scholarly journals Modeling Severe Fever with Thrombocytopenia Syndrome Virus Infection in Golden Syrian Hamsters: Importance of STAT2 in Preventing Disease and Effective Treatment with Favipiravir

2016 ◽  
Vol 91 (3) ◽  
Author(s):  
Brian B. Gowen ◽  
Jonna B. Westover ◽  
Jinxin Miao ◽  
Arnaud J. Van Wettere ◽  
Johanna D. Rigas ◽  
...  
Keyword(s):  
South Korea ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Etiologic Agent ◽  
Genetically Engineered ◽  
Medical Attention ◽  
Type I ◽  
Hamster Model ◽  
Content Type ◽  
Severe Fever

ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease endemic in parts of Asia. The etiologic agent, SFTS virus (SFTSV; family Bunyaviridae, genus Phlebovirus) has caused significant morbidity and mortality in China, South Korea, and Japan, with key features of disease being intense fever, thrombocytopenia, and leukopenia. Case fatality rates are estimated to be in the 30% range, and no antivirals or vaccines are approved for use for treatment and prevention of SFTS. There is evidence that in human cells, SFTSV sequesters STAT proteins in replication complexes, thereby inhibiting type I interferon signaling. Here, we demonstrate that hamsters devoid of functional STAT2 are highly susceptible to as few as 10 PFU of SFTSV, with animals generally succumbing within 5 to 6 days after subcutaneous challenge. The disease included marked thrombocytopenia and inflammatory disease characteristic of the condition in humans. Infectious virus titers were present in the blood and most tissues 3 days after virus challenge, and severe inflammatory lesions were found in the spleen and liver samples of SFTSV-infected hamsters. We also show that SFTSV infection in STAT2 knockout (KO) hamsters is responsive to favipiravir treatment, which protected all animals from lethal disease and reduced serum and tissue viral loads by 3 to 6 orders of magnitude. Taken together, our results provide additional insights into the pathogenesis of SFTSV infection and support the use of the newly described STAT2 KO hamster model for evaluation of promising antiviral therapies. IMPORTANCE Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease for which there are currently no therapeutic options or available vaccines. The causative agent, SFTS virus (SFTSV), is present in China, South Korea, and Japan, and infections requiring medical attention result in death in as many as 30% of the cases. Here, we describe a novel model of SFTS in hamsters genetically engineered to be deficient in a protein that helps protect humans and animals against viral infections. These hamsters were found to be susceptible to SFTSV and share disease features associated with the disease in humans. Importantly, we also show that SFTSV infection in hamsters can be effectively treated with a broad-spectrum antiviral drug approved for use in Japan. Our findings suggest that the new SFTS model will be an excellent resource to better understand SFTSV infection and disease as well as a valuable tool for evaluating promising antiviral drugs.

scholarly journals Species-Specific Pathogenicity of Severe Fever with Thrombocytopenia Syndrome Virus Is Determined by Anti-STAT2 Activity of NSs

2019 ◽  
Vol 93 (10) ◽  
Author(s):  
Rokusuke Yoshikawa ◽  
Saori Sakabe ◽  
Shuzo Urata ◽  
Jiro Yasuda
Keyword(s):  
Innate Immunity ◽  
South Korea ◽  
Nonstructural Protein ◽  
Case Fatality ◽  
Type I ◽  
Type I Ifn ◽  
Gene Encoding ◽  
Syrian Hamsters ◽  
Severe Fever ◽  
Deficient Mice

ABSTRACT Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel emerging virus that has been identified in China, South Korea, and Japan, and it induces thrombocytopenia and leukocytopenia in humans with a high case fatality rate. SFTSV is pathogenic to humans, while immunocompetent adult mice and golden Syrian hamsters infected with SFTSV never show apparent symptoms. However, mice deficient for the gene encoding the α chain of the alpha- and beta-interferon receptor (Ifnar1−/− mice) and golden Syrian hamsters deficient for the gene encoding signal transducer and activator of transcription 2 (Stat2−/− hamsters) are highly susceptible to SFTSV infection, with infection resulting in death. The nonstructural protein (NSs) of SFTSV has been reported to inhibit the type I IFN response through sequestration of human STAT proteins. Here, we demonstrated that SFTSV induces lethal acute disease in STAT2-deficient mice but not in STAT1-deficient mice. Furthermore, we discovered that NSs cannot inhibit type I IFN signaling in murine cells due to an inability to bind to murine STAT2. Taken together, our results imply that the dysfunction of NSs in antagonizing murine STAT2 can lead to inefficient replication and the loss of pathogenesis of SFTSV in mice. IMPORTANCE Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTSV, which has been reported in China, South Korea, and Japan. Here, we revealed that mice lacking STAT2, which is an important factor for antiviral innate immunity, are highly susceptible to SFTSV infection. We also show that SFTSV NSs cannot exert its anti-innate immunity activity in mice due to the inability of the protein to bind to murine STAT2. Our findings suggest that the dysfunction of SFTSV NSs as an IFN antagonist in murine cells confers a loss of pathogenicity of SFTSV in mice.

scholarly journals Reverse Genetics System for Severe Fever with Thrombocytopenia Syndrome Virus

2014 ◽  
Vol 89 (6) ◽  
pp. 3026-3037 ◽  
Author(s):  
Benjamin Brennan ◽  
Ping Li ◽  
Shuo Zhang ◽  
Aqian Li ◽  
Mifang Liang ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Far East ◽  
Gastrointestinal Symptoms ◽  
Case Fatality ◽  
The United States ◽  
Cdna Clones ◽  
Wild Type ◽  
Content Type ◽  
Recombinant Viruses ◽  
Severe Fever

ABSTRACTSevere fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that was first reported in China in 2009. Phylogenetic analysis of the viral genome showed thatSFTS virusrepresents a new lineage within thePhlebovirusgenus, distinct from the existing sandfly fever and Uukuniemi virus groups, in the familyBunyaviridae. SFTS disease is characterized by gastrointestinal symptoms, chills, joint pain, myalgia, thrombocytopenia, leukocytopenia, and some hemorrhagic manifestations with a case fatality rate of about 2 to 15%. Here we report the development of reverse genetics systems to study STFSV replication and pathogenesis. We developed and optimized functional T7 polymerase-based M- and S-segment minigenome assays, which revealed errors in the published terminal sequences of the S segment of the Hubei 29 strain of SFTSV. We then generated recombinant viruses from cloned cDNAs prepared to the antigenomic RNAs both of the minimally passaged virus (HB29) and of a cell culture-adapted strain designated HB29pp. The growth properties, pattern of viral protein synthesis, and subcellular localization of viral N and NSs proteins of wild-type HB29pp (wtHB29pp) and recombinant HB29pp viruses were indistinguishable. We also show that the viruses fail to shut off host cell polypeptide production. The robust reverse genetics system described will be a valuable tool for the design of therapeutics and the development of killed and attenuated vaccines against this important emerging pathogen.IMPORTANCESFTSV and related tick-borne phleboviruses such as Heartland virus are emerging viruses shown to cause severe disease in humans in the Far East and the United States, respectively. Study of these novel pathogens would be facilitated by technology to manipulate these viruses in a laboratory setting using reverse genetics. Here, we report the generation of infectious SFTSV from cDNA clones and demonstrate that the behavior of recombinant viruses is similar to that of the wild type. This advance will allow for further dissection of the roles of each of the viral proteins in the context of virus infection, as well as help in the development of antiviral drugs and protective vaccines.

scholarly journals Therapeutic effects of favipiravir against severe fever with thrombocytopenia syndrome virus infection in a lethal mouse model: dose-efficacy studies upon oral administration

2018 ◽  
Author(s):  
Hideki Tani ◽  
Takashi Komeno ◽  
Aiko Fukuma ◽  
Shuetsu Fukushi ◽  
Satoshi Taniguchi ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Oral Administration ◽  
Post Infection ◽  
Case Fatality Rate ◽  
Case Fatality ◽  
Type I ◽  
Fatality Rate ◽  
High Case Fatality Rate ◽  
Severe Fever

AbstractBackgroundSevere fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), is a viral hemorrhagic fever with a high case fatality rate. Favipiravir was reported to be effective in the treatment of SFTSV infection in vivo in type I interferon receptor knockout (IFNAR-/-) mice at treatment dosages of both 60 mg/kg/day and 300 mg/kg/day for a duration of 5 days.MethodsIn this study, the efficacy of favipiravir at dosages of 120 mg/kg/day and 200 mg/kg/day against SFTSV infection in an IFNAR-/- mouse infection model was investigated. IFNAR-/- mice were subcutaneously infected with SFTSV at a 1.0 × 106 50% tissue culture infectious dose followed by twice daily administration of favipiravir, comprising a total dose of either 120 mg/kg/day or 200 mg/kg/day. The treatment was initiated either immediately post infection or at predesignated time points post infection.ResultsAll mice treated with favipiravir at dosages of 120 mg/kg/day or 200 mg/kg/day survived when the treatment was initiated at no later than 4 days post infection. A decrease in body weight of mice was observed when the treatment was initiated at 3–4 days post infection. Furthermore, all control mice died. The body weight of mice did not decrease when treatment with favipiravir was initiated immediately post infection at dosages of 120 mg/kg/day and 200 mg/kg/day.ConclusionsSimilar to the literature-reported peritoneal administration of favipiravir at 300 mg/kg/day, the oral administration of favipiravir at dosages of 120 mg/kg/day and 200 mg/kg/day to IFNAR-/- mice infected with SFTSV was effective.Author summarySevere fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), is a generalized infectious disease with a high case fatality rate. Currently, no effective therapeutics for SFTS is available; therefore, the development of effective antiviral drugs is needed. Favipiravir exhibits antiviral activity against various RNA viruses, including SFTSV. The present study demonstrated the efficacy of favipiravir in the treatment of SFTSV infection in a lethal mouse model, when the dose was set similar to that approved for anti-influenza drug in humans by the Ministry of Health, Labour and Welfare, Japan. The present study suggests that favipiravir is a promising drug for the treatment of SFTSV infection.

scholarly journals Vaccine Development for Severe Fever with Thrombocytopenia Syndrome

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 627
Author(s):  
Tomoki Yoshikawa
Keyword(s):  
Animal Models ◽  
Vaccine Development ◽  
Viral Vector ◽  
Case Fatality ◽  
Small Animal ◽  
Primate Model ◽  
Hamster Model ◽  
Vaccine Candidates ◽  
Cat Model ◽  
Severe Fever

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.

scholarly journals M Segment-Based Minigenome System of Severe Fever with Thrombocytopenia Syndrome Virus as a Tool for Antiviral Drug Screening

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1061
Author(s):  
Hiroshi Yamada ◽  
Satoshi Taniguchi ◽  
Masayuki Shimojima ◽  
Long Tan ◽  
Miyuki Kimura ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Rna Synthesis ◽  
Severe Disease ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Polymerase Activity ◽  
Small Scale ◽  
Drug Development Research ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case fatality rates of approximately 30%. There are few treatment options for SFTSV infection. SFTSV RNA synthesis is conducted using a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are, therefore, potential antiviral targets. A library of small molecule compounds was processed using a high-throughput screening (HTS) based on an SFTSV minigenome assay (MGA) in a 96-well microplate format to identify potential lead inhibitors of SFTSV RNA synthesis. The assay confirmed inhibitory activities of previously reported SFTSV inhibitors, favipiravir and ribavirin. A small-scale screening using MGA identified four candidate inhibitors that inhibited SFTSV minigenome activity by more than 80% while exhibiting less than 20% cell cytotoxicity with selectivity index (SI) values of more than 100. These included mycophenolate mofetil, methotrexate, clofarabine, and bleomycin. Overall, these data demonstrate that the SFTSV MGA is useful for anti-SFTSV drug development research.

scholarly journals AMA1-Deficient Toxoplasma gondii Parasites Transiently Colonize Mice and Trigger an Innate Immune Response That Leads to Long-Lasting Protective Immunity

2015 ◽  
Vol 83 (6) ◽  
pp. 2475-2486 ◽  
Author(s):  
Vanessa Lagal ◽  
Márcia Dinis ◽  
Dominique Cannella ◽  
Daniel Bargieri ◽  
Virginie Gonzalez ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Distinct Type ◽  
Genetically Engineered ◽  
Host Cells ◽  
Type I ◽  
Content Type ◽  
Apical Membrane Antigen 1 ◽  
Immunocompromised Mice

The apical membrane antigen 1 (AMA1) protein was believed to be essential for the perpetuation of two Apicomplexa parasite genera,PlasmodiumandToxoplasma, until we genetically engineered viable parasites lackingAMA1. The reduction in invasiveness of theToxoplasma gondiiRH-AMA1 knockout (RH-AMA1KO) tachyzoite population,in vitro, raised key questions about the outcome associated with these tachyzoites once inoculated in the peritoneal cavity of mice. In this study, we used AMNIS technology to simultaneously quantify and image the parasitic process driven by AMA1KOtachyzoites. We report their ability to colonize and multiply in mesothelial cells and in both resident and recruited leukocytes. While the RH-AMA1KOpopulation amplification is rapidly lethal in immunocompromised mice, it is controlled in immunocompetent hosts, where immune cells in combination sense parasites and secrete proinflammatory cytokines. This innate response further leads to a long-lasting status immunoprotective against a secondary challenge by high inocula of the homologous type I or a distinct type IIT. gondiigenotypes. While AMA1 is definitively not an essential protein for tachyzoite entry and multiplication in host cells, it clearly assists the expansion of parasite populationin vivo.

scholarly journals Origins of Yersinia pestis Sensitivity to the Arylomycin Antibiotics and the Inhibition of Type I Signal Peptidase

2015 ◽  
Vol 59 (7) ◽  
pp. 3887-3898 ◽  
Author(s):  
Danielle B. Steed ◽  
Jian Liu ◽  
Elizabeth Wasbrough ◽  
Lynda Miller ◽  
Stephanie Halasohoris ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Protein Secretion ◽  
Lipid A ◽  
Etiologic Agent ◽  
Signal Peptidase ◽  
Type I ◽  
Small Contribution ◽  
Content Type ◽  
Lipopeptide Antibiotics ◽  
Signal Peptidase I

ABSTRACTYersinia pestisis the etiologic agent of the plague. Reports ofY. pestisstrains that are resistant to each of the currently approved first-line and prophylactic treatments point to the urgent need to develop novel antibiotics with activity against the pathogen. We previously reported thatY. pestisstrain KIM6+, unlike mostEnterobacteriaceae, is susceptible to the arylomycins, a novel class of natural-product lipopeptide antibiotics that inhibit signal peptidase I (SPase). In this study, we show that the arylomycin activity is conserved against a broad range ofY. pestisstrains and confirm that it results from the inhibition of SPase. We next investigated the origins of this unique arylomycin sensitivity and found that it does not result from an increased affinity of theY. pestisSPase for the antibiotic and that alterations to each component of theY. pestislipopolysaccharide—O antigen, core, and lipid A—make at most only a small contribution. Instead, the origins of the sensitivity can be traced to an increased dependence on SPase activity that results from high levels of protein secretion under physiological conditions. These results highlight the potential of targeting protein secretion in cases where there is a heavy reliance on this process and also have implications for the development of the arylomycins as an antibiotic with activity againstY. pestisand potentially other Gram-negative pathogens.

scholarly journals 2308. Comparison of Clinical Characteristics Between Laboratory-Confirmed Positive and Negative Patients with Severe Fever with Thrombocytopenia Syndrome

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S791-S791
Author(s):  
Suhyun Oh ◽  
Jeong Rae You ◽  
Sang Taek Heo ◽  
Sujin Jo
Keyword(s):  
South Korea ◽  
Clinical Characteristics ◽  
Close Contact ◽  
Case Fatality ◽  
Oral Intake ◽  
Outdoor Temperature ◽  
Rt Pcr ◽  
Laboratory Findings ◽  
Cell Counts ◽  
Severe Fever

Abstract Background Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne emerging infectious disease caused by SFTS virus (SFTSV). Mortality of SFTS estimated to be 21.8% in South Korea, and this disease is difficult differential diagnosis. Here, we analyzed clinical characteristics between SFTS positive group (SPG) and negative group (SNG) in a primary clinical setting. Methods In this prospective observational study, data were collected on patients with SFTS test performed at the single teaching hospital, in South Korea, between April 2013 and December 2018. The association between each demographic, climatic, clinical, and laboratory variable was assessed. All SFTS was confirmed at the KCDC by detecting the M segment gene of SFTSV RNA using reverse transcription-polymerase chain reaction (RT–PCR), and were confirmed at our laboratory by S segment gene of SFTSV RNA using RT–PCR about patient’s family member and those with close contact. Results Of the 199 patients in the study periods, 61 (31%) were SPG and 138 (69%) were SNG. Mean age was 55.1 ± 20.3 years, and 103 (52%) patients were male. In SPG, the comorbidity score and history of tick bite were significantly higher compared with SNG. SPG and SNG were prevalent in summer and autumn, respectively (60.7% vs. 45.7%, P < 0.05). SPG was associated with mean outdoor temperature, humidity and rainfall compared with SNG (22.9°Cvs. 18.9 ℃; 78.8% vs. 70.6%; 12.6 mm vs. 8.5 mm, all P < 0.01). Dizziness, poor oral intake, nausea, and diarrhea were common in SPG. In laboratory findings, white blood cell counts, absolute neutrophil count, and C-reactive protein were significantly lower in SPG. Lymphocyte fraction, activated partial thromboplastin time, and creatinine phosphokinase were significantly higher in SPG. Case fatality of the SPG and SNG were 9.8% and 1.0%, respectively. In multivariate analysis, mean outdoor temperature, humidity, dizziness, and low CRP were predictive factors in SPG. Conclusion Early prediction of SFTS diagnosis is important because this emerging zoonotic disease was a high fatality in endemic areas. When a physician wants to do SFTS test, they would consider according to this predictive variable for differentiating SFTS in primary care settings. Disclosures All authors: No reported disclosures.

scholarly journals M Segment-Based Minigenome System of Severe Fever with Thrombocytopenia Syndrome Virus as a Tool for Antiviral Drug Screening

2021 ◽  
Author(s):  
Hiroshi Yamada ◽  
Satoshi Taniguchi ◽  
Masayuki Shimojima ◽  
Long Tan ◽  
Miyuki Kimura ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Rna Synthesis ◽  
Severe Disease ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Polymerase Activity ◽  
Small Scale ◽  
Drug Development Research ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case fatality rates of approximately 30%. There are few treatment options for SFTSV infection. SFTSV RNA synthesis is conducted using a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are, therefore, potential antiviral targets. A library of small molecule compounds was screened using a high-throughput screening (HTS) based on an SFTSV minigenome assay (MGA) in a 96-well microplate format to identify potential lead inhibitors of SFTSV RNA synthesis. The assay confirmed inhibitory activities of previously reported SFTSV inhibitors, favipiravir, and ribavirin. A small-scale screening using MGA identified four candidate inhibitors that inhibited SFTSV minigenome activity by more than 80% while exhibiting less than 20% cell cytotoxicity with selectivity index (SI) values of more than 100. These included mycophenolate mofetil, methotrexate, clofarabine, and bleomycin. Overall, these data demonstrate that the SFTSV MGA is useful for anti-SFTSV drug development research.

scholarly journals Draft Genome Sequence of Urease-Producing Pseudorhodobacter sp. Strain E13, Isolated from the Yellow Sea in Gunsan, South Korea

2019 ◽  
Vol 8 (23) ◽  
Author(s):  
Si Chul Kim ◽  
Hyo Jung Lee
Keyword(s):  
South Korea ◽  
Genome Sequence ◽  
Yellow Sea ◽  
Draft Genome ◽  
The Yellow Sea ◽  
Draft Genome Sequence ◽  
Protein Coding ◽  
Coding Sequences ◽  
Gram Negative ◽  
Content Type

Here, we report the draft genome sequence of Pseudorhodobacter sp. strain E13, a Gram-negative, aerobic, nonflagellated, and rod-shaped bacterium which was isolated from the Yellow Sea in South Korea. The assembled genome sequence is 3,878,578 bp long with 3,646 protein-coding sequences in 159 contigs.

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