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Viruses Jun 2021Severe fever with thrombocytopenia syndrome (SFTS) is an acute febrile illness characterized by fever, leukopenia, thrombocytopenia, and gastrointestinal symptoms such... (Review)
Review
Severe fever with thrombocytopenia syndrome (SFTS) is an acute febrile illness characterized by fever, leukopenia, thrombocytopenia, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting resulting from infection with the SFTS virus (SFTSV). The SFTSV is transmitted to humans by tick bites, primarily from , , and . Human-to-human transmission has also been reported. Since the first report of an SFTS patient in China, the number of patients has also been increasing. The mortality rate of patients with SFTS remains high because the disease can quickly lead to death through multiple organ failure. In particular, an average fatality rate of approximately 20% has been reported for SFTS patients, and no treatment strategy has been established. Therefore, effective antiviral agents and vaccines are required. Here, we aim to review the epidemiology, clinical manifestations, laboratory diagnosis, and various specific treatments (i.e., antiviral agents, steroids, intravenous immunoglobulin, and plasma exchange) that have been tested to help to cope with the disease.
Topics: Animals; Antiviral Agents; Humans; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Ticks
PubMed: 34201811
DOI: 10.3390/v13071213 -
The Journal of General Virology Aug 2019Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that was first discovered in Kenya in 1930 and is now endemic throughout multiple African countries and the... (Review)
Review
Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that was first discovered in Kenya in 1930 and is now endemic throughout multiple African countries and the Arabian Peninsula. RVF virus primarily infects domestic livestock (sheep, goats, cattle) causing high rates of neonatal mortality and abortion, with human infection resulting in a wide variety of clinical outcomes, ranging from self-limiting febrile illness to life-threatening haemorrhagic diatheses, and miscarriage in pregnant women. Since its discovery, RVF has caused many outbreaks in Africa and the Arabian Peninsula with major impacts on human and animal health. However, options for the control of RVF outbreaks are limited by the lack of licensed human vaccines or therapeutics. For this reason, RVF is prioritized by the World Health Organization for urgent research and development of countermeasures for the prevention and control of future outbreaks. In this review, we highlight the current understanding of RVF, including its epidemiology, pathogenesis, clinical manifestations and status of vaccine development.
Topics: Animals; Humans; Rift Valley Fever; Rift Valley fever virus; Zoonoses
PubMed: 31310198
DOI: 10.1099/jgv.0.001296 -
Cell Sep 2021Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain...
Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection. RVFV Gn directly binds to specific Lrp1 clusters and is glycosylation independent. Exogenous addition of murine RAP domain 3 (mRAP) and anti-Lrp1 antibodies neutralizes RVFV infection in taxonomically diverse cell lines. Mice treated with mRAP and infected with pathogenic RVFV are protected from disease and death. A mutant mRAPD3 that binds Lrp1 weakly failed to protect from RVFV infection. Together, these data support Lrp1 as a host entry factor for RVFV infection and define a new target to limit RVFV infections.
Topics: Animals; Antibody Specificity; Base Sequence; Brain; CRISPR-Cas Systems; Cell Membrane; Cells, Cultured; Glycoproteins; Glycosaminoglycans; Glycosylation; Host-Pathogen Interactions; Humans; LDL-Receptor Related Protein-Associated Protein; Ligands; Low Density Lipoprotein Receptor-Related Protein-1; Membrane Glycoproteins; Mice; Protein Binding; Protein Denaturation; Rift Valley Fever; Rift Valley fever virus; Virus Internalization
PubMed: 34559985
DOI: 10.1016/j.cell.2021.09.001 -
Frontiers in Immunology 2022Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), poses a serious threat to global public health, with high fatalities and an... (Review)
Review
Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), poses a serious threat to global public health, with high fatalities and an increasing prevalence. As effective therapies and prevention strategies are limited, there is an urgent need to elucidate the pathogenesis of SFTS. SFTSV has evolved several mechanisms to escape from host immunity. In this review, we summarize the mechanisms through which SFTSV escapes host immune responses, including the inhibition of innate immunity and evasion of adaptive immunity. Understanding the pathogenesis of SFTS will aid in the development of new strategies for the treatment of this disease.
Topics: Bunyaviridae Infections; Humans; Immunity, Innate; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome
PubMed: 35967309
DOI: 10.3389/fimmu.2022.937684 -
Experimental & Molecular Medicine May 2021An emerging infectious disease first identified in central China in 2009, severe fever with thrombocytopenia syndrome (SFTS) was found to be caused by a novel... (Review)
Review
An emerging infectious disease first identified in central China in 2009, severe fever with thrombocytopenia syndrome (SFTS) was found to be caused by a novel phlebovirus. Since SFTSV was first identified, epidemics have occurred in several East Asian countries. With the escalating incidence of SFTS and the rapid, worldwide spread of SFTSV vector, it is clear this virus has pandemic potential and presents an impending global public health threat. In this review, we concisely summarize the latest findings regarding SFTSV, including vector and virus transmission, genotype diversity and epidemiology, probable pathogenic mechanism, and clinical presentation of human SFTS. Ticks most likely transmit SFTSV to animals including humans; however, human-to-human transmission has been reported. The majority of arbovirus transmission cycle includes vertebrate hosts, and potential reservoirs include a variety of both domestic and wild animals. Reports of the seroprevalence of SFTSV in both wild and domestic animals raises the probability that domestic animals act as amplifying hosts for the virus. Major clinical manifestation of human SFTS infection is high fever, thrombocytopenia, leukocytopenia, gastrointestinal symptoms, and a high case-fatality rate. Several animal models were developed to further understand the pathogenesis of the virus and aid in the discovery of therapeutics and preventive measures.
Topics: Animals; Communicable Disease Control; Communicable Diseases, Emerging; Disease Management; Disease Models, Animal; Disease Susceptibility; Genetic Variation; Host-Pathogen Interactions; Humans; Phlebovirus; Reassortant Viruses; Seroepidemiologic Studies; Severe Fever with Thrombocytopenia Syndrome; Symptom Assessment; Viral Zoonoses
PubMed: 33953322
DOI: 10.1038/s12276-021-00610-1 -
Science Advances Aug 2023Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus causing a high fatality rate of up to 30%. To date, the receptor mediating...
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus causing a high fatality rate of up to 30%. To date, the receptor mediating SFTSV entry remained uncharacterized, hindering the understanding of disease pathogenesis. Here, C-C motif chemokine receptor 2 (CCR2) was identified as a host receptor for SFTSV based on a genome-wide CRISPR-Cas9 screen. Knockout of CCR2 substantially reduced viral binding and infection. CCR2 enhanced SFTSV binding through direct binding to SFTSV glycoprotein N (Gn), which is mediated by its N-terminal extracellular domain. Depletion of CCR2 in C57BL/6J mouse model attenuated SFTSV replication and pathogenesis. The peripheral blood primary monocytes from elderly individuals or subjects with underlying diabetes mellitus showed higher CCR2 surface expression and supported stronger binding and replication of SFTSV. Together, these data indicate that CCR2 is a host entry receptor for SFTSV infection and a novel target for developing anti-SFTSV therapeutics.
Topics: Animals; Mice; Mice, Inbred C57BL; Mice, Knockout; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Receptors, CCR2
PubMed: 37531422
DOI: 10.1126/sciadv.adg6856 -
Cell Reports Mar 2020Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus that carries a high fatality rate of 12%-50%. In-depth understanding of...
Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus that carries a high fatality rate of 12%-50%. In-depth understanding of the SFTSV-induced pathogenesis mechanism is critical for developing effective anti-SFTS therapeutics. Here, we report transcriptomic analysis of blood samples from SFTS patients. We observe a strong correlation between inflammatory responses and disease progression and fatal outcome. Quantitative proteomic analysis of SFTSV infection confirms the induction of inflammation and further reveals virus-induced mitochondrial dysfunction. Mechanistically, SFTSV infection triggers BCL2 antagonist/killer 1 (BAK) upregulation and BAK/BCL2-associated X (BAX) activation, leading to mitochondrial DNA (mtDNA) oxidization and subsequent cytosolic release. The cytosolic mtDNA binds and triggers NLRP3 inflammasome activation. Notably, the BAK expression level correlates with SFTS disease progression and fatal outcome. These findings provide insights into the clinical features and molecular underpinnings of severe SFTS, which may aid in patient care and therapeutic design, and may also be conserved during infection by other highly pathogenic viruses.
Topics: Adult; Animals; Bunyaviridae Infections; Cell Line; DNA, Mitochondrial; Disease Models, Animal; Disease Progression; Female; Humans; Inflammasomes; Inflammation; Interleukin-1beta; Mice, Inbred C57BL; Mitochondria; Models, Biological; Myeloid Differentiation Factor 88; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Phlebovirus; Reactive Oxygen Species; Signal Transduction; Toll-Like Receptor 8; Transcriptome; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 32234474
DOI: 10.1016/j.celrep.2020.02.105 -
Nature Communications Oct 2023The severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne human-infecting bunyavirus, which utilizes two envelope glycoproteins, Gn and Gc, to enter...
The severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne human-infecting bunyavirus, which utilizes two envelope glycoproteins, Gn and Gc, to enter host cells. However, the structure and organization of these glycoproteins on virion surface are not yet known. Here we describe the structure of SFTSV determined by single particle reconstruction, which allows mechanistic insights into bunyavirus assembly at near-atomic resolution. The SFTSV Gn and Gc proteins exist as heterodimers and further assemble into pentameric and hexameric peplomers, shielding the Gc fusion loops by both intra- and inter-heterodimer interactions. Individual peplomers are associated mainly through the ectodomains, in which the highly conserved glycans on N914 of Gc play a crucial role. This elaborate assembly stabilizes Gc in the metastable prefusion conformation and creates some cryptic epitopes that are only accessible in the intermediate states during virus entry. These findings provide an important basis for developing vaccines and therapeutic drugs.
Topics: Humans; Viral Envelope Proteins; Severe Fever with Thrombocytopenia Syndrome; Cryoelectron Microscopy; Phlebovirus; Glycoproteins; Orthobunyavirus
PubMed: 37816705
DOI: 10.1038/s41467-023-41804-7 -
International Journal of Molecular... Sep 2022Severe fever with thrombocytopenia syndrome (SFTS) has been acknowledged as an emerging infectious disease that is caused by the SFTS virus (SFTSV). The main clinical... (Review)
Review
Severe fever with thrombocytopenia syndrome (SFTS) has been acknowledged as an emerging infectious disease that is caused by the SFTS virus (SFTSV). The main clinical features of SFTS on presentation include fever, thrombocytopenia, leukocytopenia and gastrointestinal symptoms. The mortality rate is estimated to range between 5‑30% in East Asia. However, SFTSV infection is increasing on an annual basis globally and is becoming a public health problem. The transmission cycle of SFTSV remains poorly understood, which is compounded by the pathogenesis of SFTS not being fully elucidated. Since the mechanism underlying the host immune response towards SFTSV is also unclear, there are no effective vaccines or specific therapeutic agents against SFTS, with supportive care being the only realistic option. Therefore, it is now crucial to understand all aspects of the host‑virus interaction following SFTSV infection, including the antiviral states and viral evasion mechanisms. In the present review, recent research progress into the possible host immune responses against SFTSV was summarized, which may be useful in designing novel therapeutics against SFTS.
Topics: Bunyaviridae Infections; Humans; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Thrombocytopenia
PubMed: 35856413
DOI: 10.3892/ijmm.2022.5174 -
Journal of Virology Apr 2023Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. Studies have shown that...
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. Studies have shown that SFTSV nucleoprotein (N) induces BECN1-dependent autophagy to promote viral assembly and release. However, the function of other SFTSV proteins in regulating autophagy has not been reported. In this study, we identify SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells as the virus component mediating SFTSV-induced autophagy. We found that SFTSV NSs-induced autophagy was inclusion body independent, and most phenuivirus NSs had autophagy-inducing effects. Unlike N protein-induced autophagy, SFTSV NSs was key in regulating autophagy by interacting with the host's vimentin in an inclusion body-independent manner. NSs interacted with vimentin and induced vimentin degradation through the K48-linked ubiquitin-proteasome pathway. This negatively regulating Beclin1-vimentin complex formed and promoted autophagy. Furthermore, we identified the NSs-binding domain of vimentin and found that overexpression of wild-type vimentin antagonized the induced effect of NSs on autophagy and inhibited viral replication, suggesting that vimentin is a potential antiviral target. The present study shows a novel mechanism through which SFTSV nonstructural protein activates autophagy, which provides new insights into the role of NSs in SFTSV infection and pathogenesis. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly emerging tick-borne pathogen that causes multifunctional organ failure and even death in humans. As a housekeeping mechanism for cells to maintain steady state, autophagy plays a dual role in viral infection and the host's immune response. However, the relationship between SFTSV infection and autophagy has not been described in detail yet. Here, we demonstrated that SFTSV infection induced complete autophagic flux and facilitated viral proliferation. We also identified a key mechanism underlying NSs-induced autophagy, in which NSs interacted with vimentin to inhibit the formation of the Beclin1-vimentin complex and induced vimentin degradation through K48-linked ubiquitination modification. These findings may help us understand the new functions and mechanisms of NSs and may aid in the identification of new antiviral targets.
Topics: Humans; Autophagy; Beclin-1; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Vimentin; Viral Nonstructural Proteins; Virus Replication; Down-Regulation; Protein Domains
PubMed: 37039677
DOI: 10.1128/jvi.00302-23