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Frontiers in Microbiology 2024Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe... (Review)
Review
Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe hemorrhagic fever in humans. With high mortality rates and limited treatment options, the search for effective antivirals is imperative. Current treatments, notably ribavirin and other nucleoside inhibitors, are only partially effective and have significant side effects. The high lethality and lack of treatment, coupled with the absence of vaccines for all but Junín virus, has led to the classification of these viruses as Category A pathogens by the Centers for Disease Control (CDC). This review focuses on entry inhibitors as potential therapeutics against mammarenaviruses, which include both New World and Old World arenaviruses. Various entry inhibition strategies, including small molecule inhibitors and neutralizing antibodies, have been explored through high throughput screening, genome-wide studies, and drug repurposing. Notable progress has been made in identifying molecules that target receptor binding, internalization, or fusion steps. Despite promising preclinical results, the translation of entry inhibitors to approved human therapeutics has faced challenges. Many have only been tested in or animal models, and a number of candidates showed efficacy only against specific arenaviruses, limiting their broader applicability. The widespread existence of arenaviruses in various rodent species and their potential for their zoonotic transmission also underscores the need for rapid development and deployment of successful pan-arenavirus therapeutics. The diverse pool of candidate molecules in the pipeline provides hope for the eventual discovery of a broadly effective arenavirus antiviral.
PubMed: 38650890
DOI: 10.3389/fmicb.2024.1382953 -
Frontiers in Immunology 2023The IL-6 cytokine family signals through the common signal transduction molecule gp130 combined with a cytokine-specific receptor. Gp130 signaling on CD4 T cells is...
The IL-6 cytokine family signals through the common signal transduction molecule gp130 combined with a cytokine-specific receptor. Gp130 signaling on CD4 T cells is vital in controlling chronic infection of mice with lymphocytic choriomeningitis virus clone 13 (LCMV Cl13), but the precise role of individual members of the IL-6 cytokine family is not fully understood. Transcriptional analysis highlighted the importance of gp130 signaling in promoting key processes in CD4 T cells after LCMV Cl13 infection, particularly genes associated with T follicular helper (Tfh) cell differentiation and IL-21 production. Further, mice failed to generate antibody or CD8 T-cell immunity and to control LCMV Cl13. Transcriptomics and phenotypic analyses of Tfh cells revealed that IL-6R and IL-27R signaling was required to activate key pathways within CD4 T cells. IL-6 and IL-27 signaling has distinct and overlapping roles, with IL-6 regulating Tfh differentiation, IL-27 regulating CD4 T cell survival, and both redundantly promoting IL-21.
Topics: Mice; Animals; CD4-Positive T-Lymphocytes; Interleukin-27; Interleukin-6; Cytokine Receptor gp130; Persistent Infection; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Receptors, Cytokine
PubMed: 37583704
DOI: 10.3389/fimmu.2023.1221562 -
Experimental Biology and Medicine... Oct 2023, or Sabiá virus (SABV), is a New World (NW) arenavirus associated with fulminant hemorrhagic disease in humans and the sole biosafety level 4 microorganism ever... (Review)
Review
, or Sabiá virus (SABV), is a New World (NW) arenavirus associated with fulminant hemorrhagic disease in humans and the sole biosafety level 4 microorganism ever isolated in Brazil. Since the isolation of SABV in the 1990s, studies on viral biology have been scarce, with no available countermeasures against SABV infection or disease. Here we provide a comprehensive review of SABV biology, including key aspects of SABV replication, and comparisons with related Old World and NW arenaviruses. SABV is most likely a rodent-borne virus, transmitted to humans, through exposure to urine and feces in peri-urban areas. Using protein structure prediction methods and alignments, we analyzed shared and unique features of SABV proteins (GPC, NP, Z, and L) that could be explored in search of therapeutic strategies, including repurposing intended application against arenaviruses. Highly conserved catalytic activities present in L protein could be targeted for broad-acting antiviral activity among arenaviruses, while protein-protein interactions, such as those between L and the matrix protein Z, have evolved in NW arenaviruses and should be specific to SABV. The nucleoprotein (NP) also shares targetable interaction interfaces with L and Z and exhibits exonuclease activity in the C-terminal domain, which may be involved in multiple aspects of SABV replication. Envelope glycoproteins GP1 and GP2 have been explored in the development of promising cross-reactive neutralizing antibodies and vaccines, some of which could be repurposed for SABV. GP1 remains a challenging target in SABV as evolutive pressures render it the most variable viral protein in terms of both sequence and structure, while antiviral strategies targeting the Z protein remain to be validated. In conclusion, the prediction and analysis of protein structures should revolutionize research on viruses such as SABV by facilitating the rational design of countermeasures while reducing dependence on sophisticated laboratory infrastructure for experimental validation.
Topics: Humans; Arenaviruses, New World; Viral Proteins; Arenaviridae Infections; Antiviral Agents; Molecular Biology
PubMed: 37937408
DOI: 10.1177/15353702231199071 -
Expert Review of Vaccines 2024
Topics: Humans; Vaccines; Virus Replication; Lassa virus; Lassa Fever; Arenaviridae Infections
PubMed: 38044877
DOI: 10.1080/14760584.2023.2290683 -
The Journal of General Virology Aug 2023In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum was amended and emended....
In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of as now accepted by the ICTV.
Topics: Negative-Sense RNA Viruses; RNA Viruses; RNA-Dependent RNA Polymerase
PubMed: 37622664
DOI: 10.1099/jgv.0.001864 -
Molecular Cancer Aug 2023New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. To uncover novel potentiators...
BACKGROUND
New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. To uncover novel potentiators of T cell anti-tumor immunity, we carried out an ex vivo pharmacological screen and identified 5-Nonyloxytryptamine (5-NL), a serotonin agonist, as increasing the ability of T cells to target tumor cells.
METHODS
The pharmacological screen utilized lymphocytic choriomeningitis virus (LCMV)-primed splenic T cells and melanoma B16.F10 cells expressing the LCMV gp33 CTL epitope. In vivo tumor growth in C57BL/6 J and NSG mice, in vivo antibody depletion, flow cytometry, immunoblot, CRISPR/Cas9 knockout, histological and RNA-Seq analyses were used to decipher 5-NL's immunomodulatory effects in vitro and in vivo.
RESULTS
5-NL delayed tumor growth in vivo and the phenotype was dependent on the hosts' immune system, specifically CD8 T cells. 5-NL's pro-immune effects were not directly consequential to T cells. Rather, 5-NL upregulated antigen presenting machinery in melanoma and other tumor cells in vitro and in vivo without increasing PD-L1 expression. Mechanistic studies indicated that 5-NL's induced MHC-I expression was inhibited by pharmacologically preventing cAMP Response Element-Binding Protein (CREB) phosphorylation. Importantly, 5-NL combined with anti-PD1 therapy showed significant improvement when compared to single anti-PD-1 treatment.
CONCLUSIONS
This study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Up-Regulation; Mice, Inbred C57BL; Lymphocytic choriomeningitis virus; Melanoma
PubMed: 37582744
DOI: 10.1186/s12943-023-01833-8 -
Biomedicine & Pharmacotherapy =... Oct 2023Mammarenaviruses are enveloped RNA viruses that can be associated with rodent-transmitted diseases in humans. Their virions are composed of a nucleocapsid surrounded by... (Review)
Review
Mammarenaviruses are enveloped RNA viruses that can be associated with rodent-transmitted diseases in humans. Their virions are composed of a nucleocapsid surrounded by a lipid bilayer with glycoprotein (GP) spikes interacting with receptors on target cells. Both the GP and receptors are highly glycosylated, with glycosylation patterns being crucial for virus binding and cell entry, viral tropism, immune responses, or therapy strategies. These effects have been previously described for several different viruses. In case of arenaviruses, they remain insufficiently understood. Thus, it is important to determine the mechanisms of glycosylation of viral proteins and receptors responsible for infection, in order to fully understand the biology of arenaviruses. In this article, we have summarized and critically evaluated the available literature data on the glycosylation of mammarenavirus-associated proteins to facilitate further research in this field.
Topics: Humans; Glycosylation; Virus Internalization; Receptors, Cell Surface; Arenaviridae Infections; Glycoproteins
PubMed: 37586116
DOI: 10.1016/j.biopha.2023.115196 -
Virulence Dec 2023Recent viral hemorrhagic fever (VHF) disease outbreaks caused by Ebola virus (EBOV) and Marburg virus (MARV) in West Africa are unique and alarming. The intents of this...
Recent viral hemorrhagic fever (VHF) disease outbreaks caused by Ebola virus (EBOV) and Marburg virus (MARV) in West Africa are unique and alarming. The intents of this editorial are to highlight what is known about these viruses and the disease outbreaks that they cause in the African continent and elsewhere and to raise awareness of a related virus called Lassa virus (LASV) that causes endemic viral hemorrhagic fever infections and frequent outbreaks in West Africa.
Topics: Humans; Hemorrhagic Fevers, Viral; Lassa virus; Ebolavirus; Africa, Western; Disease Outbreaks; Hemorrhagic Fever, Ebola
PubMed: 36748841
DOI: 10.1080/21505594.2023.2176980 -
Nature Communications Sep 2023Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate....
Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies.
Topics: Humans; Guinea Pigs; Animals; Lassa virus; Antibodies, Neutralizing; Arenaviridae; mRNA Vaccines; Glycoproteins
PubMed: 37699929
DOI: 10.1038/s41467-023-41376-6 -
The Journal of Allergy and Clinical... Jan 2024Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3...
BACKGROUND
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for approximately 30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene that result in impaired degranulation of cytotoxic vesicles and hence compromised T-cell- and natural killer-cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show high mortality.
OBJECTIVE
We sought to develop and evaluate a curative genome editing strategy in the preclinical FHL3 Jinx mouse model. Jinx mice harbor a cryptic splice donor site in Unc13d intron 26 and develop clinical symptoms of human FHL3 upon infection with lymphocytic choriomeningitis virus (LCMV).
METHODS
We employed clustered regularly interspaced short palindromic repeats (CRISPR)-Cas technology to delete the disease-causing mutation in HSCs and transplanted Unc13d-edited stem cells into busulfan-conditioned Jinx recipient mice. Safety studies included extensive genotyping and chromosomal aberrations analysis by single targeted linker-mediated PCR sequencing (CAST-Seq)-based off-target analyses. Cure from HLH predisposition was assessed by LCMV infection.
RESULTS
Hematopoietic cells isolated from transplanted mice revealed efficient gene editing (>95%), polyclonality of the T-cell receptor repertoire, and neither signs of off-target effects nor leukemogenesis. Unc13d transcription levels of edited and wild-type cells were comparable. While LCMV challenge resulted in acute HLH in Jinx mice transplanted with mock-edited HSCs, Jinx mice grafted with Unc13d-edited cells showed rapid virus clearance and protection from HLH.
CONCLUSIONS
Our study demonstrates that transplantation of CRISPR-Cas edited HSCs supports the development of a functional polyclonal T-cell response in the absence of genotoxicity-associated clonal outgrowth.
Topics: Humans; Mice; Animals; Lymphohistiocytosis, Hemophagocytic; T-Lymphocytes; Gene Editing; Mutation; Lymphocytic choriomeningitis virus; Hematopoietic Stem Cells; Membrane Proteins
PubMed: 37595758
DOI: 10.1016/j.jaci.2023.08.003