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EBioMedicine Feb 2024
Topics: Humans; Biology; Phlebovirus
PubMed: 38194743
DOI: 10.1016/j.ebiom.2024.104968 -
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 -
The Journal of Veterinary Medical... Feb 2024Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonotic disease, endemic to Asian regions, including western Japan. Cats appear to...
Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonotic disease, endemic to Asian regions, including western Japan. Cats appear to suffer a particularly severe form of the disease; however, feline SFTS is not clinically well characterized. Accordingly, in this study, we investigated the associations of, demographic, hematological and biochemical, immunological, and virological parameters with clinical outcome (fatal cases vs. survivors) in SFTSV-positive cats. Viral genomic analysis was also performed. Viral load in blood, total bilirubin, creatine phosphokinase, serum amyloid A, interleukin-6, tumor necrotic factor-α, and virus-specific IgM and IgG differed significantly between survivors and fatal cases, and thus may have utility as prognosticators. Furthermore, survivor profiling revealed high-level of viremia with multiple parameters (white blood cells, platelet, total bilirubin, glucose, and serum amyloid A) beyond the reference range in the 7-day acute phase, and signs of clinical recovery in the post-acute phase (parameters returning to, or tending toward, the reference range). However, SFTSV was still detectable from some survived cats even 14 days after onset of disease, indicating the risk of infection posed by close-contact exposure may persist through the post-acute phase. This study provides useful information for prognostic assessments of acute feline SFTS, and may contribute to early treatment plans for cats with SFTS. Our findings also alert pet owners and animal health professionals to the need for prolonged vigilance against animal-to-human transmission when handling cats that have been diagnosed with SFTS.
Topics: Animals; Humans; Cats; Severe Fever with Thrombocytopenia Syndrome; Prognosis; Phlebovirus; Bunyaviridae Infections; Serum Amyloid A Protein; Tick-Borne Diseases; Bilirubin; Cat Diseases
PubMed: 38171741
DOI: 10.1292/jvms.22-0427 -
Frontiers in Cellular and Infection... 2023Rift Valley fever virus (RVFV) is a (re)emerging mosquito-borne pathogen impacting human and animal health. How RVFV spreads through a population depends on...
Rift Valley fever virus (RVFV) is a (re)emerging mosquito-borne pathogen impacting human and animal health. How RVFV spreads through a population depends on population-level and individual-level interactions between vector, host and pathogen. Here, we estimated the probability for RVFV to transmit to naive animals by experimentally exposing lambs to a bite of an infectious mosquito, and assessed if and how RVFV infection subsequently developed in the exposed animal. mosquitoes, previously infected via feeding on a viremic lamb, were used to expose naive lambs to the virus. colony mosquitoes were used as they are easy to maintain and readily feed in captivity. Other mosquito spp. could be examined with similar methodology. Lambs were exposed to either 1-3 (low exposure) or 7-9 (high exposure) infectious mosquitoes. All lambs in the high exposure group became viremic and showed characteristic signs of Rift Valley fever within 2-4 days post exposure. In contrast, 3 out of 12 lambs in the low exposure group developed viremia and disease, with similar peak-levels of viremia as the high exposure group but with some heterogeneity in the onset of viremia. These results suggest that the likelihood for successful infection of a ruminant host is affected by the number of infectious mosquitoes biting, but also highlights that a single bite of an infectious mosquito can result in disease. The per bite mosquito-to-host transmission efficiency was estimated at 28% (95% confidence interval: 15 - 47%). We subsequently combined this transmission efficiency with estimates for life traits of or related mosquitoes into a Ross-McDonald mathematical model to illustrate scenarios under which major RVFV outbreaks could occur in naïve populations (i.e., R >1). The model revealed that relatively high vector-to-host ratios as well as mosquitoes feeding preferably on competent hosts are required for R to exceed 1. Altogether, this study highlights the importance of experiments that mimic natural exposure to RVFV. The experiments facilitate a better understanding of the natural progression of disease and a direct way to obtain epidemiological parameters for mathematical models.
Topics: Animals; Aedes; Mosquito Vectors; Rift Valley Fever; Rift Valley fever virus; Ruminants; Sheep; Viremia
PubMed: 38170150
DOI: 10.3389/fcimb.2023.1206089 -
The Journal of Veterinary Medical... Feb 2024Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease caused by a tick-borne virus called severe fever with thrombocytopenia syndrome virus...
Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease caused by a tick-borne virus called severe fever with thrombocytopenia syndrome virus (SFTSV). In recent years, human infections through contact with ticks and through contact with the bodily fluids of infected dogs and cats have been reported; however, no vaccine is currently available. SFTSV has two glycoproteins (Gn and Gc) on its envelope, which are vaccine-target antigens involved in immunogenicity. In the present study, we constructed novel SFTS vaccine candidates using an adeno-associated virus (AAV) vector to transport the SFTSV glycoprotein genome. AAV vectors are widely used in gene therapy and their safety has been confirmed in clinical trials. Recently, AAV vectors have been used to develop influenza and SARS-CoV-2 vaccines. Two types of vaccines (AAV9-SFTSV Gn and AAV9-SFTSV Gc) carrying SFTSV Gn and Gc genes were produced. The expression of Gn and Gc proteins in HEK293T cells was confirmed by infection with vaccines. These vaccines were inoculated into mice, and the collected sera produced anti-SFTS antibodies. Furthermore, sera from AAV9-SFTSV Gn infected mice showed a potent neutralizing ability, similar to previously reported SFTS vaccine candidates that protected animals from SFTSV infection. These findings suggest that this vaccine is a promising candidate for a new SFTS vaccine.
Topics: Animals; Humans; Cats; Mice; Dogs; Severe Fever with Thrombocytopenia Syndrome; Dependovirus; Phlebovirus; Bunyaviridae Infections; COVID-19 Vaccines; Cat Diseases; HEK293 Cells; Dog Diseases; Glycoproteins; Thrombocytopenia; Rodent Diseases
PubMed: 38143087
DOI: 10.1292/jvms.23-0375 -
Viruses Dec 2023Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonotic disease caused by the SFTS virus (SFTSV). In Thailand, three human cases of SFTS...
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonotic disease caused by the SFTS virus (SFTSV). In Thailand, three human cases of SFTS were reported in 2019 and 2020, but there was no report of SFTSV infection in animals. Our study revealed that at least 16.6% of dogs in Thailand were seropositive for SFTSV infection, and the SFTSV-positive dogs were found in several districts in Thailand. Additionally, more than 70% of the serum samples collected at one shelter possessed virus-neutralization antibodies against SFTSV and the near-complete genome sequences of the SFTSV were determined from one dog in the shelter. The dog SFTSV was genetically close to those from Thailand and Chinese patients and belonged to genotype J3. These results indicated that SFTSV has already spread among animals in Thailand.
Topics: Animals; Humans; Dogs; Severe Fever with Thrombocytopenia Syndrome; Bunyaviridae Infections; Seroepidemiologic Studies; Thailand; Antibodies, Viral; Phlebovirus; Tick-Borne Diseases
PubMed: 38140644
DOI: 10.3390/v15122403 -
Viruses Nov 2023Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing disease in livestock and humans. Whilst initially restricted to the African continent,...
Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing disease in livestock and humans. Whilst initially restricted to the African continent, recent spread to the Arabian Peninsula has highlighted the likelihood of entry into new regions. Due to the absence of a regulatory-approved human vaccine, work is ongoing to develop and assess countermeasures. As such, small animal models play a pivotal role in providing information on disease pathogenesis and elucidating which intervention strategies confer protection. To develop and establish the BALB/c mouse model, we challenged mice with RVFV grown from two separate cell lines: one derived from mosquitoes (C6/36) and the other mammalian derived (Vero E6). Following infection, we assessed the clinical course of disease progression at days 1 and 3 post-challenge and evaluated viral tropism and immune analytes. The results demonstrated that RVFV infection was affected by the cell line used to propagate the challenge virus, with those grown in insect cells resulting in a more rapid disease progression. The lowest dose that caused uniform severe disease remained the same across both virus preparations. In addition, to demonstrate reproducibility, the lowest dose was used for a subsequent infection study using male and female animals. The results further demonstrated that male mice succumbed to infection more rapidly than their female counterparts. Our results establish an RVFV mouse model and key parameters that affect the course of disease progression in BALB/c mice.
Topics: Male; Female; Humans; Animals; Mice; Rift Valley fever virus; Rift Valley Fever; Mice, Inbred BALB C; Reproducibility of Results; Disease Progression; Mammals
PubMed: 38140610
DOI: 10.3390/v15122369 -
Viruses Nov 2023Mudanjiang phlebovirus (MJPV) is a newly discovered phlebovirus, initially detected from ticks in China in 2022. In this study, by next-generation sequencing (NGS) on a...
Mudanjiang phlebovirus (MJPV) is a newly discovered phlebovirus, initially detected from ticks in China in 2022. In this study, by next-generation sequencing (NGS) on a wide variety of ticks and wild small animals in China, we detected MJPV from and . Additionally, we conducted RT-PCR and sequencing on 1815 adult ticks and 805 wild small mammals collected from eight provinces in China between 2017 and 2021. MJPV RNA-positive results were found in 0.22% (4/1815) of tick samples, as well as in 0.12% (1/805) of rodent samples. All positive detections were obtained from Heilongjiang and Inner Mongolia. Sequencing analysis revealed nucleotide similarities ranging from 98.23% to 99.11%, as well as amino acid similarities ranging from 99.12% to100%, between the current MJPV strain and previously reported strains of MJPV. Phylogenetic tree analysis demonstrated that the previously reported MJPV strain along with our two variants clustered together with other tick-borne phenuiviruses, indicating their close relationship within this viral group. This study represents the first detection of MJPV infection in wild rodents, expanding the known host range for this virus in the endemic regions.
Topics: Animals; Phlebovirus; Phylogeny; Ixodes; Animals, Wild; Viruses; Rodentia; China
PubMed: 38140594
DOI: 10.3390/v15122353 -
Viruses Nov 2023Severe Fever with Thrombocytopenia Syndrome (SFTS), caused by the SFTS Virus (SFTSV), is a global health threat. SFTSV in Taiwan has only been reported in ruminants and...
Severe Fever with Thrombocytopenia Syndrome (SFTS), caused by the SFTS Virus (SFTSV), is a global health threat. SFTSV in Taiwan has only been reported in ruminants and wild animals. Thus, we aimed to investigate the infection statuses of dogs and cats, the animals with closer human interactions. Overall, the SFTSV RNA prevalence was 23% (170/735), with dogs showing a 25.9% (111/429) prevalence and cats at 19.3% (59/306) prevalence. Noticeably, the prevalence in stray animals (39.8% 77/193) was significantly higher than in domesticated ones (17.2%, 93/542). Among the four categories analyzed, the highest SFTSV prevalence was found in the stray dogs at 53.9% (120/193), significantly higher than the 24.2% prevalence noted in stray cats. In contrast, domesticated animals exhibited similar prevalence rates, with 17.1% for dogs and 17.2% for cats. It is noteworthy that in the domesticated animal groups, a significantly elevated prevalence (45%, 9/20) was observed among cats exhibiting thrombocytopenia compared to those platelet counts in the reference range (4.8%, 1/21). The high infection rate in stray animals, especially stray dogs, indicated that exposure to various outdoor environments influences the prevalence of infections. Given the higher human interaction with dogs and cats, there is a need for proactive measures to reduce the risk associated with the infection of SFTSV in both animals and humans.
Topics: Animals; Cats; Humans; Dogs; Severe Fever with Thrombocytopenia Syndrome; Bunyaviridae Infections; Taiwan; Cat Diseases; Dog Diseases; Phlebovirus; Animals, Wild; Animals, Domestic
PubMed: 38140579
DOI: 10.3390/v15122338 -
Microorganisms Dec 2023Vector-borne viral diseases (VBVDs) continue to pose a considerable public health risk to animals and humans globally. Vectors have integral roles in autochthonous... (Review)
Review
Vector-borne viral diseases (VBVDs) continue to pose a considerable public health risk to animals and humans globally. Vectors have integral roles in autochthonous circulation and dissemination of VBVDs worldwide. The interplay of agricultural activities, population expansion, urbanization, host/pathogen evolution, and climate change, all contribute to the continual flux in shaping the epidemiology of VBVDs. In recent decades, VBVDs, once endemic to particular countries, have expanded into new regions such as Iran and its neighbors, increasing the risk of outbreaks and other public health concerns. Both Iran and its neighboring countries are known to host a number of VBVDs that are endemic to these countries or newly circulating. The proximity of Iran to countries hosting regional diseases, along with increased global socioeconomic activities, e.g., international trade and travel, potentially increases the risk for introduction of new VBVDs into Iran. In this review, we examined the epidemiology of numerous VBVDs circulating in Iran, such as Chikungunya virus, Dengue virus, Sindbis virus, West Nile virus, Crimean-Congo hemorrhagic fever virus, Sandfly-borne phleboviruses, and Hantavirus, in relation to their vectors, specifically mosquitoes, ticks, sandflies, and rodents. In addition, we discussed the interplay of factors, e.g., urbanization and climate change on VBVD dissemination patterns and the consequent public health risks in Iran, highlighting the importance of a One Health approach to further surveil and to evolve mitigation strategies.
PubMed: 38138150
DOI: 10.3390/microorganisms11123006