Coxsackie B 1 virus-induced changes in cell membrane-associated functions are not responsible for altered sensitivity to bacterial invasiveness

Modalsli, Kristin; Bukholm, Geir; Mikalsen, Svein‐Ole; Degré, Miklos

doi:10.1007/bf01309812

Cited by 5 publications

(7 citation statements)

References 18 publications

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“…The cell lysates were directly analyzed with a scintillation counter to determine the level of free [ 35 thionine transport by ϳ20% ( Fig. 8E) but caused a 30 to 40% reduction in the number of plaques, further supporting the model in which a decrease in expression of viral protein may have a dramatic impact on virus replication.…”

Section: Specific Convallatoxin Residues Dictate Potency Against CMVsupporting

confidence: 56%

“…There are viruses that are most likely resistant to glycosides, as well. Sindbis virus and coxsackie B virus downregulate Na ϩ /K ϩ -ATPase and remove the sodium gradient (34,35) and are thus unlikely to be inhibited by a cardiac glycoside. Collectively, convallatoxin may be an effective broad-spectrum antiviral due to the high demand for newly synthesized viral and cellular proteins during virus infection.…”

Section: Discussionmentioning

confidence: 99%

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Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

Cohen

Williams

Opperman

et al. 2016

J Virol

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Cytomegalovirus (CMV) is a ubiquitous human pathogen that increases the morbidity and mortality of immunocompromised individuals. The current FDA-approved treatments for CMV infection are intended to be virus specific, yet they have significant adverse side effects, including nephrotoxicity and hematological toxicity. Thus, there is a medical need for safer and more effective CMV therapeutics. Using a high-content screen, we identified the cardiac glycoside convallatoxin as an effective compound that inhibits CMV infection. Using a panel of cardiac glycoside variants, we assessed the structural elements critical for anti-CMV activity by both experimental and in silico methods. Analysis of the antiviral effects, toxicities, and pharmacodynamics of different variants of cardiac glycosides identified the mechanism of inhibition as reduction of methionine import, leading to decreased immediate-early gene translation without significant toxicity. Also, convallatoxin was found to dramatically reduce the proliferation of clinical CMV strains, implying that its mechanism of action is an effective strategy to block CMV dissemination. Our study has uncovered the mechanism and structural elements of convallatoxin, which are important for effectively inhibiting CMV infection by targeting the expression of immediate-early genes. IMPORTANCECytomegalovirus is a highly prevalent virus capable of causing severe disease in certain populations. The current FDA-approved therapeutics all target the same stage of the viral life cycle and induce toxicity and viral resistance. We identified convallatoxin, a novel cell-targeting antiviral that inhibits CMV infection by decreasing the synthesis of viral proteins. At doses low enough for cells to tolerate, convallatoxin was able to inhibit primary isolates of CMV, including those resistant to the anti-CMV drug ganciclovir. In addition to identifying convallatoxin as a novel antiviral, limiting mRNA translation has a dramatic impact on CMV infection and proliferation. C ytomegalovirus (CMV) is an extremely large betaherpesvirus with over 230,000 bp and over 200 open reading frames. While the majority of CMV infections in immunocompetent hosts are asymptomatic (1), the phenomenon of latency allows the virus to establish a permanent and persistent infection. CMV is highly seroprevalent in the human population (Ͼ60%), with broad cell tropism, and can be transmitted through bodily fluids and organ transplantation and transplacentally from mother to fetus (2). Reactivation of latent CMV can cause disease in any population but is a particular source of morbidity and mortality for immunocompromised patients (3). It is estimated that treatment of CMV costs the United States $4.4 billion every year (4), and congenital CMV infections are the leading cause of permanent congenital neurological disabilities in the United States (5). The current FDA-approved therapies all target the viral DNA polymerase, and none are approved for use in pregnant women or newborns. These compounds can cause sever...

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Section: Specific Convallatoxin Residues Dictate Potency Against CMVsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

Cohen

Williams

Opperman

et al. 2016

J Virol

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“…In addition, influenza A virus infection induces decreased expression of Na,K-ATPase in the plasma membrane of alveolar epithelial cells with paracrine factors released from infected cells [33]. Na,K-ATPase activity can also be decreased by sindbis virus [34] and enterovirus coxsackie B infection [35], causing important changes in the intracellular concentration of potassium and sodium and consequently in membrane potential [36]. Interestingly, enterovirus 71 (EV71), agent of hand- foot-and-mouth disease (HFMD) in pediatric population, interacts with the β3 subunit of the Na,K-ATPase causing an increase of its expression [37].…”

Section: Nak-atpase Function Altered By Viral Infectionmentioning

confidence: 99%

The Antiviral Effects of Na,K-ATPase Inhibition: A Minireview

Amarelle

Lecuona

2018

IJMS

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Since being first described more than 60 years ago, Na,K-ATPase has been extensively studied, while novel concepts about its structure, physiology, and biological roles continue to be elucidated. Cardiac glycosides not only inhibit the pump function of Na,K-ATPase but also activate intracellular signal transduction pathways, which are important in many biological processes. Recently, antiviral effects have been described as a novel feature of Na,K-ATPase inhibition with the use of cardiac glycosides. Cardiac glycosides have been reported to be effective against both DNA viruses such as cytomegalovirus and herpes simplex and RNA viruses such as influenza, chikungunya, coronavirus, and respiratory syncytial virus, among others. Consequently, cardiac glycosides have emerged as potential broad-spectrum antiviral drugs, with the great advantage of targeting cell host proteins, which help to minimize resistance to antiviral treatments, making them a very promising strategy against human viral infections. Here, we review the effect of cardiac glycosides on viral biology and the mechanisms by which these drugs impair the replication of this array of different viruses.

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“…After irradiation, infectivity was reduced to 10 x TCID,,,/ml. The UV-inactivated virus did not initiate significant synthesis of virus RNA within 1 day after inoculation (14).…”

Section: Virusmentioning

confidence: 94%

“…In contrast, the late phase effect, 6 h after virus inoculation, requires viable virus (12) and coincides with protein synthesis (15). Several other cellular functions such as plasma membrane permeability (12), non-receptor-mediated phagocytosis (6), and Na+-K+-activated ATPase activity (14) are altered in the early phase of the virus infection cycle. These processes, however, do not seem to directly interfere with bacterial invasiveness (14).…”

mentioning

confidence: 99%

Microinjection of HEp-2 cells with coxsackie B1 virus RNA enhances invasiveness of Shigella flexneri only after prestimulation with UV-inactivated virus

Modalsli¹,

Mikalsen²,

Bukholm³

et al. 1993

Apmis

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Coxsackie B1 virus induces increased susceptibility to invasion by Shigella flexneri when HEp‐2 cells are inoculated with the complete virus. When RNA from the same virus was microinjected into cells, virus RNA was synthesized and new virus particles were formed, but the transfected RNA had no effect on bacterial invasiveness. However, when the cells were prestimulated with UV‐inactivated virus, the microinjected RNA induced an additional enhancement of bacterial invasiveness. Microinjected whole virus particles did not replicate and did not induce any change in bacterial invasiveness. The results indicate that an initial event in virus multiplication is necessary to achieve an effect of transfected viral RNA on invasion of S. flexneri.

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Coxsackie B 1 virus-induced changes in cell membrane-associated functions are not responsible for altered sensitivity to bacterial invasiveness

Cited by 5 publications

References 18 publications

Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

The Antiviral Effects of Na,K-ATPase Inhibition: A Minireview

Microinjection of HEp-2 cells with coxsackie B1 virus RNA enhances invasiveness of Shigella flexneri only after prestimulation with UV-inactivated virus

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