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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 -
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 -
Annals of the New York Academy of... Dec 2023Phleboviruses are zoonotic pathogens found in parts of Africa, Asia, Europe, and North America and cause disease symptoms ranging from self-limiting febrile illness to... (Review)
Review
Phleboviruses are zoonotic pathogens found in parts of Africa, Asia, Europe, and North America and cause disease symptoms ranging from self-limiting febrile illness to severe disease, including hemorrhagic diathesis, encephalitis, and ocular pathologies. There are currently no approved preventative vaccines against phlebovirus infection or antivirals for the treatment of the disease. Here, we discuss the roles of neutralizing antibodies in phlebovirus infection, the antigenic targets present on the mature polyproteins Gn and Gc, progress in vaccine development, and the prospects of identifying conserved neutralizing epitopes across multiple phleboviruses. Further research in this area will pave the way for the rational design of pan-phlebovirus vaccines that will protect against both known phleboviruses but also newly emerging phleboviruses that may have pandemic potential.
Topics: Humans; Phlebovirus; Immunity, Humoral; Asia; Vaccines; North America
PubMed: 37936483
DOI: 10.1111/nyas.15080 -
The Veterinary Clinics of North... Jul 2024Rift Valley fever (RVF) is a zoonotic viral disease that affects domestic and wild ruminants such as cattle, sheep, goats, camels, and buffaloes. Rift valley fever virus... (Review)
Review
Rift Valley fever (RVF) is a zoonotic viral disease that affects domestic and wild ruminants such as cattle, sheep, goats, camels, and buffaloes. Rift valley fever virus (RVFV), the causative agent of RVF, can also infect humans. RVFV is an arthropod-borne virus (arbovirus) that is primarily spread through the bites of infected mosquitoes or exposure to infected blood. RVFV was first isolated and characterized in the Rift Valley of Kenya in 1931 and is endemic throughout sub-Saharan Africa, including Comoros and Madagascar, the Arabian Peninsula (Saudi Arabia and Yemen), and Mayotte.
Topics: Rift Valley Fever; Animals; Rift Valley fever virus; Humans; Zoonoses; Ruminants; Sheep
PubMed: 38453549
DOI: 10.1016/j.cvfa.2024.01.004 -
Redox Biology Sep 2023Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate....
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate. Thrombocytopenia is a major clinical manifestation observed in SFTS patients, but the underlying mechanism remains largely unclear. Here, we explored the effects of SFTSV infection on platelet function in vivo in severely infected SFTSV IFNar mice and on mouse and human platelet function in vitro. Results showed that SFTSV-induced platelet clearance acceleration may be the main reason for thrombocytopenia. SFTSV-potentiated platelet activation and apoptosis were also observed in infected mice. Further investigation showed that SFTSV infection induced platelet reactive oxygen species (ROS) production and mitochondrial dysfunction. In vitro experiments revealed that administration of SFTSV or SFTSV glycoprotein (Gn) increased activation, apoptosis, ROS production, and mitochondrial dysfunction in separated mouse platelets, which could be effectively ameliorated by the application of antioxidants (NAC (N-acetyl-l-cysteine), SKQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) and resveratrol). In vivo experiments showed that the antioxidants partially rescued SFTSV infection-induced thrombocytopenia by improving excessive ROS production and mitochondrial dysfunction and down-regulating platelet apoptosis and activation. Furthermore, while SFTSV and Gn directly potentiated human platelet activation, it was completely abolished by antioxidants. This study revealed that SFTSV and Gn can directly trigger platelet activation and apoptosis in an ROS-MAPK-dependent manner, which may contribute to thrombocytopenia and hemorrhage during infection, but can be abolished by antioxidants.
Topics: Humans; Animals; Mice; Severe Fever with Thrombocytopenia Syndrome; Reactive Oxygen Species; Bunyaviridae Infections; Antioxidants; Glycoproteins; Thrombocytopenia; Platelet Activation
PubMed: 37544244
DOI: 10.1016/j.redox.2023.102837 -
Journal of Medical Virology Nov 2023Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus, causing thrombocytopenia and hemorrhagic fever, with a fatality rate ranging...
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus, causing thrombocytopenia and hemorrhagic fever, with a fatality rate ranging from 12% to 30%. SFTSV possesses Gn and Gc glycoproteins, which are responsible for host cell receptor attachment and membrane fusion, respectively, to infect host cells. We have previously reported a protein subunit vaccine candidate (sGn-H-FT) of the SFTSV soluble Gn head region (sGn-H) fused with self-assembling ferritin (FT) nanoparticles, displaying strong protective immunogenicity. In this study, we present messenger RNA (mRNA) vaccine candidates encoding sGn-H or sGn-H-FT, both of which exhibit potent in vivo immunogenicity and protection capacity. Mice immunized with either sGn-H or sGn-H-FT mRNA lipid nanoparticle (LNP) vaccine produced strong total antibodies and neutralizing antibodies (NAbs) against sGn-H. Importantly, NAb titers remained high for an extended period. Finally, mice immunized with sGn-H or sGn-H-FT mRNA LNP vaccine were fully protected from a lethal dose of SFTSV challenge, showing no fatality. These findings underscore the promise of sGn-H and sGn-H-FT as vaccine antigen candidates capable of providing protective immunity against SFTSV infection.
Topics: Animals; Mice; Viral Envelope Proteins; Phlebovirus; Vaccines, Synthetic; RNA, Messenger; mRNA Vaccines
PubMed: 37909776
DOI: 10.1002/jmv.29203 -
Frontiers in Veterinary Science 2023Rift Valley fever phlebovirus (RVFV) is a zoonotic mosquito-transmitted arbovirus, presenting a serious threat to humans and animals. Susceptible hosts are of great... (Review)
Review
Rift Valley fever phlebovirus (RVFV) is a zoonotic mosquito-transmitted arbovirus, presenting a serious threat to humans and animals. Susceptible hosts are of great significance for the prevention of RVFV. Appropriate animal models are helpful to better understand the onset and development of diseases, as well as the control measures and vaccine research. This review focuses on the role of animal hosts in the maintenance of the virus, and summarizes the host range of RVFV. We list some common animal models in the process of RVFV research, which would provide some important insights into the prevention and treatment of RVFV, as well as the study of Rift Valley fever (RVF) pathogenesis and vaccines.
PubMed: 37929288
DOI: 10.3389/fvets.2023.1258172 -
Pathogens (Basel, Switzerland) Sep 2023Rift Valley Fever Virus is a mosquito-borne phlebovirus causing febrile or haemorrhagic illness in ruminants and humans. The virus can prevent the induction of the... (Review)
Review
Rift Valley Fever Virus is a mosquito-borne phlebovirus causing febrile or haemorrhagic illness in ruminants and humans. The virus can prevent the induction of the antiviral interferon response through its NSs proteins. Mutations in the NSs gene may allow the induction of innate proinflammatory immune responses and lead to attenuation of the virus. Upon infection, virus-specific antibodies and T cells are induced that may afford protection against subsequent infections. Thus, all arms of the adaptive immune system contribute to prevention of disease progression. These findings will aid the design of vaccines using the currently available platforms. Vaccine candidates have shown promise in safety and efficacy trials in susceptible animal species and these may contribute to the control of RVFV infections and prevention of disease progression in humans and ruminants.
PubMed: 37764982
DOI: 10.3390/pathogens12091174 -
Science Advances Jul 2023Rift Valley fever virus (RVFV) is an emerging arbovirus found in Africa. While RVFV is pantropic and infects many cells and tissues, viral replication and necrosis...
Rift Valley fever virus (RVFV) is an emerging arbovirus found in Africa. While RVFV is pantropic and infects many cells and tissues, viral replication and necrosis within the liver play a critical role in mediating severe disease. The low-density lipoprotein receptor-related protein 1 (Lrp1) is a recently identified host factor for cellular entry and infection by RVFV. The biological significance of Lrp1, including its role in hepatic disease in vivo, however, remains to be determined. Because Lrp1 has a high expression level in hepatocytes, we developed a mouse model in which Lrp1 is specifically deleted in hepatocytes to test how the absence of liver Lrp1 expression affects RVF pathogenesis. Mice lacking Lrp1 expression in hepatocytes showed minimal RVFV replication in the liver, longer time to death, and altered clinical signs toward neurological disease. In contrast, RVFV infection levels in other tissues showed no difference between the two genotypes. Therefore, Lrp1 is essential for RVF hepatic disease in mice.
Topics: Animals; Mice; Rift Valley Fever; Rift Valley fever virus; Africa; Hepatocytes; Low Density Lipoprotein Receptor-Related Protein-1
PubMed: 37450601
DOI: 10.1126/sciadv.adh2264 -
Virus Research Jul 2023A newly discovered tick-borne virus called the severe fever with thrombocytopenia syndrome virus (SFTSV) can cause the severe fever with thrombocytopenia syndrome...
A newly discovered tick-borne virus called the severe fever with thrombocytopenia syndrome virus (SFTSV) can cause the severe fever with thrombocytopenia syndrome (SFTS). The mortality and incidence rate of SFTS patients remain extremely high due to the fast global dissemination of its arthropod vectors, and the mechanism of viral pathogenesis remains largely unknown. In this study, high-throughput RNA sequencing (RNA-Seq) was used to sequence HEK 293 cells treated with SFTSV at four time points. 115, 191, 259, and 660 differentially expressed genes (DEGs) were identified at 6, 12, 24, and 48 h post-infection, respectively. We found that SFTSV infection induced the expression of genes responsible for numerous cytokine-related pathways, including TNF, CXCL1, CXCL2, CXCL3, CXCL8, CXCL10, and CCL20. With the extension of infection time, the expression of most genes involved in these pathways increased significantly, indicating the host's inflammatory response to SFTSV. Moreover, the expression levels of GNA13, ARHGEF12, RHOA, ROCK1, and MYL12A, elements of the platelet activation signaling pathway, were downregulated during SFTSV infection, suggesting that the SFTSV infection may cause thrombocytopenia by inhibiting platelet activation. Our results contribute to further understanding the interaction between SFTSV and the host.
Topics: Humans; Severe Fever with Thrombocytopenia Syndrome; Bunyaviridae Infections; HEK293 Cells; Phlebovirus; Signal Transduction; rho-Associated Kinases
PubMed: 37211158
DOI: 10.1016/j.virusres.2023.199138