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Nature Microbiology Jan 2023Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by a phlebovirus in the Bunyaviridae family. Infection can result in systemic...
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by a phlebovirus in the Bunyaviridae family. Infection can result in systemic inflammatory response syndrome with a high fatality rate, and there are currently no treatments or vaccines available. The microbiota has been implicated in host susceptibility to systemic viral infection and disease outcomes, but whether the gut microbiota is implicated in severe fever with thrombocytopenia syndrome virus (SFTSV) infection is unknown. Here, we analysed faecal and serum samples from patients with SFTS using 16S ribosomal RNA-sequencing and untargeted metabolomics, respectively. We found that the gut commensal Akkermansia muciniphila increased in relative abundance over the course of infection and was reduced in samples from deceased patients. Using germ-free or oral antibiotic-treated mice, we found that A. muciniphila produces the β-carboline alkaloid harmaline, which protects against SFTSV infection by suppressing NF-κB-mediated systemic inflammation. Harmaline indirectly modulated the virus-induced inflammatory response by specifically enhancing bile acid-CoA: amino acid N-acyltransferase expression in hepatic cells to increase conjugated primary bile acids, glycochenodeoxycholic acid and taurochenodeoxycholic acid. These bile acids induced transmembrane G-protein coupled receptor-5-dependent anti-inflammatory responses. These results indicate the probiotic potential of A. muciniphila in mitigating SFTSV infection.
Topics: Animals; Mice; Bunyaviridae Infections; Severe Fever with Thrombocytopenia Syndrome; Harmaline; Phlebovirus; Ticks
PubMed: 36604506
DOI: 10.1038/s41564-022-01279-6 -
Frontiers in Immunology 2022Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), poses a serious threat to global public health, with high fatalities and an... (Review)
Review
Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), poses a serious threat to global public health, with high fatalities and an increasing prevalence. As effective therapies and prevention strategies are limited, there is an urgent need to elucidate the pathogenesis of SFTS. SFTSV has evolved several mechanisms to escape from host immunity. In this review, we summarize the mechanisms through which SFTSV escapes host immune responses, including the inhibition of innate immunity and evasion of adaptive immunity. Understanding the pathogenesis of SFTS will aid in the development of new strategies for the treatment of this disease.
Topics: Bunyaviridae Infections; Humans; Immunity, Innate; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome
PubMed: 35967309
DOI: 10.3389/fimmu.2022.937684 -
International Journal of Molecular... Sep 2022Severe fever with thrombocytopenia syndrome (SFTS) has been acknowledged as an emerging infectious disease that is caused by the SFTS virus (SFTSV). The main clinical... (Review)
Review
Severe fever with thrombocytopenia syndrome (SFTS) has been acknowledged as an emerging infectious disease that is caused by the SFTS virus (SFTSV). The main clinical features of SFTS on presentation include fever, thrombocytopenia, leukocytopenia and gastrointestinal symptoms. The mortality rate is estimated to range between 5‑30% in East Asia. However, SFTSV infection is increasing on an annual basis globally and is becoming a public health problem. The transmission cycle of SFTSV remains poorly understood, which is compounded by the pathogenesis of SFTS not being fully elucidated. Since the mechanism underlying the host immune response towards SFTSV is also unclear, there are no effective vaccines or specific therapeutic agents against SFTS, with supportive care being the only realistic option. Therefore, it is now crucial to understand all aspects of the host‑virus interaction following SFTSV infection, including the antiviral states and viral evasion mechanisms. In the present review, recent research progress into the possible host immune responses against SFTSV was summarized, which may be useful in designing novel therapeutics against SFTS.
Topics: Bunyaviridae Infections; Humans; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Thrombocytopenia
PubMed: 35856413
DOI: 10.3892/ijmm.2022.5174 -
Nature Communications Oct 2023The severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne human-infecting bunyavirus, which utilizes two envelope glycoproteins, Gn and Gc, to enter...
The severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne human-infecting bunyavirus, which utilizes two envelope glycoproteins, Gn and Gc, to enter host cells. However, the structure and organization of these glycoproteins on virion surface are not yet known. Here we describe the structure of SFTSV determined by single particle reconstruction, which allows mechanistic insights into bunyavirus assembly at near-atomic resolution. The SFTSV Gn and Gc proteins exist as heterodimers and further assemble into pentameric and hexameric peplomers, shielding the Gc fusion loops by both intra- and inter-heterodimer interactions. Individual peplomers are associated mainly through the ectodomains, in which the highly conserved glycans on N914 of Gc play a crucial role. This elaborate assembly stabilizes Gc in the metastable prefusion conformation and creates some cryptic epitopes that are only accessible in the intermediate states during virus entry. These findings provide an important basis for developing vaccines and therapeutic drugs.
Topics: Humans; Viral Envelope Proteins; Severe Fever with Thrombocytopenia Syndrome; Cryoelectron Microscopy; Phlebovirus; Glycoproteins; Orthobunyavirus
PubMed: 37816705
DOI: 10.1038/s41467-023-41804-7 -
Autophagy Jul 2022Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging negatively stranded enveloped RNA bunyavirus that causes SFTS with a high case fatality rate of...
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging negatively stranded enveloped RNA bunyavirus that causes SFTS with a high case fatality rate of up to 30%. Macroautophagy/autophagy is an evolutionarily conserved process involved in the maintenance of host homeostasis, which exhibits anti-viral or pro-viral responses in reaction to different viral challenges. However, the interaction between the bunyavirus SFTSV and the autophagic process is still largely unclear. By establishing various autophagy-deficient cell lines, we found that SFTSV triggered RB1CC1/FIP200-BECN1-ATG5-dependent classical autophagy flux. SFTSV nucleoprotein induced BECN1-dependent autophagy by disrupting the BECN1-BCL2 association. Importantly, SFTSV utilized autophagy for the viral life cycle, which not only assembled in autophagosomes derived from the ERGIC and Golgi complex, but also utilized autophagic vesicles for exocytosis. Taken together, our results suggest a novel virus-autophagy interaction model in which bunyavirus SFTSV induces classical autophagy flux for viral assembly and egress processes, suggesting that autophagy inhibition may be a novel therapy for treating or releasing SFTS.
Topics: Autophagy; Humans; Orthobunyavirus; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Virus Assembly
PubMed: 34747299
DOI: 10.1080/15548627.2021.1994296 -
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 -
Antiviral Research Mar 2022Human infection with Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne pathogen in the family Nairoviridae, can result in a spectrum of outcomes, ranging from... (Review)
Review
Human infection with Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne pathogen in the family Nairoviridae, can result in a spectrum of outcomes, ranging from asymptomatic infection through mild clinical signs to severe or fatal disease. Studies of CCHFV immunobiology have investigated the relationship between innate and adaptive immune responses with disease severity, attempting to elucidate factors associated with differential outcomes. In this article, we begin by highlighting unanswered questions, then review current efforts to answer them. We discuss in detail current clinical studies and research in laboratory animals on CCHF, including immune targets of infection and adaptive and innate immune responses. We summarize data about the role of the immune response in natural infections of animals and humans and experimental studies in vitro and in vivo and from evaluating immune-based therapies and vaccines, and present recommendations for future research.
Topics: Animals; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Ticks
PubMed: 35026307
DOI: 10.1016/j.antiviral.2022.105244 -
Viruses May 2021Negative-strand (-) RNA viruses (NSVs) comprise a large and diverse group of viruses that are generally divided in those with non-segmented and those with segmented... (Review)
Review
Negative-strand (-) RNA viruses (NSVs) comprise a large and diverse group of viruses that are generally divided in those with non-segmented and those with segmented genomes. Whereas most NSVs infect animals and humans, the smaller group of the plant-infecting counterparts is expanding, with many causing devastating diseases worldwide, affecting a large number of major bulk and high-value food crops. In 2018, the taxonomy of segmented NSVs faced a major reorganization with the establishment of the order . This article overviews the major plant viruses that are part of the order, i.e., orthospoviruses (), tenuiviruses (), and emaraviruses (), and provides updates on the more recent ongoing research. Features shared with the animal-infecting counterparts are mentioned, however, special attention is given to their adaptation to plant hosts and vector transmission, including intra/intercellular trafficking and viral counter defense to antiviral RNAi.
Topics: Bunyaviridae; Plant Diseases; Plant Viruses; Plants; RNA Viruses
PubMed: 34066457
DOI: 10.3390/v13050842 -
The Journal of General Virology Apr 2023Unlike many segmented negative-sense RNA viruses, most members of the bud at Golgi membranes, as opposed to the plasma membrane. Central players in this assembly... (Review)
Review
Unlike many segmented negative-sense RNA viruses, most members of the bud at Golgi membranes, as opposed to the plasma membrane. Central players in this assembly process are the envelope glycoproteins, Gn and Gc, which upon translation undergo proteolytic processing, glycosylation and trafficking to the Golgi, where they interact with ribonucleoprotein genome segments and bud into Golgi-derived compartments. The processes involved in genome packaging during virion assembly can lead to the generation of reassorted viruses, if a cell is co-infected with two different bunyaviruses, due to mismatching of viral genome segment packaging. This can lead to viruses with high pathogenic potential, as demonstrated by the emergence of Schmallenberg virus. This review focuses on the assembly pathways of tri-segmented bunyaviruses, highlighting some areas in need of further research to understand these important pathogens with zoonotic potential.
Topics: Orthobunyavirus; RNA Viruses; Glycosylation; Virus Assembly
PubMed: 37083579
DOI: 10.1099/jgv.0.001845 -
Viruses May 2022Dozens of orthobunyaviruses have been isolated in Brazil, and at least thirteen have been associated with human disease. The Oropouche virus has received most attention... (Review)
Review
Dozens of orthobunyaviruses have been isolated in Brazil, and at least thirteen have been associated with human disease. The Oropouche virus has received most attention for having caused explosive epidemics with hundreds of thousands of cases in the north region between the 1960sand the 1980s, and since then has been sporadically detected elsewhere in the country. Despite their importance, little is known about their enzootic cycles of transmission, amplifying hosts and vectors, and biotic and abiotic factors involved in spillover events to humans. This overview aims to combine available data of neglected orthobunyaviruses of several serogroups, namely, Anopheles A, Anopheles B, Bunyamwera, California, Capim, Gamboa, Group C, Guama, Simbu and Turlock, in order to evaluate the current knowledge and identify research gaps in their natural transmission cycles in Brazil to ultimately point to the future direction in which orthobunyavirus research should be guided.
Topics: Animals; Anopheles; Brazil; Humans; Mosquito Vectors; Orthobunyavirus; Serogroup
PubMed: 35632729
DOI: 10.3390/v14050987