-
Oncotarget Dec 2015
Topics: Arenaviridae Infections; Arenavirus; Humans; Immune Evasion; Immunity, Innate
PubMed: 26595677
DOI: 10.18632/oncotarget.6367 -
Virulence Dec 2021Lassa fever (LF) is a deadly viral hemorrhagic disease that is endemic to West Africa. The causative agent of LF is Lassa virus (LASV), which causes approximately... (Review)
Review
Lassa fever (LF) is a deadly viral hemorrhagic disease that is endemic to West Africa. The causative agent of LF is Lassa virus (LASV), which causes approximately 300,000 infections and 5,000 deaths annually. There are currently no approved therapeutics or FDA-approved vaccines against LASV. The high genetic variability between LASV strains and immune evasion mediated by the virus complicate the development of effective therapeutics and vaccines. Here, we aim to provide a comprehensive review of the basic biology of LASV and its mechanisms of disease pathogenesis and virulence in various animal models, as well as an update on prospective vaccines, therapeutics, and diagnostics for LF. Until effective vaccines and/or therapeutics are available for use to prevent or treat LF, a better level of understanding of the basic biology of LASV, its natural genetic variations and immune evasion mechanisms as potential pathogenicity factors, and of the rodent reservoir-vector populations and their geographical distributions, is necessary for the development of accurate diagnostics and effective therapeutics and vaccines against this deadly human viral pathogen.
Topics: Animals; Immune Evasion; Lassa Fever; Lassa virus; Viral Vaccines; Virulence
PubMed: 34747339
DOI: 10.1080/21505594.2021.2000290 -
Viruses Dec 2022Although many arenaviruses cause severe diseases with high fatality rates each year, treatment options are limited to off-label use of ribavirin, and a Food and Drug...
Although many arenaviruses cause severe diseases with high fatality rates each year, treatment options are limited to off-label use of ribavirin, and a Food and Drug Administration (FDA)-approved vaccine is not available. To identify novel therapeutic candidates against arenaviral diseases, an RNA polymerase I-driven minigenome (MG) expression system for Lassa virus (LASV) was developed and optimized for high-throughput screening (HTS). Using this system, we screened 2595 FDA-approved compounds for inhibitors of LASV genome replication and identified multiple compounds including pixantrone maleate, a topoisomerase II inhibitor, as hits. Other tested topoisomerase II inhibitors also suppressed LASV MG activity. These topoisomerase II inhibitors also inhibited Junin virus (JUNV) MG activity and effectively limited infection by the JUNV Candid #1 strain, and siRNA knockdown of both topoisomerases (IIα and IIβ) restricted JUNV replication. These results suggest that topoisomerases II regulate arenavirus replication and can serve as molecular targets for panarenaviral replication inhibitors.
Topics: Antiviral Agents; Arenavirus; DNA Topoisomerases, Type II; Junin virus; Lassa virus; Topoisomerase II Inhibitors; Humans
PubMed: 36680145
DOI: 10.3390/v15010105 -
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 -
Antiviral Research Aug 2022Viral exoribonucleases are uncommon in the world of RNA viruses. To date, they have only been identified in the Arenaviridae and the Coronaviridae families. The...
Viral exoribonucleases are uncommon in the world of RNA viruses. To date, they have only been identified in the Arenaviridae and the Coronaviridae families. The exoribonucleases of these viruses play a crucial role in the pathogenicity and interplay with host innate immune response. Moreover, coronaviruses exoribonuclease is also involved in a proofreading mechanism ensuring the genetic stability of the viral genome. Because of their key roles in virus life cycle, they constitute attractive target for drug design. Here we developed a sensitive, robust and reliable fluorescence polarization assay to measure the exoribonuclease activity and its inhibition in vitro. The effectiveness of the method was validated on three different viral exoribonucleases, including SARS-CoV-2, Lymphocytic Choriomeningitis and Machupo viruses. We performed a screening of a focused library consisting of 113 metal chelators. Hit compounds were recovered with an IC at micromolar level. We confirmed 3 hits in SARS-CoV-2 infected Vero-E6 cells.
Topics: Animals; Antiviral Agents; Arenavirus; Chlorocebus aethiops; Exoribonucleases; Fluorescence Polarization; SARS-CoV-2; Vero Cells; Viral Nonstructural Proteins
PubMed: 35716929
DOI: 10.1016/j.antiviral.2022.105364 -
Bioscience Reports Feb 2022Lassa virus (LASV), an arenavirus endemic to West Africa, causes Lassa fever-a lethal hemorrhagic fever. Entry of LASV into the host cell is mediated by the glycoprotein... (Review)
Review
Lassa virus (LASV), an arenavirus endemic to West Africa, causes Lassa fever-a lethal hemorrhagic fever. Entry of LASV into the host cell is mediated by the glycoprotein complex (GPC), which is the only protein located on the viral surface and comprises three subunits: glycoprotein 1 (GP1), glycoprotein 2 (GP2), and a stable signal peptide (SSP). The LASV GPC is a class one viral fusion protein, akin to those found in viruses such as human immunodeficiency virus (HIV), influenza, Ebola virus (EBOV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These viruses are enveloped and utilize membrane fusion to deliver their genetic material to the host cell. Like other class one fusion proteins, LASV-mediated membrane fusion occurs through an orchestrated sequence of conformational changes in its GPC. The receptor-binding subunit, GP1, first engages with a host cell receptor then undergoes a unique receptor switch upon delivery to the late endosome. The acidic pH and change in receptor result in the dissociation of GP1, exposing the fusion subunit, GP2, such that fusion can occur. These events ultimately lead to the formation of a fusion pore so that the LASV genetic material is released into the host cell. Interestingly, the mature GPC retains its SSP as a third subunit-a feature that is unique to arenaviruses. Additionally, the fusion domain contains two separate fusion peptides, instead of a standard singular fusion peptide. Here, we give a comprehensive review of the LASV GPC components and their unusual features.
Topics: Glycoproteins; Humans; Lassa virus; Viral Envelope Proteins; Virus Internalization
PubMed: 35088070
DOI: 10.1042/BSR20211930 -
Viruses Nov 2012Arenaviruses are a family of enveloped negative-stranded RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic... (Review)
Review
Arenaviruses are a family of enveloped negative-stranded RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic fever. The bi‑segmented RNA genome encodes four polypeptides: the nucleoprotein NP, the surface glycoprotein GP, the polymerase L, and the RING finger protein Z. Although it is the smallest arenavirus protein with a length of 90 to 99 amino acids and a molecular weight of approx. 11 kDa, the Z protein has multiple functions in the viral life cycle including (i) regulation of viral RNA synthesis, (ii) orchestration of viral assembly and budding, (iii) interaction with host cell proteins, and (iv) interferon antagonism. In this review, we summarize our current understanding of the structural and functional role of the Z protein in the arenavirus replication cycle.
Topics: Animals; Antiviral Agents; Arenaviridae Infections; Arenavirus; Genome, Viral; Humans; RING Finger Domains; RNA Interference; Viral Proteins; Virion; Virus Replication
PubMed: 23202512
DOI: 10.3390/v4112973 -
Viruses Oct 2012Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000... (Review)
Review
Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between 5-10%. Currently, there are no approved vaccines against Lassa fever for use in humans. Here, we review the published literature on the life cycle of Lassa virus with the specific focus put on Lassa fever pathogenesis in humans and relevant animal models. Advancing knowledge significantly improves our understanding of Lassa virus biology, as well as of the mechanisms that allow the virus to evade the host's immune system. However, further investigations are required in order to design improved diagnostic tools, an effective vaccine, and therapeutic agents.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Genome, Viral; Humans; Immune Evasion; Lassa Fever; Lassa virus; Liver; Necrosis; Viral Load; Viremia; Virus Replication
PubMed: 23202452
DOI: 10.3390/v4102031 -
Veterinary Microbiology Jan 2010To date, the International Committee for Taxonomy of Viruses recognizes that the family Arenaviridae contains a unique genus Arenavirus that includes 22 viral species.... (Review)
Review
To date, the International Committee for Taxonomy of Viruses recognizes that the family Arenaviridae contains a unique genus Arenavirus that includes 22 viral species. There are nine additional arenaviruses that either have been discovered recently, or which taxonomic status remains pending. Arenaviruses have been classified according to their antigenic properties into two groups, the Lassa-Lymphocytic choriomeningitis (LCM) serocomplex and the Tacaribe serocomplex which has been further divided into four evolutionary lineages. Each arenavirus is more or less tightly associated with a mammal host. The distribution of the host dictates the distribution of the virus. Humans may become infected by arenaviruses through direct contact with infected rodents, including bites, or through inhalation of infectious rodent excreta and secreta. Lassa, Junin, Machupo, Guanarito, and Sabia viruses are known to cause a severe hemorrhagic fever, in western Africa, Argentina, Bolivia, Venezuela, and Brazil, respectively. Infection by LCM virus can result in acute central nervous system disease, congenital malformations, and infection in organ transplantation recipients. Detection of arenaviruses in their animal host can be achieved by virus isolation, and has recently taken advantage of PCR-based techniques. The approach based on consensus degenerate primers has shown efficient for both detection of known arenaviruses, and discovery of new arenaviruses.
Topics: Africa, Western; Americas; Animals; Arenaviridae Infections; Arenavirus; Hemorrhagic Fevers, Viral; Humans; Meningitis, Viral; Rodentia; Zoonoses
PubMed: 19748747
DOI: 10.1016/j.vetmic.2009.08.027 -
Virology Mar 2011Pathogenesis following a virus infection results from interactions between the virus and its host. The outcome is determined by tipping the balance between virulence of... (Review)
Review
Pathogenesis following a virus infection results from interactions between the virus and its host. The outcome is determined by tipping the balance between virulence of the virus or susceptibility/resistance of the host to favor one or the other. This review focuses on two important members of the Old World arenavirus family: Lassa fever virus (LFV), a robust human pathogen that causes a severe acute hemorrhagic disease; and lymphocytic choriomeningitis virus (LCMV), also a human pathogen but better known in the context of its rodent model. Research with this model has uncovered and illuminated many of our current concepts in immunobiology and viral pathogenesis. Presented here are recent advances that form the framework for a better understanding of how viruses induce and maintain persistent infection as well as for the pathogenesis associated with acute LFV infection. A major component for understanding the pathogenesis of these arenaviruses revolves around study of the interaction of virus with its receptor, alpha-dystroglycan (α-DG).
Topics: Dystroglycans; Host-Pathogen Interactions; Humans; Lassa virus; Lymphocytic choriomeningitis virus; Receptors, Virus; Virus Attachment
PubMed: 21185048
DOI: 10.1016/j.virol.2010.11.023