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Journal of Medical Virology Nov 2023The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses...
The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses.
Topics: Humans; Furin; Viral Envelope Proteins; Monensin; Arenavirus; Antiviral Agents
PubMed: 37975336
DOI: 10.1002/jmv.29211 -
Current Topics in Microbiology and... 2023Individuals living in endemic hotspots of Lassa fever have recurrent exposure to Lassa virus (LASV) via spillover from the primary host reservoir Mastomys natalensis....
Individuals living in endemic hotspots of Lassa fever have recurrent exposure to Lassa virus (LASV) via spillover from the primary host reservoir Mastomys natalensis. Despite M. natalensis being broadly distributed across sub-Saharan Africa, Lassa fever is only found in West Africa. In recent years, new LASV reservoirs have been identified. Erudition of rodent habitats, reproduction and fecundity, movement patterns, and spatial preferences are essential to institute preventative measures against Lassa fever. Evolutionary insights have also added to our knowledge of closely related mammarenavirus distribution amongst rodents throughout the continent.
Topics: Animals; Lassa virus; Lassa Fever; Disease Reservoirs; Murinae
PubMed: 33564902
DOI: 10.1007/82_2020_231 -
Frontiers in Immunology 2022Viral hemorrhagic fever (VHF) is a term referring to a group of life-threatening infections caused by several virus families (, , and ). Depending on the virus, the... (Review)
Review
Viral hemorrhagic fever (VHF) is a term referring to a group of life-threatening infections caused by several virus families (, , and ). Depending on the virus, the infection can be mild and can be also characterized by an acute course with fever accompanied by hypervolemia and coagulopathy, resulting in bleeding and shock. It has been suggested that the course of the disease is strongly influenced by the activation of signaling pathways leading to RIG-I-like receptor-dependent interferon production. RIG-I-like receptors (RLRs) are one of two major receptor families that detect viral nucleic acid. RLR receptor activation is influenced by a number of factors that may have a key role in the differences that occur during the antiviral immune response in VHF. In the present study, we collected data on RLR receptors in viral hemorrhagic fevers and described factors that may influence the activation of the antiviral response. RLR receptors seem to be a good target for VHF research, which may contribute to better therapeutic and diagnostic strategies. However, due to the difficulty of conducting such studies in humans, we suggest using as an animal model for VHF.
Topics: Animals; Antiviral Agents; Arenaviridae; DEAD-box RNA Helicases; Hemorrhagic Fevers, Viral; Humans; Interferons; Nucleic Acids
PubMed: 36248895
DOI: 10.3389/fimmu.2022.1010635 -
Expert Opinion on Drug Discovery 2016Arenaviruses are enveloped negative stranded viruses endemic in Africa, Europe and the Americas. Several arenaviruses cause severe viral hemorrhagic fever with high... (Review)
Review
INTRODUCTION
Arenaviruses are enveloped negative stranded viruses endemic in Africa, Europe and the Americas. Several arenaviruses cause severe viral hemorrhagic fever with high mortality in humans and pose serious public health threats. So far, there are no FDA-approved vaccines and therapeutic options are restricted to the off-label use of ribavirin. The major human pathogenic arenaviruses are classified as Category A agents and require biosafety level (BSL)-4 containment.
AREAS COVERED
Herein, the authors cover the recent progress in the development of BSL2 surrogate systems that recapitulate the entire or specific steps of the arenavirus life cycle and are serving as powerful platforms for drug discovery. Furthermore, they highlight the identification of selected novel drugs that target individual steps of arenavirus multiplication describing their discovery, their targets, and mode of action.
EXPERT OPINION
The lack of effective drugs against arenaviruses is an unmatched challenge in current medical virology. Novel technologies have provided important insights into the basic biology of arenaviruses and the mechanisms underlying virus-host cell interaction. Significant progress of our understanding of how the virus invades the host cell paved the way to develop powerful novel screening platforms. Recent efforts have provided a range of promising drug candidates currently under evaluation for therapeutic intervention in vivo.
Topics: Animals; Antiviral Agents; Arenaviridae Infections; Arenavirus; Drug Design; Drug Discovery; Humans; Viral Vaccines
PubMed: 26882218
DOI: 10.1517/17460441.2016.1153626 -
Cells Nov 2020Mammarenaviruses are a diverse genus of emerging viruses that include several causative agents of severe viral hemorrhagic fevers with high mortality in humans. Although...
Mammarenaviruses are a diverse genus of emerging viruses that include several causative agents of severe viral hemorrhagic fevers with high mortality in humans. Although these viruses share many similarities, important differences with regard to pathogenicity, type of immune response, and molecular mechanisms during virus infection are different between and within New World and Old World viral infections. Viruses rely exclusively on the host cellular machinery to translate their genome, and therefore to replicate and propagate. miRNAs are the crucial factor in diverse biological processes such as antiviral defense, oncogenesis, and cell development. The viral infection can exert a profound impact on the cellular miRNA expression profile, and numerous RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. Our present study indicates that mammarenavirus infection induces metabolic reprogramming of host cells, probably manipulating cellular microRNAs. A number of metabolic pathways, including valine, leucine, and isoleucine biosynthesis, d-Glutamine and d-glutamate metabolism, thiamine metabolism, and pools of several amino acids were impacted by the predicted miRNAs that would no longer regulate these pathways. A deeper understanding of mechanisms by which mammarenaviruses handle these signaling pathways is critical for understanding the virus/host interactions and potential diagnostic and therapeutic targets, through the inhibition of specific pathologic metabolic pathways.
Topics: Animals; Arenaviridae; Cellular Microenvironment; MicroRNAs
PubMed: 33238430
DOI: 10.3390/cells9112525 -
An updated review and current challenges of Guanarito virus infection, Venezuelan hemorrhagic fever.Archives of Virology Sep 2022Guanarito virus (GTOV) is a member of the family Arenaviridae and has been designated a category A bioterrorism agent by the US Centers for Disease Control and... (Review)
Review
Guanarito virus (GTOV) is a member of the family Arenaviridae and has been designated a category A bioterrorism agent by the US Centers for Disease Control and Prevention. It is endemic to Venezuela's western region, and it is the etiological agent of "Venezuelan hemorrhagic fever" (VHF). Similar to other arenaviral hemorrhagic fevers, VHF is characterized by fever, mild hemorrhagic signs, nonspecific symptoms, thrombocytopenia, and leukopenia. Patients with severe disease usually develop signs of internal bleeding. Due to the absence of reference laboratories that can handle GTOV in endemic areas, diagnosis is primarily clinical and epidemiological. No antiviral therapies are available; thus, treatment includes only supportive analgesia and fluids. GTOV is transmitted by contact with the excreta of its rodent reservoir, Zygodontomys brevicauda. The main reasons for the emergence of the disease may be the increase in the human population, migration, and changes in land use patterns in rural areas. Social and environmental changes could make VHF an important cause of underdiagnosed acute febrile illnesses in regions near the endemic areas. Although there is evidence that GTOV circulates among rodents in different Venezuelan states, VHF cases have only been reported in the states of Portuguesa and Barinas. However, due to the increased frequency of invasions by humans into wildlife habitats, it is probable that VHF could become a public health problem in the nearby regions of Colombia and Brazil. The current Venezuelan political crisis is causing an increase in the migration of people and livestock, representing a risk for the redistribution and re-emergence of infectious diseases.
Topics: Animals; Arenaviridae; Arenaviridae Infections; Arenaviruses, New World; Hemorrhagic Fevers, Viral; Humans; Rodentia; Sigmodontinae
PubMed: 35579715
DOI: 10.1007/s00705-022-05453-3 -
Oncotarget Dec 2015
Topics: Arenaviridae Infections; Arenavirus; Humans; Immune Evasion; Immunity, Innate
PubMed: 26595677
DOI: 10.18632/oncotarget.6367 -
Oncotarget Dec 2015
Topics: Animals; Arenaviridae; Filoviridae; Flaviviridae; Hemorrhagic Fevers, Viral; Host-Pathogen Interactions; Humans; Immune Tolerance; Immunity, Innate; Orthobunyavirus; Signal Transduction
PubMed: 26657729
DOI: 10.18632/oncotarget.6509 -
Current Opinion in Virology Feb 2019Next-generation sequencing technologies have revolutionized our knowledge of virus diversity and evolution. In the case of arenaviruses, which are the focus of this... (Review)
Review
Next-generation sequencing technologies have revolutionized our knowledge of virus diversity and evolution. In the case of arenaviruses, which are the focus of this review, metagenomic/metatranscriptomic approaches identified reptile-infecting and fish-infecting viruses, also showing that bi-segmented genomes are not a universal feature of the Arenaviridae family. Novel mammarenaviruses were described, allowing inference of their geographic origin and evolutionary dynamics. Extensive sequencing of Lassa virus (LASV) genomes revealed the zoonotic nature of most human infections and a Nigerian origin of LASV, which subsequently spread westward. Future efforts will likely identify many more arenaviruses and hopefully provide insight into the ultimate origin of the family, the pathogenic potential of its members, as well as the determinants of their geographic distribution.
Topics: Animals; Arenaviridae Infections; Arenavirus; Evolution, Molecular; Fishes; Genetic Variation; Genome, Viral; High-Throughput Nucleotide Sequencing; Host Microbial Interactions; Humans; Reptiles; Zoonoses
PubMed: 30497052
DOI: 10.1016/j.coviro.2018.11.001 -
Mini Reviews in Medicinal Chemistry 2023Viral hemorrhagic fevers (VHFs) are a group of clinical syndromes caused by several different RNA virus families, including several members of the arenavirus,... (Review)
Review
BACKGROUND
Viral hemorrhagic fevers (VHFs) are a group of clinical syndromes caused by several different RNA virus families, including several members of the arenavirus, bunyavirus, filovirus, and flavivirus families. VHFs have high mortality rates, and they have been associated with vascular permeability, malaise, fever, variable degrees of hemorrhage, reduced plasma volume, and coagulation abnormalities. To treat such conditions, antigen-presenting cells target dysregulated immune reactions and productive infections. Monocytes and macrophages produce inflammatory cytokines that damage adaptive immunity, while infected dendritic cells fail to mature correctly, compromising adaptive immunity. Inflammation and uncontrolled virus replication are associated with vascular leakage and coagulopathy.
OBJECTIVE
VHF infects both humans and animals and if not treated, causes hemorrhagic manifestations and lethal platelet dysfunction. Besides pharmacological and immunological solutions, the intervention of natural products for VHF management is of great interest. In this review, we gathered current data about the effectiveness of natural products for VHF management.
METHODS
Data were extracted from Scopus, Google Scholar, PubMed, and Cochrane library in terms of clinical and animal studies published in English between 1981 to February 2022.
RESULTS
Several plants from diverse families and species were identified with antiviral activity against VHF. The combination of botanical therapeutics and multitarget synergistic therapeutic effects is now the widely accepted explanation for the treatment of VHF. Most of these herbal therapeutics have shown promising immunomodulatory effects in vivo and in vitro VHF models. They can probably modulate the immune system in VHF-infected subjects mainly by interfering with certain inflammatory mediators involved in various infectious diseases.
CONCLUSION
Natural, in particular, herbal sources can be valuable for the management of various VHFs and their related complications.
Topics: Humans; Animals; Hemorrhagic Fevers, Viral; Arenavirus; Dengue Virus; Cytokines; RNA Viruses
PubMed: 36733245
DOI: 10.2174/1389557523666230202111337