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The Lancet. Infectious Diseases Aug 2023
Topics: Animals; Humans; Rift Valley Fever; Rift Valley fever virus; Viral Vaccines; Antibodies, Viral
PubMed: 37060918
DOI: 10.1016/S1473-3099(23)00134-2 -
EBioMedicine Jan 2024Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes severe hemorrhagic fever in humans, but no FDA-approved specific...
BACKGROUND
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes severe hemorrhagic fever in humans, but no FDA-approved specific antivirals or vaccines are available to treat or prevent SFTS.
METHODS
The plasmids construction and transfection were performed to generate the recombinant SFTSV harboring the nanoluciferase gene (SFTSV-Nluc). Immunostaining plaque assay was performed to measure viral titers, and DNA electrophoresis and Sanger sequencing were performed to evaluate the genetic stability. Luciferase assay and quantitative RT-PCR were performed to evaluate the efficacy of antivirals in vitro. Bioluminescence imaging, titration of virus from excised organs, hematology, and histopathology and immunohistochemistry were performed to evaluate the efficacy of antivirals in vivo.
FINDINGS
SFTSV-Nluc exhibited high genetic stability and replication kinetics similar to those of wild-type virus (SFTSVwt), then a rapid high-throughput screening system for identifying inhibitors to treat SFTS was developed, and a nucleoside analog, 4-FlU, was identified to effectively inhibit SFTSV in vitro. SFTSV-Nluc mimicked the replication characteristics and localization of SFTSVwt in counterpart model mice. Bioluminescence imaging of SFTSV-Nluc allowed real-time visualization and quantification of SFTSV replication in the mice. 4-FlU was demonstrated to inhibit the replication of SFTSV with more efficiency than T-705 and without obvious adverse effect in vivo.
INTERPRETATION
The high-throughput screening system based on SFTSV-Nluc for use in vitro and in vivo revealed that a safe and effective antiviral nucleoside analog, 4-FlU, may be a basis for the strategic treatment of SFTSV and other bunyavirus infections, paving the way for the discovery of antivirals.
FUNDING
This work was supported by grants from the National Key Research and Development Plan of China (2021YFC2300700 to L. Zhang, 2022YFC2303300 to L. Zhang), Strategic Priority Research Program of Chinese Academy of Sciences (XDB0490000 to L. Zhang), National Natural Science Foundation of China (31970165 to L. Zhang, U22A20379 to G. Xiao), the Science and Technology Commission of Shanghai Municipality (21S11903100 to Y. Xie), Hubei Natural Science Foundation for Distinguished Young Scholars (2022CFA099 to L. Zhang).
Topics: Humans; Animals; Mice; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Nucleosides; China; Antiviral Agents; Fever
PubMed: 38176215
DOI: 10.1016/j.ebiom.2023.104944 -
EMBO Molecular Medicine Mar 2024Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective...
Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective therapies or vaccines available, understanding the disease's mechanisms is crucial. Recent studies found increased expression of programmed cell death-1 (PD-1) on dysfunctional T cells in SFTS patients. However, the role of the PD-1/programmed cell death-ligand 1 (PD-L1) pathway in SFTS progression remains unclear. We investigated PD-1 blockade as a potential therapeutic strategy against SFTSV replication. Our study analyzed clinical samples and performed in vitro experiments, revealing elevated PD-1/PD-L1 expression in various immune cells following SFTSV infection. An anti-PD-1 nanobody, NbP45, effectively inhibited SFTSV infection in peripheral blood mononuclear cells (PBMCs), potentially achieved through the mitigation of apoptosis and the augmentation of T lymphocyte proliferation. Intriguingly, subcutaneous administration of NbP45 showed superior efficacy compared to a licensed anti-PD-1 antibody in an SFTSV-infected humanized mouse model. These findings highlight the involvement of the PD-1/PD-L1 pathway during acute SFTSV infection and suggest its potential as a host target for immunotherapy interventions against SFTSV infection.
Topics: Animals; Humans; Mice; Bunyaviridae Infections; Phlebovirus; B7-H1 Antigen; Severe Fever with Thrombocytopenia Syndrome; Leukocytes, Mononuclear; Programmed Cell Death 1 Receptor
PubMed: 38366162
DOI: 10.1038/s44321-024-00026-0 -
The American Journal of Tropical... Dec 2023Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) belong to the severe fever with thrombocytopenia...
Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) belong to the severe fever with thrombocytopenia syndrome/Heartland group of genus Bandavirus in the family Phenuiviridae of order Bunyavirales. Severe fever with thrombocytopenia syndrome virus and HRTV, identified from ticks from Asia and America, respectively, are important pathogens causing severe febrile diseases in humans. Guertu virus, closely related to these two viruses, is a potential pathogen, but no confirmed infection has been identified. So far, human-derived neutralizing monoclonal antibodies (mAbs) against SFTSV have been identified as having a great potential to be developed as antivirals; however, there is still a lack of neutralizing mAbs to GTV and HRTV. In this study, five neutralizing the mAbs against GTV and HRTV were obtained by hybridoma screening technology, four of which (14B4, 14D8, and 20D4 derived from GTV, and 27C8 derived from HRTV) showed cross reactivity and neutralization to all three viruses, and one derived from HRTV (10D6) neutralized HRTV specifically. The possible mechanisms of mAbs cross neutralization among the three viruses are discussed by analyzing their glycoprotein (GP) sequences and structures. Generating these neutralizing mAbs provides important antiviral candidates against GTV, HRTV, and SFTSV despite their differential activities, and their protective effect could be further evaluated in virus-infected mice. Their differential neutralizing efficiency and specificity further suggested that the three viruses share common mechanisms on the basis of GP functioning, and that HRTV poses a unique mechanism that differs from the other viruses. These findings shed light on developing broad-spectrum antiviral strategies against bandaviruses and promoting an understanding of the bandavirus infection process.
Topics: Animals; Humans; Mice; Antibodies, Neutralizing; Phlebovirus; Antibodies, Monoclonal; Severe Fever with Thrombocytopenia Syndrome; Glycoproteins; RNA Viruses; Antiviral Agents
PubMed: 37931293
DOI: 10.4269/ajtmh.23-0073 -
Journal of Medical Entomology Nov 2023Heartland (HRTV) and Bourbon (BRBV) viruses are newly identified tick-borne viruses, isolated from serious clinical cases in 2009 and 2014, respectively. Both viruses... (Review)
Review
Heartland (HRTV) and Bourbon (BRBV) viruses are newly identified tick-borne viruses, isolated from serious clinical cases in 2009 and 2014, respectively. Both viruses originated in the lower Midwest United States near the border of Missouri and Kansas, cause similar disease manifestations, and are presumably vectored by the same tick species, Amblyomma americanum Linnaeus (Ixodida: Ixodidae). In this article, we provide a current review of HRTV and BRBV, including the virology, epidemiology, and ecology of the viruses with an emphasis on the tick vector. We touch on current challenges of vector control and surveillance, and we discuss future directions in the study of these emergent pathogens.
Topics: United States; Animals; Ixodidae; Ticks; Amblyomma; Phlebovirus; Missouri
PubMed: 37862097
DOI: 10.1093/jme/tjad060 -
Life Science Alliance Jul 2023Viruses with an RNA genome are often the cause of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid...
Viruses with an RNA genome are often the cause of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid insertion-mutagenized mouse embryonic cell library for clones that are resistant to Rift Valley fever virus (RVFV). This screen returned the low-density lipoprotein receptor-related protein 1 (LRP1) as a top hit, a plasma membrane protein involved in a wide variety of cell activities. Inactivation of in human cells reduced RVFV RNA levels already at the attachment and entry stages of infection. Moreover, the role of LRP1 in promoting RVFV infection was dependent on physiological levels of cholesterol and on endocytosis. In the human cell line HuH-7, LRP1 also promoted early infection stages of sandfly fever Sicilian virus and La Crosse virus, but had a minor effect on late infection by vesicular stomatitis virus, whereas encephalomyocarditis virus was entirely LRP1-independent. Moreover, siRNA experiments in human Calu-3 cells demonstrated that also SARS-CoV-2 infection benefitted from LRP1. Thus, we identified LRP1 as a host factor that supports infection by a spectrum of RNA viruses.
Topics: Animals; Humans; Mice; Low Density Lipoprotein Receptor-Related Protein-1; COVID-19; SARS-CoV-2; Rift Valley fever virus; RNA, Small Interfering; Lipoproteins, LDL
PubMed: 37072184
DOI: 10.26508/lsa.202302005 -
Clinical Microbiology and Infection :... Apr 2024
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; Severe Fever with Thrombocytopenia Syndrome; Retrospective Studies; Phlebovirus; Thrombocytopenia
PubMed: 38266706
DOI: 10.1016/j.cmi.2024.01.009 -
Zhonghua Liu Xing Bing Xue Za Zhi =... Jul 2023To understand the epidemiological characteristics of tick-borne infectious diseases (TBID) and the risk factors of severe illness and death in Hubei Province from 2016...
To understand the epidemiological characteristics of tick-borne infectious diseases (TBID) and the risk factors of severe illness and death in Hubei Province from 2016 to 2021. Based on the incidence data of fever with thrombocytopenia syndrome (SFTS), tsutsugamushi disease, typhus and other TBID reported during 2016-2021, the epidemiological analysis was conducted. Field investigation results of TBID in areas with high incidence in 2021, logistic regression analysis of population characteristics, epidemiological history and other factors were used to explore the risk factors of severe and fatal cases. In the field vector investigation, free ticks and surface ticks of the host animals in the cases' home and surrounding grassland were monitored and detected. A total of 3 826 TBID cases were reported in Hubei from 2016 to 2021, of which 71.30% (2 728/3 826) were SFTS, 13.04% (499/3 826) were tsutsugamushi disease and 15.66% (599/3 826) were typhus. A total of 44 cases died in 6 years; the fatality rate was 1.15% (44/3 826). In the peak seasons of incidence from May to July, the cases in people engaged in agriculture related work accounted for 84.61% (3 237/3 826). The incidence rate in women was higher than that in men, and the cases aged ≥50 years accounted for 81.02% of the total (3 100/3 826), and the incidence rate increased with age (<0.001). The TBID cases were distributed in 86 counties and districts in 16 prefectures (municipality). The incidence rates of different areas had significant differences (<0.05), and there was a certain spatial-temporal clustering and expasion. and were captured in the field, and the positive rates in host animals and grassland ticks were 10.94% (7/64) and 40.00% (2/5), respectively. Univariate logistic regression analysis results showed that age ≥50 years and leukocyte <2.0×10/L were risk factors for severe illness and death. The TBID reported in Hubei were mainly SFTS, tsutsugamushi disease and typhus. In order to reduce the incidence of TBID, it is necessary to strengthen the prevention and control in women aged ≥50 years and reduce field exposure and tick bites during the epidemic period.
Topics: Animals; Female; Typhus, Epidemic Louse-Borne; Scrub Typhus; Severe Fever with Thrombocytopenia Syndrome; Ticks; Communicable Diseases; Phlebovirus; China; Tick-Borne Diseases
PubMed: 37482709
DOI: 10.3760/cma.j.cn112338-20221009-00866 -
Microbiome Feb 2024Haemaphysalis longicornis is drawing attentions for its geographic invasion, extending population, and emerging disease threat. However, there are still substantial gaps...
BACKGROUND
Haemaphysalis longicornis is drawing attentions for its geographic invasion, extending population, and emerging disease threat. However, there are still substantial gaps in our knowledge of viral composition in relation to genetic diversity of H. longicornis and ecological factors, which are important for us to understand interactions between virus and vector, as well as between vector and ecological elements.
RESULTS
We conducted the meta-transcriptomic sequencing of 136 pools of H. longicornis and identified 508 RNA viruses of 48 viral species, 22 of which have never been reported. Phylogenetic analysis of mitochondrion sequences divided the ticks into two genetic clades, each of which was geographically clustered and significantly associated with ecological factors, including altitude, precipitation, and normalized difference vegetation index. The two clades showed significant difference in virome diversity and shared about one fifth number of viral species that might have evolved to "generalists." Notably, Bandavirus dabieense, the pathogen of severe fever with thrombocytopenia syndrome was only detected in ticks of clade 1, and half number of clade 2-specific viruses were aquatic-animal-associated.
CONCLUSIONS
These findings highlight that the virome diversity is shaped by internal genetic evolution and external ecological landscape of H. longicornis and provide the new foundation for promoting the studies on virus-vector-ecology interaction and eventually for evaluating the risk of H. longicornis for transmitting the viruses to humans and animals. Video Abstract.
Topics: Animals; Humans; Ixodidae; Haemaphysalis longicornis; Virome; Phylogeny; Phlebovirus; Ticks
PubMed: 38378577
DOI: 10.1186/s40168-024-01753-9 -
China CDC Weekly Aug 2023Severe fever with thrombocytopenia syndrome (SFTS) is a growing concern as an emerging tick-borne infectious disease originating from the SFTS virus (SFTSV), a recent...
Severe fever with thrombocytopenia syndrome (SFTS) is a growing concern as an emerging tick-borne infectious disease originating from the SFTS virus (SFTSV), a recent addition to the genus under the family of bunyaviruses. SFTS is typically identified by symptoms such as fever, thrombocytopenia, leukopenia, and gastrointestinal problems, accompanied by a potentially high case fatality rate. Thus, early and accurate diagnosis is essential for effective treatment and disease management. This review delves into the existing methodologies for SFTS detection, including pathogenic, molecular, and immunological technologies.
PubMed: 37593140
DOI: 10.46234/ccdcw2023.132