scholarly journals TRIM69 Inhibits Vesicular Stomatitis Indiana Virus

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Suzannah J. Rihn ◽  
Muhamad Afiq Aziz ◽  
Douglas G. Stewart ◽  
Joseph Hughes ◽  
Matthew L. Turnbull ◽  
...  
Keyword(s):  
Viral Replication ◽  
Influenza A ◽  
Viral Infections ◽  
Rift Valley Fever Virus ◽  
Host Cells ◽  
Human Populations ◽  
Valley Fever ◽  
Expression Screening ◽  
Interferon Stimulated Genes ◽  
Vesicular Stomatitis

ABSTRACT Vesicular stomatitis Indiana virus (VSIV), formerly known as vesicular stomatitis virus (VSV) Indiana (VSVIND), is a model virus that is exceptionally sensitive to the inhibitory action of interferons (IFNs). Interferons induce an antiviral state by stimulating the expression of hundreds of interferon-stimulated genes (ISGs). These ISGs can constrain viral replication, limit tissue tropism, reduce pathogenicity, and inhibit viral transmission. Since VSIV is used as a backbone for multiple oncolytic and vaccine strategies, understanding how ISGs restrict VSIV not only helps in understanding VSIV-induced pathogenesis but also helps us evaluate and understand the safety and efficacy of VSIV-based therapies. Thus, there is a need to identify and characterize the ISGs that possess anti-VSIV activity. Using arrayed ISG expression screening, we identified TRIM69 as an ISG that potently inhibits VSIV. This inhibition was highly specific as multiple viruses, including influenza A virus, HIV-1, Rift Valley fever virus, and dengue virus, were unaffected by TRIM69. Indeed, just one amino acid substitution in VSIV can govern sensitivity/resistance to TRIM69. Furthermore, TRIM69 is highly divergent in human populations and exhibits signatures of positive selection that are consistent with this gene playing a key role in antiviral immunity. We propose that TRIM69 is an IFN-induced inhibitor of VSIV and speculate that TRIM69 could be important in limiting VSIV pathogenesis and might influence the specificity and/or efficacy of vesiculovirus-based therapies. IMPORTANCE Vesicular stomatitis Indiana virus (VSIV) is a veterinary pathogen that is also used as a backbone for many oncolytic and vaccine strategies. In natural and therapeutic settings, viral infections like VSIV are sensed by the host, and as a result the host cells make proteins that can protect them from viruses. In the case of VSIV, these antiviral proteins constrain viral replication and protect most healthy tissues from virus infection. In order to understand how VSIV causes disease and how healthy tissues are protected from VSIV-based therapies, it is crucial that we identify the proteins that inhibit VSIV. Here, we show that TRIM69 is an antiviral defense that can potently and specifically block VSIV infection.

scholarly journals TRIM69 inhibits Vesicular Stomatitis Indiana Virus (VSIV)

2019 ◽  
Author(s):  
Suzannah J. Rihn ◽  
Muhamad Afiq Aziz ◽  
Douglas G. Stewart ◽  
Joseph Hughes ◽  
Matthew L. Turnbull ◽  
...  
Keyword(s):  
Viral Replication ◽  
Influenza A ◽  
Rift Valley Fever Virus ◽  
Host Cells ◽  
Human Populations ◽  
Valley Fever ◽  
Expression Screening ◽  
Interferon Stimulated Genes ◽  
Vesicular Stomatitis ◽  
Therapeutic Settings

ABSTRACTVesicular Stomatitis Indiana Virus (VSIV) is a model virus that is exceptionally sensitive to the inhibitory action of interferons. Interferons induce an antiviral state by stimulating the expression of hundreds of interferon stimulated genes (ISGs). These ISGs constrain viral replication, limit tissue tropism, reduce pathogenicity and inhibit viral transmission. Because VSIV is used as a backbone for multiple oncolytic and vaccine strategies, understanding how ISGs restrict VSIV, not only helps in understanding VSIV-pathogenesis, but helps evaluate and understand the safety and efficacy of VSIV-based therapies. Thus there is a need to identify and characterize the ISGs that possess anti-VSIV activity. Using arrayed ISG expression screening, we identified TRIM69 as an ISG that potently inhibits VSIV. This inhibition was highly specific as multiple viruses (including influenza A virus, HIV-1, Rift Valley Fever Virus and dengue virus) were not affected by TRIM69. Indeed, just one amino acid substitution in VSIV can govern sensitivity/resistance to TRIM69. TRIM69 is highly divergent in human populations and exhibits signatures of positive selection that are consistent with this gene playing a key role in antiviral immunity. We propose that TRIM69 is an IFN-induced inhibitor of VSIV and speculate that TRIM69 could be important in limiting VSIV pathogenesis and might influence the specificity and/or efficacy of vesiculovirus-based therapies.IMPORTANCEVesicular Stomatitis Indiana Virus (VSIV) is a veterinary pathogen that is also used as a backbone for many oncolytic and vaccine strategies. In natural and therapeutic settings, VSIV infection is sensed by the host and host-cells make proteins that protect them from viruses. In the case of VSIV, these antiviral proteins constrain viral replication and protect most healthy tissues from virus infection. In order to understand how VSIV causes disease and how healthy tissues are protected from VSIV-based therapies, it is crucial that we identify the proteins that inhibit VSIV. Here we show that TRIM69 is an antiviral defence that can potently and specifically block VSIV infection.

scholarly journals Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine

2019 ◽  
Author(s):  
Petter I. Andersen ◽  
Klara Krpina ◽  
Aleksandr Ianevski ◽  
Nastassia Shtaida ◽  
Eunji Jo ◽  
...  
Keyword(s):  
Influenza A ◽  
Rift Valley Fever Virus ◽  
Antiviral Agents ◽  
Viral Disease ◽  
World Health ◽  
Valley Fever ◽  
The World ◽  
Health Organization ◽  
Hiv 1

Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Re-purposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), human immunodeficiency virus 1 (HIV-1), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FluAV), niclosamide against HSV-2, brequinar against HIV-1, and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vivo tests.

scholarly journals The role of livestock movements in the spread of Rift Valley fever virus in animals and humans in Mayotte, 2018–19

2021 ◽  
Vol 15 (3) ◽  
pp. e0009202
Author(s):  
Younjung Kim ◽  
Raphaëlle Métras ◽  
Laure Dommergues ◽  
Chouanibou Youssouffi ◽  
Soihibou Combo ◽  
...  
Keyword(s):  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Human Infection ◽  
Temporal Sequence ◽  
Spatial Proximity ◽  
Human Populations ◽  
Public Health Importance ◽  
Valley Fever ◽  
Livestock Density

Rift Valley fever (RVF) is a vector-borne viral disease of major animal and public health importance. In 2018–19, it caused an epidemic in both livestock and human populations of the island of Mayotte. Using Bayesian modelling approaches, we assessed the spatio-temporal pattern of RVF virus (RVFV) infection in livestock and human populations across the island, and factors shaping it. First, we assessed if (i) livestock movements, (ii) spatial proximity from communes with infected animals, and (iii) livestock density were associated with the temporal sequence of RVFV introduction into Mayotte communes’ livestock populations. Second, we assessed whether the rate of human infection was associated with (a) spatial proximity from and (b) livestock density of communes with infected animals. Our analyses showed that the temporal sequence of RVFV introduction into communes’ livestock populations was associated with livestock movements and spatial proximity from communes with infected animals, with livestock movements being associated with the best model fit. Moreover, the pattern of human cases was associated with their spatial proximity from communes with infected animals, with the risk of human infection sharply increasing if livestock in the same or close communes were infected. This study highlights the importance of understanding livestock movement networks in informing the design of risk-based RVF surveillance programs.

scholarly journals Interferon-Stimulated Gene (ISG)-Expression Screening Reveals the Specific Antibunyaviral Activity of ISG20

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Junjie Feng ◽  
Arthur Wickenhagen ◽  
Matthew L. Turnbull ◽  
Veronica V. Rezelj ◽  
Felix Kreher ◽  
...  
Keyword(s):  
Viral Infections ◽  
Rhesus Macaques ◽  
Type I ◽  
Emerging Viruses ◽  
Content Type ◽  
Expression Screening ◽  
Interferon Stimulated Genes ◽  
Life Threatening

ABSTRACT Bunyaviruses pose a significant threat to human health, prosperity, and food security. In response to viral infections, interferons (IFNs) upregulate the expression of hundreds of interferon-stimulated genes (ISGs), whose cumulative action can potently inhibit the replication of bunyaviruses. We used a flow cytometry-based method to screen the ability of ∼500 unique ISGs from humans and rhesus macaques to inhibit the replication of Bunyamwera orthobunyavirus (BUNV), the prototype of both the Peribunyaviridae family and the Bunyavirales order. Candidates possessing antibunyaviral activity were further examined using a panel of divergent bunyaviruses. Interestingly, one candidate, ISG20, exhibited potent antibunyaviral activity against most viruses examined from the Peribunyaviridae , Hantaviridae , and Nairoviridae families, whereas phleboviruses ( Phenuiviridae ) largely escaped inhibition. Similar to the case against other viruses known to be targeted by ISG20, the antibunyaviral activity of ISG20 is dependent upon its functional RNase activity. Through use of an infectious virus-like particle (VLP) assay (based on the BUNV minigenome system), we confirmed that gene expression from all 3 viral segments is strongly inhibited by ISG20. Using in vitro evolution, we generated a substantially ISG20-resistant BUNV and mapped the determinants of ISG20 sensitivity/resistance. Taking all the data together, we report that ISG20 is a broad and potent antibunyaviral factor but that some bunyaviruses are remarkably ISG20 resistant. Thus, ISG20 sensitivity/resistance may influence the pathogenesis of bunyaviruses, many of which are emerging viruses of clinical or veterinary significance. IMPORTANCE There are hundreds of bunyaviruses, many of which cause life-threatening acute diseases in humans and livestock. The interferon (IFN) system is a key component of innate immunity, and type I IFNs limit bunyaviral propagation both in vitro and in vivo . Type I IFN signaling results in the upregulation of hundreds of IFN-stimulated genes (ISGs), whose concerted action generates an “antiviral state.” Although IFNs are critical in limiting bunyaviral replication and pathogenesis, much is still unknown about which ISGs inhibit bunyaviruses. Using ISG-expression screening, we examined the ability of ∼500 unique ISGs to inhibit Bunyamwera orthobunyavirus (BUNV), the prototypical bunyavirus. Using this approach, we identified ISG20, an interferon-stimulated exonuclease, as a potent inhibitor of BUNV. Interestingly, ISG20 possesses highly selective antibunyaviral activity, with multiple bunyaviruses being potently inhibited while some largely escape inhibition. We speculate that the ability of some bunyaviruses to escape ISG20 may influence their pathogenesis.

scholarly journals Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Komudi Singh ◽  
Yun-Ching Chen ◽  
Shahin Hassanzadeh ◽  
Kim Han ◽  
Jennifer T. Judy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Influenza A ◽  
Expression Profiles ◽  
Mitochondrial Fission ◽  
Transcriptional Response ◽  
Transcriptome Profiling ◽  
Host Cells ◽  
Autophagic Flux ◽  
Interferon Stimulated Genes ◽  
Human Samples

Analyzing host cells' transcriptional response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will help delineate biological processes underlying viral pathogenesis. First, analysis of expression profiles of lung cell lines A549 and Calu3 revealed upregulation of antiviral interferon signaling genes in response to all three SARS-CoV-2, MERS-CoV, or influenza A virus (IAV) infections. However, perturbations in expression of genes involved in inflammatory, mitochondrial, and autophagy processes were specifically observed in SARS-CoV-2-infected cells. Next, a validation study in infected human nasopharyngeal samples also revealed perturbations in autophagy and mitochondrial processes. Specifically, mTOR expression, mitochondrial ribosomal, mitochondrial complex I, lysosome acidification, and mitochondrial fission promoting genes were concurrently downregulated in both infected cell lines and human samples. SARS-CoV-2 infection impeded autophagic flux either by upregulating GSK3B in lung cell lines or by downregulating autophagy genes, SNAP29, and lysosome acidification genes in human samples, contributing to increased viral replication. Therefore, drugs targeting lysosome acidification or autophagic flux could be tested as intervention strategies. Finally, age-stratified SARS-CoV-2-positive human data revealed impaired upregulation of chemokines, interferon-stimulated genes, and tripartite motif genes that are critical for antiviral signaling. Together, this analysis has revealed specific aspects of autophagic and mitochondrial function that are uniquely perturbed in SARS-CoV-2-infected host cells.

scholarly journals Novel Ionophores Active against La Crosse Virus Identified through Rapid Antiviral Screening

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Zachary J. Sandler ◽  
Mason R. Firpo ◽  
Oreoluwa S. Omoba ◽  
Michelle N. Vu ◽  
Vineet D. Menachery ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Virus Replication ◽  
Viral Infections ◽  
Rift Valley Fever Virus ◽  
Virus Titer ◽  
Potassium Ions ◽  
Dependent Manner ◽  
La Crosse Virus ◽  
Human Pathogens ◽  
Valley Fever

ABSTRACT Bunyaviruses are significant human pathogens, causing diseases ranging from hemorrhagic fevers to encephalitis. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic, dozens of cases of encephalitis are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection. Here, we developed a method to rapidly test potential antivirals against LACV infection. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families, including bunyaviruses (Rift Valley fever virus, Keystone virus), enteroviruses (coxsackievirus, rhinovirus), flavirivuses (Zika virus), and coronaviruses (human coronavirus 229E [HCoV-229E] and Middle East respiratory syndrome CoV [MERS-CoV]). In all viral infections, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection, suggesting a potential therapeutic target to disrupt virus replication.

scholarly journals Rift Valley Fever Virus Strain MP-12 Enters Mammalian Host Cells via Caveola-Mediated Endocytosis

2012 ◽  
Vol 86 (23) ◽  
pp. 12954-12970 ◽  
Author(s):  
B. Harmon ◽  
B. R. Schudel ◽  
D. Maar ◽  
C. Kozina ◽  
T. Ikegami ◽  
...  
Keyword(s):  
Virus Strain ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Host Cells ◽  
Mammalian Host ◽  
Valley Fever

scholarly journals Mammalian and Avian Host Cell Influenza A Restriction Factors

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 522
Author(s):  
Joe McKellar ◽  
Antoine Rebendenne ◽  
Mélanie Wencker ◽  
Olivier Moncorgé ◽  
Caroline Goujon
Keyword(s):  
Influenza A ◽  
Influenza Pandemic ◽  
Host Cells ◽  
Modular System ◽  
Avian Host ◽  
Restriction Factors ◽  
Interferon Stimulated Genes ◽  
Antiviral Proteins ◽  
Viral Lifecycle

The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade triggered by sensing subsequently induces protection for themselves and their surrounding neighbors, termed interferon (IFN) response. This response induces the upregulation of hundreds of interferon-stimulated genes (ISGs), including antiviral effectors, establishing an antiviral state. As well as the antiviral proteins induced through the IFN system, cells also possess a so-called intrinsic immunity, constituted of antiviral proteins that are constitutively expressed, creating a first barrier preceding the induction of the interferon system. All these combined antiviral effectors inhibit the virus at various stages of the viral lifecycle, using a wide array of mechanisms. Here, we provide a review of mammalian and avian influenza A restriction factors, detailing their mechanism of action and in vivo relevance, when known. Understanding their mode of action might help pave the way for the development of new influenza treatments, which are absolutely required if we want to be prepared to face a new pandemic.

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