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 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 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 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 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.

scholarly journals A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection

2015 ◽  
Vol 90 (3) ◽  
pp. 1414-1423 ◽  
Author(s):  
Amber M. Riblett ◽  
Vincent A. Blomen ◽  
Lucas T. Jae ◽  
Louis A. Altamura ◽  
Robert W. Doms ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Golgi Complex ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Hemorrhagic Fever ◽  
Cell Types ◽  
Fever Virus ◽  
Host Cells ◽  
Valley Fever

ABSTRACTRift Valley fever virus (RVFV) causes recurrent insect-borne epizootics throughout the African continent, and infection of humans can lead to a lethal hemorrhagic fever syndrome. Deep mutagenesis of haploid human cells was used to identify host factors required for RVFV infection. This screen identified a suite of enzymes involved in glycosaminoglycan (GAG) biogenesis and transport, including several components of thecis-oligomeric Golgi (COG) complex, one of the central components of Golgi complex trafficking. In addition, disruption ofPTAR1led to RVFV resistance as well as reduced heparan sulfate surface levels, consistent with recent observations that PTAR1-deficient cells exhibit altered Golgi complex morphology and glycosylation defects. A variety of biochemical and genetic approaches were utilized to show that both pathogenic and attenuated RVFV strains require GAGs for efficient infection on some, but not all, cell types, with the block to infection being at the level of virion attachment. Examination of other members of theBunyaviridaefamily for GAG-dependent infection suggested that the interaction with GAGs is not universal among bunyaviruses, indicating that these viruses, as well as RVFV on certain cell types, employ additional unidentified virion attachment factors and/or receptors.IMPORTANCERift Valley fever virus (RVFV) is an emerging pathogen that can cause severe disease in humans and animals. Epizootics among livestock populations lead to high mortality rates and can be economically devastating. Human epidemics of Rift Valley fever, often initiated by contact with infected animals, are characterized by a febrile disease that sometimes leads to encephalitis or hemorrhagic fever. The global burden of the pathogen is increasing because it has recently disseminated beyond Africa, which is of particular concern because the virus can be transmitted by widely distributed mosquito species. There are no FDA-licensed vaccines or antiviral agents with activity against RVFV, and details of its life cycle and interaction with host cells are not well characterized. We used the power of genetic screening in human cells and found that RVFV utilizes glycosaminoglycans to attach to host cells. This furthers our understanding of the virus and informs the development of antiviral therapeutics.

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