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Viruses Mar 2021Lagos bat virus (LBV), one of the 17 accepted viral species of the genus, was the first rabies-related virus described in 1956. This virus is endemic to the African... (Review)
Review
Lagos bat virus (LBV), one of the 17 accepted viral species of the genus, was the first rabies-related virus described in 1956. This virus is endemic to the African continent and is rarely encountered. There are currently four lineages, although the observed genetic diversity exceeds existing lyssavirus species demarcation criteria. Several exposures to rabid bats infected with LBV have been reported; however, no known human cases have been reported to date. This review provides the history of LBV and summarizes previous knowledge as well as new detections. Genetic diversity, pathogenesis and prevention are re-evaluated and discussed.
Topics: Animals; Chiroptera; Genetic Variation; Humans; Lyssavirus; Phylogeny; Rabies; Rhabdoviridae Infections; South Africa
PubMed: 33805487
DOI: 10.3390/v13040576 -
Viruses May 2023Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic species from the genus within the paramyxovirus family and are harbored by Flying Fox species....
Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic species from the genus within the paramyxovirus family and are harbored by Flying Fox species. Henipaviruses cause severe respiratory disease, neural symptoms, and encephalitis in various animals and humans, with human mortality rates exceeding 70% in some NiV outbreaks. The henipavirus matrix protein (M), which drives viral assembly and budding of the virion, also performs non-structural functions as a type I interferon antagonist. Interestingly, M also undergoes nuclear trafficking that mediates critical monoubiquitination for downstream cell sorting, membrane association, and budding processes. Based on the NiV and HeV M X-ray crystal structures and cell-based assays, M possesses a putative monopartite nuclear localization signal (NLS) (residues KRKKIR; NLS1 HeV), positioned on an exposed flexible loop and typical of how many NLSs bind importin alpha (IMPα), and a putative bipartite NLS (RR-10X-KRK; NLS2 HeV), positioned within an α-helix that is far less typical. Here, we employed X-ray crystallography to determine the binding interface of these M NLSs and IMPα. The interaction of both NLS peptides with IMPα was established, with NLS1 binding the IMPα major binding site, and NLS2 binding as a non-classical NLS to the minor site. Co-immunoprecipitation (co-IP) and immunofluorescence assays (IFA) confirm the critical role of NLS2, and specifically K258. Additionally, localization studies demonstrated a supportive role for NLS1 in M nuclear localization. These studies provide additional insight into the critical mechanisms of M nucleocytoplasmic transport, the study of which can provide a greater understanding of viral pathogenesis and uncover a potential target for novel therapeutics for henipaviral diseases.
Topics: Animals; Humans; Nuclear Localization Signals; Active Transport, Cell Nucleus; Nipah Virus; alpha Karyopherins; Hendra Virus; Henipavirus Infections; Protein Binding
PubMed: 37376602
DOI: 10.3390/v15061302 -
Microbes and Infection 2019Nipah virus is an emerging zoonotic paramyxovirus that causes severe and often fatal respiratory and neurological disease in humans. The virus was first discovered after... (Review)
Review
Nipah virus is an emerging zoonotic paramyxovirus that causes severe and often fatal respiratory and neurological disease in humans. The virus was first discovered after an outbreak of encephalitis in pig farmers in Malaysia and Singapore with subsequent outbreaks in Bangladesh or India occurring almost annually. Due to the highly pathogenic nature of NiV, its pandemic potential, and the lack of licensed vaccines or therapeutics, there is a requirement for research and development into highly sensitive and specific diagnostic tools as well as antivirals and vaccines to help prevent and control future outbreak situations.
Topics: Animals; Antiviral Agents; Clinical Laboratory Techniques; Disease Outbreaks; Henipavirus Infections; Humans; Models, Biological; Nipah Virus; Viral Vaccines; Zoonoses
PubMed: 30817995
DOI: 10.1016/j.micinf.2019.02.002 -
Viruses Mar 2020Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include... (Review)
Review
Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre- and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.
Topics: Animals; Antiviral Agents; Binding Sites; Drug Discovery; Humans; Models, Molecular; Paramyxoviridae Infections; Paramyxovirinae; Pneumovirus; Pneumovirus Infections; Protein Binding; Structure-Activity Relationship; Virus Internalization
PubMed: 32245118
DOI: 10.3390/v12030342 -
Vector Borne and Zoonotic Diseases... Sep 2022Outbreaks of African filoviruses often have high mortality, including more than 11,000 deaths among 28,562 cases during the West Africa Ebola outbreak of 2014-2016.... (Review)
Review
Outbreaks of African filoviruses often have high mortality, including more than 11,000 deaths among 28,562 cases during the West Africa Ebola outbreak of 2014-2016. Numerous studies have investigated the factors that contributed to individual filovirus outbreaks, but there has been little quantitative synthesis of this work. In addition, the ways in which the typical causes of filovirus outbreaks differ from other zoonoses remain poorly described. In this study, we quantify factors associated with 45 outbreaks of African filoviruses (ebolaviruses and Marburg virus) using a rubric of 48 candidate causal drivers. For filovirus outbreaks, we reviewed >700 peer-reviewed and gray literature sources and developed a list of the factors reported to contribute to each outbreak (, a "driver profile" for each outbreak). We compare and contrast the profiles of filovirus outbreaks to 200 background outbreaks, randomly selected from a global database of 4463 outbreaks of bacterial and viral zoonotic diseases. We also test whether the quantitative patterns that we observed were robust to the influences of six covariates, country-level factors such as gross domestic product, population density, and latitude that have been shown to bias global outbreak data. We find that, regardless of whether covariates are included or excluded from models, the driver profile of filovirus outbreaks differs from that of background outbreaks. Socioeconomic factors such as trade and travel, wild game consumption, failures of medical procedures, and deficiencies in human health infrastructure were more frequently reported in filovirus outbreaks than in the comparison group. Based on our results, we also present a review of drivers reported in at least 10% of filovirus outbreaks, with examples of each provided.
Topics: Animals; Disease Outbreaks; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Marburg Virus Disease; Marburgvirus
PubMed: 36084314
DOI: 10.1089/vbz.2022.0020 -
Scientific Reports Jul 2023Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers's bats...
Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers's bats (Miniopterus schreibersii) in the Iberian Peninsula in 2002 led to its initial discovery. Recent studies with recombinant and wild-type LLOV isolates confirmed the zoonotic nature of the virus in vitro. We examined bat samples from Italy for the presence of LLOV in an area outside of the currently known distribution range of the virus. We detected one positive sample from 2020, sequenced the complete coding region of the viral genome and established an infectious isolate of the virus. In addition, we performed the first comprehensive evolutionary analysis of the virus, using the Spanish, Hungarian and the Italian sequences. The most important achievement of this study is the establishment of an additional infectious LLOV isolate from a bat sample using the SuBK12-08 cells, demonstrating that this cell line is highly susceptible to LLOV infection and confirming the previous observation that these bats are effective hosts of the virus in nature. This result further strengthens the role of bats as the natural hosts for zoonotic filoviruses.
Topics: Animals; Chiroptera; Filoviridae; Marburgvirus; Cell Line; Italy; Phylogeny
PubMed: 37443182
DOI: 10.1038/s41598-023-38364-7 -
The Journal of Infectious Diseases Nov 2023Ebola virus (EBOV) disease is marked by rapid virus replication and spread. EBOV enters the cell by macropinocytosis and replicates in the cytoplasm, and nascent virions...
Ebola virus (EBOV) disease is marked by rapid virus replication and spread. EBOV enters the cell by macropinocytosis and replicates in the cytoplasm, and nascent virions egress from the cell surface to infect neighboring cells. Here, we show that EBOV uses an alternate route to disseminate: tunneling nanotubes (TNTs). TNTs, an actin-based long-range intercellular communication system, allows for direct exchange of cytosolic constituents between cells. Using live, scanning electron, and high-resolution quantitative 3-dimensional microscopy, we show that EBOV infection of primary human cells results in the enhanced formation of TNTs containing viral nucleocapsids. TNTs promote the intercellular transfer of nucleocapsids in the absence of live virus, and virus could replicate in cells devoid of entry factors after initial stall. Our studies suggest an alternate model of EBOV dissemination within the host, laying the groundwork for further investigations into the pathogenesis of filoviruses and, importantly, stimulating new areas of antiviral design.
Topics: Humans; Ebolavirus; Hemorrhagic Fever, Ebola; Nanotubes; Cell Communication
PubMed: 37723997
DOI: 10.1093/infdis/jiad400 -
Viruses Dec 2021Viruses of the family share a common and complex molecular machinery for transcribing and replicating their genomes. Their non-segmented, negative-strand RNA genome is... (Review)
Review
Viruses of the family share a common and complex molecular machinery for transcribing and replicating their genomes. Their non-segmented, negative-strand RNA genome is encased in a tight homopolymer of viral nucleoproteins (N). This ribonucleoprotein complex, termed a nucleocapsid, is the template of the viral polymerase complex made of the large protein (L) and its co-factor, the phosphoprotein (P). This review summarizes the current knowledge on several aspects of paramyxovirus transcription and replication, including structural and functional data on (1) the architecture of the nucleocapsid (structure of the nucleoprotein, interprotomer contacts, interaction with RNA, and organization of the disordered C-terminal tail of N), (2) the encapsidation of the genomic RNAs (structure of the nucleoprotein in complex with its chaperon P and kinetics of RNA encapsidation in vitro), and (3) the use of the nucleocapsid as a template for the polymerase complex (release of the encased RNA and interaction network allowing the progress of the polymerase complex). Finally, this review presents models of paramyxovirus transcription and replication.
Topics: Gene Expression Regulation, Viral; Humans; Nucleocapsid; Nucleocapsid Proteins; Paramyxoviridae Infections; Paramyxovirinae; Phylogeny; RNA, Viral
PubMed: 34960734
DOI: 10.3390/v13122465 -
EMBO Molecular Medicine Oct 2023Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current...
Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre-symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti-lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11-dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell-dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ-binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization-independent T cell-mediated effects, even against an established CNS infection by a lethal neurotropic virus.
Topics: Animals; Humans; Lyssavirus; Rhabdoviridae Infections; CD4-Positive T-Lymphocytes; Rabies virus; Immunotherapy; Central Nervous System Infections; Antibodies, Monoclonal; Rabies; Chiroptera
PubMed: 37767784
DOI: 10.15252/emmm.202216394 -
The Journal of Clinical Investigation Feb 2023The emergence of the novel henipavirus, Langya virus, received global attention after the virus sickened over three dozen people in China. There is heightened concern...
The emergence of the novel henipavirus, Langya virus, received global attention after the virus sickened over three dozen people in China. There is heightened concern that henipaviruses, as respiratory pathogens, could spark another pandemic, most notably the deadly Nipah virus (NiV). NiV causes near-annual outbreaks in Bangladesh and India and induces a highly fatal respiratory disease and encephalitis in humans. No licensed countermeasures against this pathogen exist. An ideal NiV vaccine would confer both fast-acting and long-lived protection. Recently, we reported the generation of a recombinant vesicular stomatitis virus-based (rVSV-based) vaccine expressing the NiV glycoprotein (rVSV-ΔG-NiVBG) that protected 100% of nonhuman primates from NiV-associated lethality within a week. Here, to evaluate the durability of rVSV-ΔG-NiVBG, we vaccinated African green monkeys (AGMs) one year before challenge with an uniformly lethal dose of NiV. The rVSV-ΔG-NiVBG vaccine induced stable and robust humoral responses, whereas cellular responses were modest. All immunized AGMs (whether receiving a single dose or prime-boosted) survived with no detectable clinical signs or NiV replication. Transcriptomic analyses indicated that adaptive immune signatures correlated with vaccine-mediated protection. While vaccines for certain respiratory infections (e.g., COVID-19) have yet to provide durable protection, our results suggest that rVSV-ΔG-NiVBG elicits long-lasting immunity.
Topics: Animals; Humans; Chlorocebus aethiops; Nipah Virus; Antibodies, Viral; Viral Vaccines; Vesicular Stomatitis; COVID-19; Vesiculovirus
PubMed: 36445779
DOI: 10.1172/JCI164946