special focus on direct-acting antivirals, though host factor-targeting inhibitors (including compounds from medicinal plant extracts) are mentioned too. The following categories of direct Coxsackieviruses B3 inhibitors are discussed in details: capsid binders (pleconaril and its derivatives), viral 3C protease inhibitors (rupintrivir and its analogs), drugs, targeting the viral replication (both nucleoside analogs and non-nucleoside inhibitors). Results of drug repurposing screens for amiloride, benzerazide, dibucaine and fluoxetine are also included.

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“…Enteroviruses are the most common pathogens in human viral myocarditis and are also associated with some DCMs ( 60 ). CVB3 is included in the genus Enterovirus within the family Picornaviridae and is a major causative agent of cardiac muscle infection, but the mechanism is still unclear ( 61 ). More recent studies have suggested that CVB3 may be a contributing factor in KD and that Se deficiency has additional, wide-ranging effects ( 62 ).…”

Section: Viral Infectionsmentioning

confidence: 99%

Keshan Disease: A Potentially Fatal Endemic Cardiomyopathy in Remote Mountains of China

et al. 2021

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Keshan disease (KD) as an endemic, highly lethal cardiomyopathy, first reported in northeast China's Keshan County in 1935. The clinical manifestations of patients with KD include primarily congestive heart failure, acute heart failure, and cardiac arrhythmia. Even though some possible etiologies, such as viral infection, fungal infection, microelement deficiency, and malnutrition, have been reported, the exact causes of KD remain poorly known. The endemic areas where KD is found are remote and rural, and many are poor and mountainous places where people are the most socioeconomically disadvantaged in terms of housing, income, education, transportation, and utilization of health services. To date, KD is a huge burden to and severely restricts the economic development of the local residents and health systems of the endemic areas. Although efforts have been made by the government to control, treat, and interrupt disease transmission, the cure for or complete eradication of KD still requires global attention. For this reason, in this review, we systematically describe the etiological hypothesis, clinical manifestations, incidence characteristics, and treatment of KD, to facilitate the better understanding of and draw more attention to this non-representative cardiovascular disease, with the aim of accelerating its elimination.

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Manassantin B shows antiviral activity against coxsackievirus B3 infection by activation of the STING/TBK-1/IRF3 signalling pathway

Cited by 23 publications

References 54 publications

TBK1 and GABARAP family members suppress Coxsackievirus B infection by limiting viral production and promoting autophagic degradation of viral extracellular vesicles

TBK1 and GABARAP family members suppress Coxsackievirus B infection by limiting viral production and promoting autophagic degradation of viral extracellular vesicles

Development of antiviral therapeutics combating coxsackievirus type B3 infection

Keshan Disease: A Potentially Fatal Endemic Cardiomyopathy in Remote Mountains of China

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