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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 2021Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), is a tick-borne emerging zoonosis with a high case-fatality rate. At present,... (Review)
Review
Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), is a tick-borne emerging zoonosis with a high case-fatality rate. At present, there is no approved SFTS vaccine, although the development of a vaccine would be one of the best strategies for preventing SFTS. This article focused on studies aimed at establishing small animal models of SFTS that are indispensable for evaluating vaccine candidates, developing these vaccine candidates, and establishing more practical animal models for evaluation. Innate immune-deficient mouse models, a hamster model, an immunocompetent ferret model and a cat model have been developed for SFTS. Several vaccine candidates for SFTS have been developed, and their efficacy has been confirmed using these animal models. The candidates consist of live-attenuated virus-based, viral vector-based, or DNA-based vaccines. SFTS vaccines are expected to be used for humans and companion dogs and cats. Hence for practical use, the vaccine candidates should be evaluated for efficacy using not only nonhuman primates but also dogs and cats. There is no practical nonhuman primate model of SFTS; however, the cat model is available to evaluate the efficacy of these candidate SFTS vaccines on domesticated animals.
Topics: Animals; Cat Diseases; Cats; Cricetinae; Disease Models, Animal; Dog Diseases; Dogs; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phlebovirus; Primates; Severe Fever with Thrombocytopenia Syndrome; Viral Vaccines
PubMed: 33917632
DOI: 10.3390/v13040627 -
Viruses May 2023Severe fever with thrombocytopenia syndrome (SFTS) caused by a novel bunyavirus (SFTSV) is an emerging infectious disease with up to 30% case fatality. Currently, there...
Severe fever with thrombocytopenia syndrome (SFTS) caused by a novel bunyavirus (SFTSV) is an emerging infectious disease with up to 30% case fatality. Currently, there are no specific antiviral drugs or vaccines for SFTS. Here, we constructed a reporter SFTSV in which the virulent factor nonstructural protein (NSs) was replaced by eGFP for drug screening. First, we developed a reverse genetics system based on the SFTSV HBMC5 strain. Then, the reporter virus SFTSV-delNSs-eGFP was constructed, rescued, and characterized in vitro. SFTSV-delNSs-eGFP showed similar growth kinetics with the wild-type virus in Vero cells. We further detected the antiviral efficacy of favipiravir and chloroquine against wild-type and recombinant SFTSV by the quantification of viral RNA, and compared the results with that of fluorescent assay using high-content screening. The results showed that SFTSV-delNSs-eGFP could be used as a reporter virus for antiviral drug screening in vitro. In addition, we analyzed the pathogenesis of SFTSV-delNSs-eGFP in interferon receptor-deficient (IFNAR) C57BL/6J mice and found that unlike the fatal infection of the wild-type virus, no obvious pathological change or viral replication were observed in SFTSV-delNSs-eGFP-infected mice. Taken together, the green fluorescence and attenuated pathogenicity make SFTSV-delNSs-eGFP a potent tool for the future high-throughput screening of antiviral drugs.
Topics: Chlorocebus aethiops; Animals; Mice; Antiviral Agents; Severe Fever with Thrombocytopenia Syndrome; Vero Cells; Drug Evaluation, Preclinical; Mice, Inbred C57BL; Phlebovirus; Bunyaviridae Infections
PubMed: 37243233
DOI: 10.3390/v15051147 -
Infectious Diseases of Poverty Jul 2022Viral pathogens belonging to the order Bunyavirales pose a continuous background threat to global health, but the fact remains that they are usually neglected and their...
BACKGROUND
Viral pathogens belonging to the order Bunyavirales pose a continuous background threat to global health, but the fact remains that they are usually neglected and their distribution is still ambiguously known. We aim to map the geographical distribution of Bunyavirales viruses and assess the environmental suitability and transmission risk of major Bunyavirales viruses in China.
METHODS
We assembled data on all Bunyavirales viruses detected in humans, animals and vectors from multiple sources, to update distribution maps of them across China. In addition, we predicted environmental suitability at the 10 km × 10 km pixel level by applying boosted regression tree models for two important Bunyavirales viruses, including Crimean-Congo hemorrhagic fever virus (CCHFV) and Rift Valley fever virus (RVFV). Based on model-projected risks and air travel volume, the imported risk of RVFV was also estimated from its endemic areas to the cities in China.
RESULTS
Here we mapped all 89 species of Bunyavirales viruses in China from January 1951 to June 2021. Nineteen viruses were shown to infect humans, including ten species first reported as human infections. A total of 447,848 cases infected with Bunyavirales viruses were reported, and hantaviruses, Dabie bandavirus and Crimean-Congo hemorrhagic fever virus (CCHFV) had the severest disease burden. Model-predicted maps showed that Xinjiang and southwestern Yunnan had the highest environmental suitability for CCHFV occurrence, mainly related to Hyalomma asiaticum presence, while southern China had the highest environmental suitability for Rift Valley fever virus (RVFV) transmission all year round, mainly driven by livestock density, mean precipitation in the previous month. We further identified three cities including Guangzhou, Beijing and Shanghai, with the highest imported risk of RVFV potentially from Egypt, South Africa, Saudi Arabia and Kenya.
CONCLUSIONS
A variety of Bunyavirales viruses are widely distributed in China, and the two major neglected Bunyavirales viruses including CCHFV and RVFV, both have the potential for outbreaks in local areas of China. Our study can help to promote the understanding of risk distribution and disease burden of Bunyavirales viruses in China, and the risk maps of CCHFV and RVFV occurrence are crucial to the targeted surveillance and control, especially in seasons and locations at high risk.
Topics: Animals; China; Hemorrhagic Fever Virus, Crimean-Congo; Ixodidae; Kenya; Rift Valley fever virus
PubMed: 35799306
DOI: 10.1186/s40249-022-00993-x -
Emerging Infectious Diseases May 2021We describe a series of severe neuroinvasive infections caused by Toscana virus, identified by real-time reverse transcription PCR testing, in 8 hospitalized patients in...
We describe a series of severe neuroinvasive infections caused by Toscana virus, identified by real-time reverse transcription PCR testing, in 8 hospitalized patients in Bucharest, Romania, during the summer seasons of 2017 and 2018. Of 8 patients, 5 died. Sequencing showed that the circulating virus belonged to lineage A.
Topics: Bunyaviridae Infections; Humans; Romania; Sandfly fever Naples virus
PubMed: 33900182
DOI: 10.3201/eid2705.204598 -
Journal of Virology Feb 2022Rift Valley fever virus (RVFV) belongs to the order and is the type species of genus , which accounts for over 50% of family species. RVFV is mosquito-borne and causes...
Rift Valley fever virus (RVFV) belongs to the order and is the type species of genus , which accounts for over 50% of family species. RVFV is mosquito-borne and causes severe diseases in both humans and livestock, and consists of three segments (S, M, L) in the genome. The L segment encodes an RNA-dependent RNA polymerase (RdRp, L protein) that is responsible for facilitating the replication and transcription of the virus. It is essential for the virus and has multiple drug targets. Here, we established an expression system and purification procedures for full-length L protein, which is composed of an endonuclease domain, RdRp domain, and cap-binding domain. A cryo-EM L protein structure was reported at 3.6 Å resolution. In this first L protein structure of genus , the priming loop of RVFV L protein is distinctly different from those of other L proteins and undergoes large movements related to its replication role. Structural and biochemical analyses indicate that a single template can induce initiation of RNA synthesis, which is notably enhanced by 5' viral RNA. These findings help advance our understanding of the mechanism of RNA synthesis and provide an important basis for developing antiviral inhibitors. The zoonosis RVF virus (RVFV) is one of the most serious arbovirus threats to both human and animal health. RNA-dependent RNA polymerase (RdRp) is a multifunctional enzyme catalyzing genome replication as well as viral transcription, so the RdRp is essential for studying the virus and has multiple drug targets. In our study, we report the structure of RVFV L protein at 3.6 Å resolution by cryo-EM. This is the first L protein structure of genus . Strikingly, a single template can initiate RNA replication. The structure and assays provide a comprehensive and in-depth understanding of the catalytic and substrate recognition mechanism of RdRp.
Topics: Amino Acid Motifs; Catalytic Domain; Chemical Phenomena; Conserved Sequence; Cryoelectron Microscopy; Models, Molecular; Protein Conformation; Protein Interaction Domains and Motifs; RNA-Dependent RNA Polymerase; Recombinant Fusion Proteins; Rift Valley fever virus; Viral Proteins
PubMed: 34787453
DOI: 10.1128/JVI.01713-21 -
Antiviral Research Feb 2020Rift Valley fever phlebovirus (RVFV) is an arthropod-borne virus that has caused substantial epidemics throughout Africa and in the Arabian Peninsula. The virus can... (Review)
Review
Rift Valley fever phlebovirus (RVFV) is an arthropod-borne virus that has caused substantial epidemics throughout Africa and in the Arabian Peninsula. The virus can cause severe disease in livestock and humans and therefore the control and prevention of viral outbreaks is of utmost importance. The epidemiology of RVFV has some particular characteristics. Unexpected and significant epidemics have been observed in spatially and temporally divergent patterns across the African continent. Sudden epidemics in previously unaffected areas are followed by periods of long-term apparent absence of virus and sudden, unpredictable reoccurrence in disparate regions. Therefore, the elucidation of underlying mechanisms of viral maintenance is one of the largest gaps in the knowledge of RVFV ecology. It remains unknown whether the virus needs to be reintroduced before RVF outbreaks can occur, or if unperceived viral circulation in local vertebrates or mosquitoes is sufficient for maintenance of the virus. To gain insight into these knowledge gaps, we here review existing data that describe potential mechanisms of RVFV maintenance, as well as molecular and serological studies in endemic and non-endemic areas that provide evidence of an inter- or pre-epidemic virus presence. Basic and country-specific mechanisms of RVFV introduction into non-endemic countries are summarized and an overview of studies using mathematical modeling of RVFV persistence is given.
Topics: Animals; Antibodies, Viral; Culicidae; Epidemics; Humans; Models, Theoretical; Rift Valley Fever; Rift Valley fever virus; Seroepidemiologic Studies
PubMed: 31870761
DOI: 10.1016/j.antiviral.2019.104692 -
Viruses Jan 2021Phleboviruses transmitted by phlebotomine sandflies are endemic in the Mediterranean basin. (TOSV), (SFSV), and (SFNV) are responsible of summer fever, with...
Phleboviruses transmitted by phlebotomine sandflies are endemic in the Mediterranean basin. (TOSV), (SFSV), and (SFNV) are responsible of summer fever, with well-known pathogenic potential for humans ranging from asymptomatic to mild fever, in addition to neuro-invasive infections during summer. Although TOSV, in particular, is a significant and well-known human pathogen, SFVs remain neglected, with many gaps in the relevant knowledge. Sero-epidemiological studies and case reports recently showed a geographical wider distribution than previously considered, although the real incidence of phleboviruses infections in the Mediterranean area is still unknown. Here we retrospectively evaluated the circulation of phleboviruses during summer seasons between 2007 and 2019 in 649 patients showing neurological symptoms using both molecular and serological approaches. We found that 42/649 (6.5%) subjects experienced phlebovirus infection and only 10/42 cases were detected by molecular assays, whereas the other 32/42 were identified using serological approaches, including neutralization assays. During the 2013 summer, an outbreak in the Lombardy region is described because the prevalence of phlebovirus infection reached 37.2% (19/51 subjects). Interestingly, only 5/19 (26.5%) reported traveling in endemic areas. Of note, no cross-neutralization was observed between different strains tested, showing the possibility to be reinfected by newly discovered phlebovirus strains. In conclusion, phlebovirus infections are still inadequately considered by physicians and are generally underestimated. However, based on our results, sandfly fever viruses should be routinely included in diagnostic panels during summer period, including in Northern Italy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antibodies, Neutralizing; Female; Humans; Immunoglobulin G; Immunoglobulin M; Italy; Male; Middle Aged; Phlebotomus Fever; Phlebovirus; RNA, Viral; Retrospective Studies; Seasons; Young Adult
PubMed: 33573092
DOI: 10.3390/v13020209 -
Microbiology Spectrum Oct 2022Blood-sucking ticks are obligate parasites and vectors of a variety of human and animal viruses. Some tick-borne viruses have been identified as pathogens of infectious...
Blood-sucking ticks are obligate parasites and vectors of a variety of human and animal viruses. Some tick-borne viruses have been identified as pathogens of infectious diseases in humans or animals, potentially imposing significant public health burdens and threats to the husbandry industry. Therefore, identifying the profiles of tick-borne viruses will provide valuable information about the evolution and pathogen ecology of tick-borne viruses. In this study, we investigated the viromes of parasitic ticks collected from the body surfaces of herbivores in Xinjiang Uyghur Autonomous Region and Inner Mongolia Autonomous Region of China, two regions in northwest China. By using a metatranscriptomic approach, 17 RNA viruses with high diversity in genomic organization and evolution were identified. Among them, nine are proposed to be novel species. The classified viruses belonged to six viral families, including , , , , , and , and unclassified viruses were also identified. In addition, although some viruses from different sampling locations shared significant similarities, the abundance and diversity of viruses notably varied among the different collection locations. This study demonstrates the diversity of tick-borne viruses in Xinjiang and Inner Mongolia and provides informative data for further study of the evolution and pathogenicity of these RNA viruses. Ticks are widely distributed in pastoral areas in northwestern China and act as vectors that carry and transmit a variety of pathogens, especially viruses. Our study revealed the diversity of tick viruses in Xinjiang and Inner Mongolia and uncovered the phylogenetic relationships of some RNA viruses, especially the important zoonotic tick-borne severe fever with thrombocytopenia syndrome virus in Inner Mongolia. These data suggest a complex and diverse evolutionary history and potential ecological factors associated with pathogenic viruses. The pathogenicity of these tick-borne viruses currently remains unclear. Therefore, future research should focus on evaluating the transmissability and pathogenicity of these tick-borne viruses.
Topics: Humans; Animals; Ticks; Phylogeny; Virome; Phlebovirus; RNA Viruses; China; Viruses; Tick-Borne Diseases
PubMed: 36214702
DOI: 10.1128/spectrum.01115-22 -
The Journal of Biological Chemistry Jun 2023Severe fever with thrombocytopenia syndrome virus (SFTSV), which has been reported in China, Korea, Japan, Vietnam, and Taiwan, is a causative agent of severe fever...
Severe fever with thrombocytopenia syndrome virus (SFTSV), which has been reported in China, Korea, Japan, Vietnam, and Taiwan, is a causative agent of severe fever thrombocytopenia syndrome. This virus has a high mortality and induces thrombocytopenia and leukocytopenia in humans, cats, and aged ferrets, whereas immunocompetent adult mice infected with SFTSV never show symptoms. Anti-SFTSV antibodies have been detected in several animals-including goats, sheep, cattle, and pigs. However, there are no reports of severe fever thrombocytopenia syndrome in these animals. Previous studies have reported that the nonstructural protein NSs of SFTSV inhibits the type I interferon (IFN-I) response through the sequestration of human signal transducer and activator of transcription (STAT) proteins. In this study, comparative analysis of the function of NSs as IFN antagonists in human, cat, dog, ferret, mouse, and pig cells revealed a correlation between pathogenicity of SFTSV and the function of NSs in each animal. Furthermore, we found that the inhibition of IFN-I signaling and phosphorylation of STAT1 and STAT2 by NSs depended on the binding ability of NSs to STAT1 and STAT2. Our results imply that the function of NSs in antagonizing STAT2 determines the species-specific pathogenicity of SFTSV.
Topics: Aged; Animals; Cattle; Dogs; Humans; Mice; Ferrets; Interferon Type I; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Sheep; Signal Transduction; Swine; Thrombocytopenia; Viral Nonstructural Proteins
PubMed: 37187292
DOI: 10.1016/j.jbc.2023.104819