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Viruses Jul 2023Rabies kills approximately 60,000 humans each year, with deaths mostly occurring in developing countries, where rabies lyssavirus (RABV) variants are maintained in dog...
Rabies kills approximately 60,000 humans each year, with deaths mostly occurring in developing countries, where rabies lyssavirus (RABV) variants are maintained in dog populations [...].
Topics: Humans; Animals; Dogs; Rabies; Lyssavirus; Rabies virus; Dog Diseases
PubMed: 37515243
DOI: 10.3390/v15071557 -
The Journal of Infectious Diseases Aug 2023Ebola virus (EBOV) disease (EVD) is one of the most severe and fatal viral hemorrhagic fevers and appears to mimic many clinical and laboratory manifestations of...
BACKGROUND
Ebola virus (EBOV) disease (EVD) is one of the most severe and fatal viral hemorrhagic fevers and appears to mimic many clinical and laboratory manifestations of hemophagocytic lymphohistiocytosis syndrome (HLS), also known as macrophage activation syndrome. However, a clear association is yet to be firmly established for effective host-targeted, immunomodulatory therapeutic approaches to improve outcomes in patients with severe EVD.
METHODS
Twenty-four rhesus monkeys were exposed intramuscularly to the EBOV Kikwit isolate and euthanized at prescheduled time points or when they reached the end-stage disease criteria. Three additional monkeys were mock-exposed and used as uninfected controls.
RESULTS
EBOV-exposed monkeys presented with clinicopathologic features of HLS, including fever, multiple organomegaly, pancytopenia, hemophagocytosis, hyperfibrinogenemia with disseminated intravascular coagulation, hypertriglyceridemia, hypercytokinemia, increased concentrations of soluble CD163 and CD25 in serum, and the loss of activated natural killer cells.
CONCLUSIONS
Our data suggest that EVD in the rhesus macaque model mimics pathophysiologic features of HLS/macrophage activation syndrome. Hence, regulating inflammation and immune function might provide an effective treatment for controlling the pathogenesis of acute EVD.
Topics: Animals; Lymphohistiocytosis, Hemophagocytic; Hemorrhagic Fever, Ebola; Macrophage Activation Syndrome; Macaca mulatta; Ebolavirus
PubMed: 37279544
DOI: 10.1093/infdis/jiad203 -
Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories.Nature Communications Jul 2023Ebola virus (EBOV) infection induces the formation of membrane-less, cytoplasmic compartments termed viral factories, in which multiple viral proteins gather and...
Ebola virus (EBOV) infection induces the formation of membrane-less, cytoplasmic compartments termed viral factories, in which multiple viral proteins gather and coordinate viral transcription, replication, and assembly. Key to viral factory function is the recruitment of EBOV polymerase, a multifunctional machine that mediates transcription and replication of the viral RNA genome. We show that intracellularly reconstituted EBOV viral factories are biomolecular condensates, with composition-dependent internal exchange dynamics that likely facilitates viral replication. Within the viral factory, we found the EBOV polymerase clusters into foci. The distance between these foci increases when viral replication is enabled. In addition to the typical droplet-like viral factories, we report the formation of network-like viral factories during EBOV infection. Unlike droplet-like viral factories, network-like factories are inactive for EBOV nucleocapsid assembly. This unique view of EBOV propagation suggests a form-to-function relationship that describes how physical properties and internal structures of biomolecular condensates influence viral biogenesis.
Topics: Humans; Ebolavirus; Hemorrhagic Fever, Ebola; Viral Replication Compartments; Transcription, Genetic; Virus Replication; Nucleotidyltransferases
PubMed: 37443171
DOI: 10.1038/s41467-023-39821-7 -
The Journal of Infectious Diseases Nov 2023Ebolaviruses Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) cause severe human disease, which may be accompanied by hemorrhagic syndrome, with high case fatality...
BACKGROUND
Ebolaviruses Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) cause severe human disease, which may be accompanied by hemorrhagic syndrome, with high case fatality rates. Monovalent vaccines do not offer cross-protection against these viruses whose endemic areas overlap. Therefore, development of a panebolavirus vaccine is a priority. As a vaccine vector, human parainfluenza virus type 3 (HPIV3) has the advantages of needle-free administration and induction of both systemic and local mucosal antibody responses in the respiratory tract.
METHODS
To minimize the antivector immunity, genes encoding the HPIV3 envelope proteins F and HN were removed from the vaccine constructs, resulting in expression of only the ebolavirus envelope protein-glycoprotein. These second-generation vaccine constructs were used to develop a combination vaccine against EBOV, SUDV, and BDBV.
RESULTS
A single intranasal vaccination of guinea pigs or ferrets with the trivalent combination vaccine elicited humoral responses to each of the targeted ebolaviruses, including binding and neutralizing antibodies, as well as Fc-mediated effector functions. This vaccine protected animals from death and disease caused by lethal challenges with EBOV, SUDV, or BDBV.
CONCLUSIONS
The combination vaccine elicited protection that was comparable to that induced by the monovalent vaccines, thus demonstrating the value of this combination trivalent vaccine.
Topics: Animals; Humans; Guinea Pigs; Antibodies, Viral; Ebola Vaccines; Ferrets; Hemorrhagic Fever, Ebola; Ebolavirus; Antibodies, Neutralizing; Vaccines, Combined
PubMed: 37469133
DOI: 10.1093/infdis/jiad266 -
Viruses Dec 2023Henipaviruses are zoonotic viruses, including some highly pathogenic and capable of serious disease and high fatality rates in both animals and humans. Hendra virus and... (Review)
Review
Henipaviruses are zoonotic viruses, including some highly pathogenic and capable of serious disease and high fatality rates in both animals and humans. Hendra virus and Nipah virus are the most notable henipaviruses, resulting in significant outbreaks across South Asia, South-East Asia, and Australia. Pteropid fruit bats have been identified as key zoonotic reservoirs; however, the increased discovery of henipaviruses outside the geographic distribution of Pteropid fruit bats and the detection of novel henipa-like viruses in other species such as the shrew, rat, and opossum suggest that Pteropid bats are not the sole reservoir for henipaviruses. In this review, we provide an update on henipavirus spillover events and describe the recent detection of novel unclassified henipaviruses, with a strong focus on the shrew and its emerging role as a key host of henipaviruses.
Topics: Humans; Animals; Rats; Henipavirus Infections; Shrews; Chiroptera; Nipah Virus; Hendra Virus
PubMed: 38140648
DOI: 10.3390/v15122407 -
PLoS Pathogens Aug 2023Ebola (EBOV) and Marburg viruses (MARV) cause severe hemorrhagic fever associated with high mortality rates in humans. A better understanding of filovirus-host...
Ebola (EBOV) and Marburg viruses (MARV) cause severe hemorrhagic fever associated with high mortality rates in humans. A better understanding of filovirus-host interactions that regulate the EBOV and MARV lifecycles can provide biological and mechanistic insight critical for therapeutic development. EBOV glycoprotein (eGP) and MARV glycoprotein (mGP) mediate entry into host cells primarily by actin-dependent macropinocytosis. Here, we identified actin-binding cytoskeletal crosslinking proteins filamin A (FLNa) and B (FLNb) as important regulators of both EBOV and MARV entry. We found that entry of pseudotype psVSV-RFP-eGP, infectious recombinant rVSV-eGP-mCherry, and live authentic EBOV and MARV was inhibited in filamin A knockdown (FLNaKD) cells, but was surprisingly enhanced in filamin B knockdown (FLNbKD) cells. Mechanistically, our findings suggest that differential regulation of macropinocytosis by FLNa and FLNb likely contributes to their specific effects on EBOV and MARV entry. This study is the first to identify the filamin family of proteins as regulators of EBOV and MARV entry. These findings may provide insight into the development of new countermeasures to prevent EBOV and MARV infections.
Topics: Humans; Filamins; Ebolavirus; Actins; Hemorrhagic Fever, Ebola; Marburgvirus; Glycoproteins
PubMed: 37585478
DOI: 10.1371/journal.ppat.1011595 -
Nature Methods Mar 2024
Topics: Neurons; Rabies virus
PubMed: 38472461
DOI: 10.1038/s41592-024-02220-x -
Nature Communications Oct 2023Marburg and Ebola filoviruses are two of the deadliest infectious agents and several outbreaks have occurred in the last decades. Although several receptors and...
Marburg and Ebola filoviruses are two of the deadliest infectious agents and several outbreaks have occurred in the last decades. Although several receptors and co-receptors have been reported for Ebola virus, key host factors remain to be elucidated. In this study, using a haploid cell screening platform, we identify the guanine nucleotide exchange factor CCZ1 as a key host factor in the early stage of filovirus replication. The critical role of CCZ1 for filovirus infections is validated in 3D primary human hepatocyte cultures and human blood-vessel organoids, both critical target sites for Ebola and Marburg virus tropism. Mechanistically, CCZ1 controls early to late endosomal trafficking of these viruses. In addition, we report that CCZ1 has a role in the endosomal trafficking of endocytosis-dependent SARS-CoV-2 infections, but not in infections by Lassa virus, which enters endo-lysosomal trafficking at the late endosome stage. Thus, we have identified an essential host pathway for filovirus infections in cell lines and engineered human target tissues. Inhibition of CCZ1 nearly completely abolishes Marburg and Ebola infections. Thus, targeting CCZ1 could potentially serve as a promising drug target for controlling infections caused by various viruses, such as SARS-CoV-2, Marburg, and Ebola.
Topics: Animals; Humans; Ebolavirus; Hemorrhagic Fever, Ebola; Lysosomes; Marburg Virus Disease; Marburgvirus; Vesicular Transport Proteins
PubMed: 37880247
DOI: 10.1038/s41467-023-42526-6 -
Methods in Molecular Biology (Clifton,... 2024Vectored RNA vaccines offer a variety of possibilities to engineer targeted vaccines. They are cost-effective and safe, but replication competent, activating the humoral... (Review)
Review
Vectored RNA vaccines offer a variety of possibilities to engineer targeted vaccines. They are cost-effective and safe, but replication competent, activating the humoral as well as the cellular immune system.This chapter focuses on RNA vaccines derived from negative-strand RNA viruses from the order Mononegavirales with special attention to Newcastle disease virus-based vaccines and their generation. It shall provide an overview on the advantages and disadvantages of certain vector platforms as well as their scopes of application, including an additional section on experimental COVID-19 vaccines.
Topics: Animals; Humans; COVID-19; Genetic Vectors; Newcastle disease virus; RNA Viruses; SARS-CoV-2; Viral Vaccines; mRNA Vaccines
PubMed: 38814390
DOI: 10.1007/978-1-0716-3770-8_3 -
Viruses Jul 2023Nosocomial pneumonia (NP) represents a leading cause of morbidity and mortality in hospitalized patients. Historically, clinicians have considered hospital-acquired... (Review)
Review
Nosocomial pneumonia (NP) represents a leading cause of morbidity and mortality in hospitalized patients. Historically, clinicians have considered hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), which comprise NP, to be essentially bacterial processes. As such, patients suspected of having either HAP or VAP are initially treated with broad-spectrum antibiotics, and few clinicians search for a possible culprit virus. Recent reports which build on earlier studies, however, indicate that viruses likely play an important role in NP. Studies employing viral diagnostics as part of the evaluation for NP indicate that common respiratory viruses can spread nosocomially and lead to HAP and VAP. Similarly, studies of the general epidemiology of respiratory viral infections, such as influenza, respiratory syncytial virus, adenovirus, and rhinovirus, confirm that these pathogens are important causes of NP, especially among immunosuppressed and pediatric patients. More importantly, these more contemporary analyses reveal that one cannot, based on clinical characteristics, distinguish a viral from a bacterial cause of NP. Additionally, viral HAP and VAP result in crude mortality rates that rival or exceed those reported in bacterial NP. Rigorous prospective, multicenter trials are needed to confirm the significance of respiratory viruses in NP, as are studies of novel therapeutics for these viral infections.
Topics: Humans; Child; Cross Infection; Prospective Studies; Healthcare-Associated Pneumonia; Adenoviridae; Respiratory Syncytial Virus, Human
PubMed: 37632017
DOI: 10.3390/v15081676