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Antimicrob Agents Chemother 2021 Jun 21:AAC0024421. Epub 2021 Jun 21.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Venezuelan equine encephalitis virus (VEEV) is a re-emerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against VEEV-induced cytopathic effects. Analysis of viral replication in cells identified several quinolinone compounds with potent inhibitory activity against vaccine and virulent strains of VEEV. Read More

Viruses 2021 May 12;13(5). Epub 2021 May 12.

National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA.

Venezuelan equine encephalitis virus (VEEV) is an alphavirus that causes encephalitis. Previous work indicated that VEEV infection induced early growth response 1 (EGR1) expression, leading to cell death via the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of the unfolded protein response (UPR) pathway. Loss of PERK prevented EGR1 induction and decreased VEEV-induced death. Read More

Vet Parasitol Reg Stud Reports 2021 Apr 2;24:100566. Epub 2021 Apr 2.

Laboratorio de Diagnóstico, Clinica Equina SRL, Alem 1698 - Capitan Sarmiento, Buenos Aires, Argentina.

Northern Argentina hosts equine populations living under preserved natural areas and extensive breeding conditions, with limited access to veterinary care. Horses can be in contact with i) wildlife considered to be a potential reservoir of horse pathogens (e.g. Read More

J Virol 2021 May 19. Epub 2021 May 19.

Aix Marseille Université, CNRS, AFMB UMR 7257, Marseille, France

Venezuelan equine encephalitis virus (VEEV) is a re-emerging arthropod-borne virus causing encephalitis in humans and domesticated animals. VEEV possesses a positive single-stranded RNA genome capped at its 5'-end. The capping process is performed by the non-structural protein nsP1, which bears methyl and guanylyltransferases activities. Read More

Antiviral Res 2021 Jul 7;191:105087. Epub 2021 May 7.

National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, 20110, USA; Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA; Center for Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA. Electronic address:

Marine microorganisms have been a resource for novel therapeutic drugs for decades. In addition to anticancer drugs, the drug acyclovir, derived from a marine sponge, is FDA-approved for the treatment of human herpes simplex virus-1 infections. Most alphaviruses that are infectious to terrestrial animals and humans, such as Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV), lack efficient antiviral drugs and it is imperative to develop these remedies. Read More

Virology 2021 Feb 5. Epub 2021 Feb 5.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA. Electronic address:

There is a pressing need for vaccines against mosquito-borne alphaviruses such as Venezualen and eastern equine encephalitis viruses (VEEV, EEEV). We demonstrate an approach to vaccine development based on physicochemical properties (PCP) of amino acids to design a PCP-consensus sequence of the epitope-rich B domain of the VEEV major antigenic E2 protein. The consensus "spike" domain was incorporated into a live-attenuated VEEV vaccine candidate (ZPC/IRESv1). Read More

Pathogens 2021 Mar 2;10(3). Epub 2021 Mar 2.

National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA.

Alphaviruses are a genus of the family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are currently no approved therapeutics or vaccines available for alphaviruses. Read More

PLoS Negl Trop Dis 2021 03 31;15(3):e0009306. Epub 2021 Mar 31.

Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.

Venezuelan Equine Encephalitis Virus (VEEV) is a major biothreat agent that naturally causes outbreaks in humans and horses particularly in tropical areas of the western hemisphere, for which no antiviral therapy is currently available. The host response to VEEV and the cellular factors this alphavirus hijacks to support its effective replication or evade cellular immune responses are largely uncharacterized. We have previously demonstrated tremendous cell-to-cell heterogeneity in viral RNA (vRNA) and cellular transcript levels during flaviviral infection using a novel virus-inclusive single-cell RNA-Seq approach. Read More

Emerg Infect Dis 2021 Apr;27(4)

Although essential for control strategies, knowledge about transmission cycles is limited for Venezuelan equine encephalitis complex alphaviruses (VEEVs). After testing 1,398 bats from French Guiana for alphaviruses, we identified and isolated a new strain of the encephalitogenic VEEV species Tonate virus (TONV). Bats may contribute to TONV spread in Latin America. Read More

Viruses 2021 02 27;13(3). Epub 2021 Feb 27.

Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.

Alphaviruses are arthropod-borne RNA viruses which can cause either mild to severe febrile arthritis which may persist for months, or encephalitis which can lead to death or lifelong cognitive impairments. The non-assembly molecular role(s), functions, and protein-protein interactions of the alphavirus capsid proteins have been largely overlooked. Here we detail the use of a BioID2 biotin ligase system to identify the protein-protein interactions of the Sindbis virus capsid protein. Read More

Plants (Basel) 2021 Feb 12;10(2). Epub 2021 Feb 12.

Bachelor Degree Program in Marine Biotechnology, College of Life Sciences, National Taiwan Ocean University, 2 Pei-Ning Rd., Keelung 202301, Taiwan.

The host proteins Protein Kinase B (AKT) and glycogen synthase kinase-3 (GSK-3) are associated with multiple neurodegenerative disorders. They are also important for the replication of Venezuelan equine encephalitis virus (VEEV), thereby making the AKT/GSK-3 pathway an attractive target for developing anti-VEEV therapeutics. Resveratrol, a natural phytochemical, has been shown to substantially inhibit the AKT pathway. Read More

Front Cell Dev Biol 2021 11;9:625711. Epub 2021 Feb 11.

Laboratory of Virology, Wageningen University, Wageningen, Netherlands.

Alphaviruses infect a diverse range of host organisms including mosquitoes, mammals, and birds. The enigmatic alphavirus non-structural protein 3 (nsP3) has an intrinsically disordered, C-terminal hypervariable domain (HVD) that can interact with a variety of host proteins associated with stress granules (SGs). The HVD displays the highest variability across the more than 30 known alphaviruses, yet it also contains several motifs that are conserved amongst different subgroups of alphaviruses. Read More

Front Med (Lausanne) 2021 28;8:626028. Epub 2021 Jan 28.

U.S. Naval Research Laboratory, Center for BioMolecular Science and Engineering, Washington, DC, United States.

A single domain antibody (clone CC3) previously found to neutralize a vaccine strain of the chikungunya virus (PRNT = 2. 5 ng/mL) was found to be broadly neutralizing. Clone CC3 is not only able to neutralize a wild-type (WT) strain of chikungunya virus (CHIKV), but also neutralizes WT strains of Mayaro virus (MAYV) and Ross River virus (RRV); both arthralgic, Old World alphaviruses. Read More

Front Immunol 2020 19;11:598847. Epub 2021 Jan 19.

Bavarian Nordic GmbH, Martinsried, Germany.

Venezuelan, eastern and western equine encephalitis viruses (EEV) can cause severe disease of the central nervous system in humans, potentially leading to permanent damage or death. Yet, no licensed vaccine for human use is available to protect against these mosquito-borne pathogens, which can be aerosolized and therefore pose a bioterror threat in addition to the risk of natural outbreaks. Using the mouse aerosol challenge model, we evaluated the immunogenicity and efficacy of EEV vaccines that are based on the modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine platform: three monovalent vaccines expressing the envelope polyproteins E3-E2-6K-E1 of the respective EEV virus, a mixture of these three monovalent EEV vaccines (Triple-Mix) as a first approach to generate a multivalent vaccine, and a true multivalent alphavirus vaccine (MVA-WEV, Trivalent) encoding the polyproteins of all three EEVs in a single non-replicating MVA viral vector. Read More

Front Chem 2020 23;8:573121. Epub 2020 Dec 23.

Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Biomedical Discovery Institute, Monash University, Monash, VIC, Australia.

The development of new drugs is costly and time-consuming, with estimates of over $US1 billion and 15 years for a product to reach the market. As understanding of the molecular basis of disease improves, various approaches have been used to target specific molecular interactions in the search for effective drugs. These include high-throughput screening (HTS) for novel drug identification and computer-aided drug design (CADD) to assess the properties of putative drugs before experimental work begins. Read More

Virulence 2021 12;12(1):430-443

Headquarters Division, United States Army Medical Research Institute of Infectious Diseases , Fort Detrick, Maryland, USA.

Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus that can cause debilitating, acute febrile illness and potentially result in encephalitis. Currently, there are no FDA-licensed vaccines or specific therapeutics for VEEV. Previous studies have demonstrated that VEEV infection results in increased blood-brain barrier (BBB) permeability that is mediated by matrix metalloproteinases (MMPs). Read More

Biochem Soc Trans 2021 02;49(1):281-295

Nuclear Signaling Lab., Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.

Although transport into the nucleus mediated by the importin (IMP) α/β1-heterodimer is central to viral infection, small molecule inhibitors of IMPα/β1-dependent nuclear import have only been described and shown to have antiviral activity in the last decade. Their robust antiviral activity is due to the strong reliance of many different viruses, including RNA viruses such as human immunodeficiency virus-1 (HIV-1), dengue (DENV), and Zika (ZIKV), on the IMPα/β1-virus interface. High-throughput compound screens have identified many agents that specifically target this interface. Read More

Int J Environ Res Public Health 2020 12 30;18(1). Epub 2020 Dec 30.

International Institute for Wildlife Conservation and Management, National University of Costa Rica, Heredia 40101, Costa Rica.

Venezuelan equine encephalitis virus (VEEV) is an arbovirus transmitted by arthropods, widely distributed in the Americas that, depending on the subtype, can produce outbreaks or yearly cases of encephalitis in horses and humans. The symptoms are similar to those caused by dengue virus and in the worst-case scenario, involve encephalitis, and death. MaxEnt is software that uses climatological, geographical, and occurrence data of a particular species to create a model to estimate possible niches that could have these favorable conditions. Read More

Mol Ther 2021 03 21;29(3):1174-1185. Epub 2020 Dec 21.

Department of Infectious Disease, Imperial College London, London W21PG, UK. Electronic address:

Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. Read More

Biochem Biophys Res Commun 2021 01 21;538:163-172. Epub 2020 Oct 21.

Cancer Targeting and Nuclear Therapeutics Lab., Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia. Electronic address:

FDA approved for parasitic indications, the small molecule ivermectin has been the focus of growing attention in the last 8 years due to its potential as an antiviral. We first identified ivermectin in a high throughput compound library screen as an agent potently able to inhibit recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host importin (IMP) α/β1 heterodimer, and recently demonstrated its ability to bind directly to IMPα to cause conformational changes that prevent its function in nuclear import of key viral as well as host proteins. Cell culture experiments have shown robust antiviral action towards a whole range of viruses, including HIV-1, dengue, Zika and West Nile Virus, Venezuelan equine encephalitis virus, Chikungunya, pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Read More

Molecules 2020 Dec 10;25(24). Epub 2020 Dec 10.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA.

In recent years, intrinsically disordered proteins (IDPs) and disordered domains have attracted great attention. Many of them contain linear motifs that mediate interactions with other factors during formation of multicomponent protein complexes. NMR spectrometry is a valuable tool for characterizing this type of interactions on both amino acid (aa) and atomic levels. Read More

Sci Rep 2020 12 8;10(1):21491. Epub 2020 Dec 8.

National Center for Biodefence and Infectious Disease, Biomedical Research Laboratory, School of Systems Biology, George Mason University, Manassas, VA, USA.

Venezuelan equine encephalitis virus (VEEV), a New World alphavirus of the Togaviridae family of viruses causes periodic outbreaks of disease in humans and equines. Disease following VEEV infection manifests as a febrile illness with flu-like symptoms, which can progress to encephalitis and cause permanent neurological sequelae in a small number of cases. VEEV is classified as a category B select agent due to ease of aerosolization and high retention of infectivity in the aerosol form. Read More

J Drug Target 2021 04 16;29(4):403-419. Epub 2020 Dec 16.

College of Pharmacy, QU Health, Qatar University, Doha, Qatar.

Some viral outbreaks have plagued the world since antiquity, including the most recent COVID-19 pandemic. The continuous spread and emergence of new viral diseases have urged the discovery of novel treatment options that can overcome the limitations of currently marketed antiviral drugs. Chalcones are natural open chain flavonoids that are found in various plants and can be synthesised in labs. Read More

ACS Med Chem Lett 2020 Nov 2;11(11):2139-2145. Epub 2020 Sep 2.

Department of Chemistry, Physics, and Atmospheric Sciences, Jackson State University, Jackson, Mississippi 39217-0095, United States.

Emerging infectious diseases like those caused by arboviruses such as Venezuelan equine encephalitis virus (VEEV) pose a serious threat to public health systems. Development of medical countermeasures against emerging infectious diseases are of utmost importance. In this work, an acrylate and vinyl sulfone-based chemical series was investigated as promising starting scaffolds against VEEV and as inhibitors of the cysteine protease domain of VEEV's nonstructural protein 2 (nsP2). Read More

Nature 2020 12 18;588(7837):308-314. Epub 2020 Nov 18.

Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.

Venezuelan equine encephalitis virus (VEEV) is a neurotropic alphavirus transmitted by mosquitoes that causes encephalitis and death in humans. VEEV is a biodefence concern because of its potential for aerosol spread and the current lack of sufficient countermeasures. The host factors that are required for VEEV entry and infection remain poorly characterized. Read More

Nature 2020 12;588(7837):223-224

Cells 2020 11 5;9(11). Epub 2020 Nov 5.

Platform Degenerative Diseases, German Primate Center, GmbH, Leibniz Institute for Primate Research, 37077 Göttingen, Germany.

Induced pluripotent stem cells (iPSCs) hold enormous potential for the development of cell-based therapies; however, the safety and efficacy of potential iPSC-based treatments need to be verified in relevant animal disease models before their application in the clinic. Here, we report the derivation of iPSCs from common marmoset monkeys () using self-replicating mRNA vectors based on the Venezuelan equine encephalitis virus (VEE-mRNAs). By transfection of marmoset fibroblasts with VEE-mRNAs carrying the human , and and culture in the presence of small molecule inhibitors CHIR99021 and SB431542, we first established intermediate primary colonies with neural progenitor-like properties. Read More

Antiviral Res 2020 12 1;184:104966. Epub 2020 Nov 1.

Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Department of Microbiology and Immunology, Stanford University, CA, USA. Electronic address:

Global health is threatened by emerging viruses, many of which lack approved therapies and effective vaccines, including dengue, Ebola, and Venezuelan equine encephalitis. We previously reported that AAK1 and GAK, two of the four members of the understudied Numb-associated kinases (NAK) family, control intracellular trafficking of RNA viruses. Nevertheless, the role of BIKE and STK16 in viral infection remained unknown. Read More

Am J Trop Med Hyg 2020 12 22;103(6):2429-2437. Epub 2020 Oct 22.

Department of Statistics, University of Oxford, Oxford, United Kingdom.

Madariaga virus (MADV) has recently been associated with severe human disease in Panama, where the closely related Venezuelan equine encephalitis virus (VEEV) also circulates. In June 2017, a fatal MADV infection was confirmed in a community of Darien Province. We conducted a cross-sectional outbreak investigation with human and mosquito collections in July 2017, where sera were tested for alphavirus antibodies and viral RNA. Read More

Int J Mol Sci 2020 Oct 16;21(20). Epub 2020 Oct 16.

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

The non-structural protein 2 (nsP2) of alphavirus Venezuelan equine encephalitis virus (VEEV) is a cysteine protease that is responsible for processing of the viral non-structural polyprotein and is an important drug target owing to the clinical relevance of VEEV. In this study we designed two recombinant VEEV nsP2 constructs to study the effects of an N-terminal extension on the protease activity and to investigate the specificity of the elongated enzyme in vitro. The N-terminal extension was found to have no substantial effect on the protease activity. Read More