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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 -
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 -
Cell Research Sep 2019Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top...
Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top 10 priority infectious diseases by the World Health Organization due to its high fatality of 12%-50% and possibility of pandemic transmission. Currently, effective anti-SFTSV intervention remains unavailable. Here, by screening a library of FDA-approved drugs, we found that benidipine hydrochloride, a calcium channel blocker (CCB), inhibited SFTSV replication in vitro. Benidipine hydrochloride was revealed to inhibit virus infection through impairing virus internalization and genome replication. Further experiments showed that a broad panel of CCBs, including nifedipine, inhibited SFTSV infection. The anti-SFTSV effect of these two CCBs was further analyzed in a humanized mouse model in which CCB treatment resulted in reduced viral load and decreased fatality rate. Importantly, by performing a retrospective clinical investigation on a large cohort of 2087 SFTS patients, we revealed that nifedipine administration enhanced virus clearance, improved clinical recovery, and remarkably reduced the case fatality rate by >5-fold. These findings are highly valuable for developing potential host-oriented therapeutics for SFTS and other lethal acute viral infections known to be inhibited by CCBs in vitro.
Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Cell Line; Chlorocebus aethiops; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred C57BL; Nifedipine; Phlebotomus Fever; Phlebovirus; RNA Interference; RNA, Small Interfering; Retrospective Studies; Vero Cells; Viral Load; Virus Replication
PubMed: 31444469
DOI: 10.1038/s41422-019-0214-z -
Emerging Microbes & Infections Dec 2022Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne bunyavirus, causes mild-to-moderate infection to critical illness or even death in...
Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne bunyavirus, causes mild-to-moderate infection to critical illness or even death in human patients. The effect of virus variations on virulence and related clinical significance is unclear. We prospectively recruited SFTSV-infected patients in a hotspot region of SFTS endemic in China from 2011 to 2020, sequenced whole genome of SFTSV, and assessed the association of virus genomic variants with clinical data, viremia, and inflammatory response. We identified seven viral clades (I-VII) based on phylogenetic characterization of 805 SFTSV genome sequences. A significantly increased case fatality rate (32.9%) was revealed in one unique clade (IV) that possesses a specific co-mutation pattern, compared to other three common clades (I, 16.7%; II, 13.8%; and III, 11.8%). The phenotype-genotype association (hazard ratios ranged 1.327-2.916) was confirmed by multivariate regression adjusting age, sex, and hospitalization delay. We revealed a pronounced inflammation response featured by more production of CXCL9, IL-10, IL-6, IP-10, M-CSF, and IL-1β, in clade IV, which was also related to severe complications. We observed enhanced cytokine expression from clade IV inoculated PBMCs and infected mice. Moreover, the neutralization activity of convalescent serum from patients infected with one specified clade was remarkably reduced to other viral clades. Together, our findings revealed a significant association between one specific viral clade and SFTS fatality, highlighting the need for molecular surveillance for highly lethal strains in endemic regions and unravelled the importance of evaluating cross-clade effect in development of vaccines and therapeutics.
Topics: Animals; Bunyaviridae Infections; Genomics; Humans; Mice; Phlebovirus; Phylogeny; Severe Fever with Thrombocytopenia Syndrome
PubMed: 35603493
DOI: 10.1080/22221751.2022.2081617 -
Frontiers in Cellular and Infection... 2023Increased human activities around the globe and the rapid development of once rural regions have increased the probability of contact between humans and wild animals. A... (Review)
Review
Increased human activities around the globe and the rapid development of once rural regions have increased the probability of contact between humans and wild animals. A majority of bunyaviruses are of zoonotic origin, and outbreaks may result in the substantial loss of lives, economy contraction, and social instability. Many bunyaviruses require manipulation in the highest levels of biocontainment, such as Biosafety Level 4 (BSL-4) laboratories, and the scarcity of this resource has limited the development speed of vaccines for these pathogens. Meanwhile, new technologies have been created, and used to innovate vaccines, like the mRNA vaccine platform and bioinformatics-based antigen design. Here, we summarize current vaccine developments for three different bunyaviruses requiring work in the highest levels of biocontainment: Crimean-Congo Hemorrhagic Fever Virus (CCHFV), Rift Valley Fever Virus (RVFV), and Hantaan virus (HTNV), and provide perspectives and potential future directions that can be further explored to advance specific vaccines for humans and livestock.
Topics: Animals; Humans; Rift Valley fever virus; Hemorrhagic Fever Virus, Crimean-Congo; Vaccines; Hemorrhagic Fever, Crimean
PubMed: 37274315
DOI: 10.3389/fcimb.2023.1174030 -
Viruses Feb 2021is a large family of arthropod-borne viruses with over 100 species worldwide. Several cause severe diseases in both humans and livestock. Global warming and the... (Review)
Review
is a large family of arthropod-borne viruses with over 100 species worldwide. Several cause severe diseases in both humans and livestock. Global warming and the apparent geographical expansion of arthropod vectors are good reasons to seriously consider these viruses potential agents of emerging diseases. With an increasing frequency and number of epidemics, some phenuiviruses represent a global threat to public and veterinary health. This review focuses on the early stage of phenuivirus infection in mammalian host cells. We address current knowledge on each step of the cell entry process, from virus binding to penetration into the cytosol. Virus receptors, endocytosis, and fusion mechanisms are discussed in light of the most recent progress on the entry of banda-, phlebo-, and uukuviruses, which together constitute the three prominent genera in the family.
Topics: Animals; Bunyaviridae Infections; Endocytosis; Humans; Mammals; Phlebovirus; Virus Attachment; Virus Internalization
PubMed: 33672975
DOI: 10.3390/v13020299 -
Viruses Oct 2022Since the intricate and complex steps in pathogenesis and host-viral interactions of arthropod-borne viruses or arboviruses are not completely understood, the... (Review)
Review
Since the intricate and complex steps in pathogenesis and host-viral interactions of arthropod-borne viruses or arboviruses are not completely understood, the multi-omics approaches, which encompass proteomics, transcriptomics, genomics and metabolomics network analysis, are of great importance. We have reviewed the omics studies on mosquito-borne viruses of the , and families, specifically for Chikungunya, Mayaro, Oropouche and Rift Valley Fever viruses. Omics studies can potentially provide a new perspective on the pathophysiology of arboviruses, contributing to a better comprehension of these diseases and their effects and, hence, provide novel insights for the development of new antiviral drugs or therapies.
Topics: Animals; Humans; Arboviruses; Alphavirus; Orthobunyavirus; Phlebovirus; Antiviral Agents
PubMed: 36298749
DOI: 10.3390/v14102194 -
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 -
Viruses Apr 2023Sever fever with thrombocytopenia syndrome (SFTS) is a new infectious disease that has emerged in recent years and is widely distributed, highly contagious, and lethal,... (Review)
Review
Sever fever with thrombocytopenia syndrome (SFTS) is a new infectious disease that has emerged in recent years and is widely distributed, highly contagious, and lethal, with a mortality rate of up to 30%, especially in people with immune system deficiencies and elderly patients. SFTS is an insidious, negative-stranded RNA virus that has a major public health impact worldwide. The development of a vaccine and the hunt for potent therapeutic drugs are crucial to the prevention and treatment of Bunyavirus infection because there is no particular treatment for SFTS. In this respect, investigating the mechanics of SFTS-host cell interactions is crucial for creating antiviral medications. In the present paper, we summarized the mechanism of interaction between SFTS and pattern recognition receptors, endogenous antiviral factors, inflammatory factors, and immune cells. Furthermore, we summarized the current therapeutic drugs used for SFTS treatment, aiming to provide a theoretical basis for the development of targets and drugs against SFTS.
Topics: Humans; Aged; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Bunyaviridae Infections; Thrombocytopenia; Antiviral Agents
PubMed: 37112920
DOI: 10.3390/v15040940