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Mechanisms by which SFTS inhibits key immune signalling pathways and promotes inflammation. This diagram illustrates the main mechanism by which the host cell pathway is impacted by the NS proteins of SFTSV. Interferon release, the primary signaling mechanism for immune evasion, is inhibited by NSs in a number of ways, including the following: (1) NSs inhibit IFN production by isolating TRIM21/25, TBK1, STAT1/2, and IRF3/7 into their inclusion bodies. (2) Inhibition of the JAK/STAT signaling pathway, thereby inhibiting IFN production. The toxic NS proteins of SFTS induce inflammation through two pathways, including the following: (1) NSs produce inflammatory factors by promoting the transcription of NF-kB into the nucleus. (2) NSs trigger BAK upregulation and BAX activation through infection, leading to mitochondrial DNA oxidation and subsequent cytosol release and triggering NLRP3 inflammasome activation, which leads to inflammatory factor production.
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Sever fever with thrombocytopenia syndrome (SFTS) is a new infectious disease that has emerged in recent years and is widely distributed, highly contagious, and lethal, with a mortality rate of up to 30%, especially in people with immune system deficiencies and elderly patients. SFTS is an insidious, negative-stranded RNA virus that has a major pub...
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... 5) Vaccines and drugs used to control HRTV infection need to be explored and developed as soon as possible. Several promising SFTSV candidate vaccines and anti-SFTSV drugs have been reported [82] and similar strategies can be used to test their inhibitory activity against HRTV. ...
Heartland virus (HRTV), an emerging tick-borne pathogenic bunyavirus, has been a concern since 2012, with an increasing incidence, expanding geographical distribution, and high pathogenicity in the United States. Infection from HRTV results in fever, thrombocytopenia, and leucopenia in humans, and in some cases, symptoms can progress to severe outcomes, including haemorrhagic disease, multi-organ failure, and even death. Currently, no vaccines or antiviral drugs are available for treatment of the HRTV disease. Moreover, little is known about HRTV-host interactions, viral replication mechanisms, pathogenesis and virulence, further hampering the development of vaccines and antiviral interventions. Here, we aimed to provide a brief review of HRTV epidemiology, molecular biology, pathogenesis and virulence on the basis of published article data to better understand this virus and provide clues for further study.
... HEK293T cells were plated in six-well plates. The cells were infected with SFTSV for different times beginning 12 h after seeding (12,24, and 48 h) or infected with SFTSV at different MOIs. The cells were collected, 300 µL of digitalis saponin separation buffer was added to resuspend the cell precipitate, and the suspension was placed on a 4°C rotator for 10 min to complete lysis. ...
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus with high pathogenicity. There has been a gradual increase in the number of reported cases in recent years, with high morbidity and mortality rates. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an important role in the innate immune defense activated by viral infection; however, the role of the cGAS-STING signaling pathway during SFTSV infection is still unclear. In this study, we investigated the relationship between SFTSV infection and cGAS-STING signaling. We found that SFTSV infection caused the release of mitochondrial DNA into the cytoplasm and inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. We found that the SFTSV envelope glycoprotein Gn was a potent inhibitor of the cGAS-STING pathway and blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Gn of SFTSV interacted with STING to inhibit STING dimerization and inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. In addition, Gn was found to be involved in inducing STING degradation, further inhibiting the downstream immune response. In conclusion, this study identified the important role of the glycoprotein Gn in the antiviral innate immune response and revealed a novel mechanism of immune escape for SFTSV. Moreover, this study increases the understanding of the pathogenic mechanism of SFTSV and provides new insights for further treatment of SFTS.
IMPORTANCE
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered virus associated with severe hemorrhagic fever in humans. However, the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway during SFTSV infection is still unclear. We found that SFTSV infection inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. In addition, SFTSV Gn blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Moreover, we determined that Gn of SFTSV inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. We found that the SFTSV envelope glycoprotein Gn is a potent inhibitor of the cGAS-STING pathway. In conclusion, this study highlights the crucial function of the glycoprotein Gn in the antiviral innate immune response and reveals a new method of immune escape of SFTSV.
... 4 Hemgenix, have been approved by the FDA [2,19,35]. Moreover, several follow-up clinical trials have shown that AAV vectors are safer than other viral vectors, such as adenovirus vectors [20]. ...
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.
... SFTS has mainly been reported in countries such as China, South Korea, Japan, and Pakistan [4][5][6], with major symptoms including fever, leukopenia, thrombocytopenia, and gastrointestinal symptoms. This disease is highly contagious, with a mortality of up to 30% [2,7]. The primary transmission route of SFTS is believed to be through tick bites [1,8]. ...
This study aims to evaluate the predictive role of age-adjusted Charlson comorbidity index (ACCI) scores for in-hospital prognosis of severe fever in thrombocytopenia syndrome (SFTS) patients. A total of 192 patients diagnosed with SFTS were selected as the study subjects. Clinical data were retrospectively collected. Receiver operating characteristic curves were used to evaluate the diagnostic value of ACCI for the mortality of SFTS patients, and Cox regression models were used to assess the association between predictive factors and prognosis. The 192 SFTS patients were divided into two groups according to the clinical endpoints (survivors/non-survivors). The results showed that the mortality of the 192 hospitalized SFTS patients was 26.6%. The ACCI score of the survivor group was significantly lower than that of the non-survivor group. Multivariate Cox regression analysis showed that the increased ACCI score was a significant predictor of poor prognosis in SFTS. Kaplan–Meier survival analysis showed that SFTS patients with an ACCI >2.5 had shorter mean survival times, indicating a poor prognosis. Our findings suggest that ACCI, as an easy-to-use clinical indicator, may offer a simple and feasible approach for clinicians to determine the severity of SFTS.
