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Science Immunology Oct 2023High neonatal susceptibility to meningitis has been attributed to the anatomical barriers that act to protect the central nervous system (CNS) from infection being...
High neonatal susceptibility to meningitis has been attributed to the anatomical barriers that act to protect the central nervous system (CNS) from infection being immature and not fully developed. However, the mechanisms by which pathogens breach CNS barriers are poorly understood. Using the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) to study virus propagation into the CNS during systemic infection, we demonstrate that mortality in neonatal, but not adult, mice is high after infection. Virus propagated extensively from the perivenous sinus region of the dura mater to the leptomeninges, choroid plexus, and cerebral cortex. Although the structural barrier of CNS border tissues is comparable between neonates and adults, immunofluorescence staining and single-cell RNA sequencing analyses revealed that the neonatal dural immune cells are immature and predominantly composed of CD206 macrophages, with major histocompatibility complex class II (MHCII) macrophages being rare. In adults, however, perivenous sinus immune cells were enriched in MHCII macrophages that are specialized for producing antiviral molecules and chemokines compared with CD206 macrophages and protected the CNS against systemic virus invasion. Our findings clarify how systemic pathogens enter the CNS through its border tissues and how the immune barrier at the perivenous sinus region of the dura blocks pathogen access to the CNS.
Topics: Mice; Animals; Central Nervous System; Meningoencephalitis; Lymphocytic Choriomeningitis; Meninges; Lymphocytic choriomeningitis virus; Meningitis, Viral; Encephalitis, Viral
PubMed: 37801517
DOI: 10.1126/sciimmunol.adg6155 -
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 -
Virologica Sinica Oct 2016Mammarenaviruses, including lethal pathogens such as Lassa virus and Junín virus, can cause severe hemorrhagic fever in humans. Entry is a key step for virus infection,... (Review)
Review
Mammarenaviruses, including lethal pathogens such as Lassa virus and Junín virus, can cause severe hemorrhagic fever in humans. Entry is a key step for virus infection, which starts with binding of the envelope glycoprotein (GP) to receptors on target cells and subsequent fusion of the virus with target cell membranes. The GP precursor is synthesized as a polypeptide, and maturation occurs by two cleavage events, yielding a tripartite GP complex (GPC) formed by a stable signal peptide (SSP), GP1 and GP2. The unique retained SSP interacts with GP2 and plays essential roles in virion maturation and infectivity. GP1 is responsible for binding to the cell receptor, and GP2 is a class I fusion protein. The native structure of the tripartite GPC is unknown. GPC is critical for the receptor binding, membrane fusion and neutralization antibody recognition. Elucidating the molecular mechanisms underlining the structure-function relationship of the three subunits is the key for understanding their function and can facilitate novel avenues for combating virus infections. This review summarizes the basic aspects and recent research of the structure-function relationship of the three subunits. We discuss the structural basis of the receptor-binding domain in GP1, the interaction between SSP and GP2 and its role in virion maturation and membrane fusion, as well as the mechanism by which glycosylation stabilizes the GPC structure and facilitates immune evasion. Understanding the molecular mechanisms involved in these aspects will contribute to the development of novel vaccines and treatment strategies against mammarenaviruses infection.
Topics: Animals; Arenaviridae; Arenaviridae Infections; Humans; Viral Envelope Proteins
PubMed: 27562602
DOI: 10.1007/s12250-016-3815-4 -
Journal of Molecular Biology Jun 2018Viral hemorrhagic fevers caused by emerging RNA viruses of the Arenavirus family are among the most devastating human diseases. Climate change, global trade, and... (Review)
Review
Viral hemorrhagic fevers caused by emerging RNA viruses of the Arenavirus family are among the most devastating human diseases. Climate change, global trade, and increasing urbanization promote the emergence and re-emergence of these human pathogenic viruses. Emerging pathogenic arenaviruses are of zoonotic origin and reservoir-to-human transmission is crucial for spillover into human populations. Host cell attachment and entry are the first and most fundamental steps of every virus infection and represent major barriers for zoonotic transmission. During host cell invasion, viruses critically depend on cellular factors, including receptors, co-receptors, and regulatory proteins of endocytosis. An in-depth understanding of the complex interaction of a virus with cellular factors implicated in host cell entry is therefore crucial to predict the risk of zoonotic transmission, define the tissue tropism, and assess disease potential. Over the past years, investigation of the molecular and cellular mechanisms underlying host cell invasion of human pathogenic arenaviruses uncovered remarkable viral strategies and provided novel insights into viral adaptation and virus-host co-evolution that will be covered in the present review.
Topics: Animals; Arenaviridae Infections; Arenavirus; Host Microbial Interactions; Humans; Viral Tropism; Virus Attachment; Virus Internalization; Zoonoses
PubMed: 29705070
DOI: 10.1016/j.jmb.2018.04.026 -
FEBS Open Bio Apr 2021Arenaviruses are enveloped viruses containing a segmented, negative, and ambisense single-stranded RNA genome wrapped with a nucleoprotein (NP). The NP is the most...
Arenaviruses are enveloped viruses containing a segmented, negative, and ambisense single-stranded RNA genome wrapped with a nucleoprotein (NP). The NP is the most abundant viral protein in infected cells and plays a critical role in both replication/transcription and virion assembly. The NP associates with RNA to form a ribonucleoprotein (RNP) complex, and this implies self-assembly while the exact structure of this polymer is not yet known. Here, we report a measurement of the full-length Mopeia virus NP by negative stain transmission electron microscopy. We observed RNP complex particles with diameter 15 ± 1 nm as well as symmetric circular heptamers of the same diameter, consistent with previous observations.
Topics: Amino Acid Sequence; Arenavirus; Models, Molecular; Nucleoproteins; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; RNA-Binding Proteins; Recombinant Proteins; Viral Proteins
PubMed: 33534950
DOI: 10.1002/2211-5463.13106 -
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 -
Current Opinion in Virology Aug 2018The structure of a prefusion arenavirus GPC was enigmatic for many years, owing to the metastable and non-covalent nature of the association between the receptor binding... (Review)
Review
The structure of a prefusion arenavirus GPC was enigmatic for many years, owing to the metastable and non-covalent nature of the association between the receptor binding and fusion subunits. Recent engineering efforts to stabilize the glycoprotein of the Old World arenavirus Lassa in a native, yet cleaved state, allowed the first structure of any arenavirus prefusion GPC trimer to be determined. Comparison of this structure with the structures of other arenavirus glycoprotein subunits reveals surprising findings: that the receptor binding subunit, GP1, of Lassa virus is conformationally labile, while the GP1 subunit of New World arenaviruses is not, and that the arenavirus GPC adopts a trimeric state unlike other glycoproteins with similar fusion machinery. Structural analysis, combined with recent biochemical data regarding antibody epitopes and receptor binding requirements, provides a basis for rational vaccine design.
Topics: Arenavirus; Epitopes; Glycoproteins; Humans; Lassa virus; Protein Binding; Protein Structure, Tertiary; Viral Envelope Proteins; Virus Internalization
PubMed: 29843991
DOI: 10.1016/j.coviro.2018.05.002 -
Frontiers in Immunology 2019Hemorrhagic fevers (HF) resulting from pathogenic arenaviral infections have traditionally been neglected as tropical diseases primarily affecting African and South... (Review)
Review
Hemorrhagic fevers (HF) resulting from pathogenic arenaviral infections have traditionally been neglected as tropical diseases primarily affecting African and South American regions. There are currently no FDA-approved vaccines for arenaviruses, and treatments have been limited to supportive therapy and use of non-specific nucleoside analogs, such as Ribavirin. Outbreaks of arenaviral infections have been limited to certain geographic areas that are endemic but known cases of exportation of arenaviruses from endemic regions and socioeconomic challenges for local control of rodent reservoirs raise serious concerns about the potential for larger outbreaks in the future. This review synthesizes current knowledge about arenaviral evolution, ecology, transmission patterns, life cycle, modulation of host immunity, disease pathogenesis, as well as discusses recent development of preventative and therapeutic pursuits against this group of deadly viral pathogens.
Topics: Africa; Arenaviridae Infections; Arenavirus; Disease Outbreaks; Hemorrhagic Fevers, Viral; Humans; Immune Tolerance; Ribavirin; South America
PubMed: 30918506
DOI: 10.3389/fimmu.2019.00372 -
Methods in Molecular Biology (Clifton,... 2018Independent expression of the VP40 or Z matrix proteins of filoviruses (marburgviruses and ebolaviruses) and arenaviruses (Lassa fever and Junín), respectively, gives...
Independent expression of the VP40 or Z matrix proteins of filoviruses (marburgviruses and ebolaviruses) and arenaviruses (Lassa fever and Junín), respectively, gives rise to the production and release of virus-like particles (VLPs) that are morphologically identical to infectious virions. We can detect and quantify VLP production and egress in mammalian cells by transient transfection, SDS-PAGE, Western blotting, and live cell imaging techniques such as total internal reflection fluorescence (TIRF) microscopy. Since the VLP budding assay accurately mimics budding of infectious virus, this BSL-2 assay is safe and useful for the interrogation of both viral and host determinants required for budding and can be used as an initial screen to identify and validate small molecule inhibitors of virus release and spread.
Topics: Animals; Arenavirus; Blotting, Western; Ebolavirus; Electrophoresis, Polyacrylamide Gel; Filoviridae; Hemorrhagic Fever, Ebola; Humans; Junin virus; Lassa Fever; Marburgvirus; Viral Matrix Proteins; Virus Release
PubMed: 28986836
DOI: 10.1007/978-1-4939-6981-4_15 -
International Journal of Infectious... Apr 2021This article is one of a series on acute, severe diseases of humans caused by emerging viruses for which there are no or limited licensed medical countermeasures. We... (Review)
Review
OBJECTIVES
This article is one of a series on acute, severe diseases of humans caused by emerging viruses for which there are no or limited licensed medical countermeasures. We approached this summary on South American Hemorrhagic Fevers (SAHF) from a clinical perspective that focuses on pathogenesis, clinical features, and diagnostics with an emphasis on therapies and vaccines that have demonstrated potential for use in an emergency situation through their evaluation in nonhuman primates (NHPs) and/or in humans.
METHODS
A standardized literature review was conducted on the clinical, pathological, vaccine, and treatment factors for SAHF as a group and for each individual virus/disease.
RESULTS
We identified 2 treatments and 1 vaccine platform that have demonstrated potential benefit for treating or preventing infection in humans and 4 other potential treatments currently under investigation.
CONCLUSION
We provide succinct summaries of these countermeasures to give the busy clinician a head start in reviewing the literature if faced with a patient with South American Hemorrhagic Fever. We also provide links to other authoritative sources of information.
Topics: Arenaviridae; Hemorrhagic Fever, American; Humans; Viral Vaccines
PubMed: 33610781
DOI: 10.1016/j.ijid.2021.02.046