Current status of severe fever with thrombocytopenia syndrome in China (Review)

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging tick-borne infectious disease caused by the novel Bunyavirus/SFTS virus (SFTSV). The clinical manifestations mainly include fever, thrombocytopenia and multi-organ dysfunction, with a fatality rate as high as 30%. Since its first report in China in 2009, cases have subsequently emerged in multiple countries across East and Southeast Asia. SFTS demonstrates clear seasonal trends from May to November and tends to cluster geographically, mainly in hilly and mountainous areas. The virus is transmitted through tick bites, animal contact and human-to-human transmission. Its genetic diversity and frequent genetic recombination exacerbate public health threats. Pathogenic mechanism studies have shown that SFTSV uses glycoproteins Gn/Gc to mediate host cell invasion. In the early stage, the virus uses its non-structural protein NSs to inhibit innate immune signal transduction. Massive replication of the virus leads to excessive immune activation, triggering cytokine storms and abnormal platelet activation, and eventually resulting in bleeding and multiple organ failure. The clinical management primarily relies on supportive care, while broad-spectrum antiviral drugs and neutralizing antibodies remain investigational. Although numerous vaccine candidates have been designed and developed, none have progressed to clinical trials. This review systematically integrates current knowledge spanning virology, epidemiology, pathogenic mechanisms, therapeutic interventions and vaccine development, offering actionable insights for public health strategies and clinical practice.

1. Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease caused by SFTS virus (SFTSV). The primary clinical manifestations include fever, thrombocytopenia, leukopenia and gastrointestinal symptoms, such as nausea and vomiting (1). Approximately 37.5% of patients progress to severe cases, developing multi-organ dysfunction, disseminated intravascular coagulation, shock and other life-threatening conditions, with a case fatality rate of as high as 30% (2,3). In addition to typical symptoms, complications such as myocardial dysfunction and neurological disorders may occur (4,5). Tick bites are recognized as the primary transmission route of SFTSV, with a high susceptibility in humans, particularly among middle-aged and elderly populations (6-9). The disease was first reported in 2009 in rural areas of the Dabie Mountain region in central China (10). Subsequently, researchers isolated and identified a novel virus from patient sera, initially classified under the genus Phlebovirus within the family Bunyaviridae and named 'severe fever with thrombocytopenia syndrome virus' (11). In 2020, based on genomic and phylogenetic analyses, the International Committee on Taxonomy of Viruses reclassified it as Dabie bandavirus under the order of Bunyavirales (12). However, in clinical and public health contexts, the virus is still commonly referred to as SFTSV or the 'novel Bunyavirus' (13). SFTS is predominantly endemic in East Asian countries such as China (10), Japan (14) and South Korea (15), with increasing case reports from countries such as Vietnam (16), Thailand (17), Myanmar (18), Pakistan (19) and Kenya (20), garnering global attention. In 2009, a similar disease caused by Heartland virus (HRTV) was reported in the US (21). A retrospective study in Japan traced the earliest suspected SFTS cases back to 2005 (22). In 2017, the World Health Organization listed SFTS as one of the nine priority diseases for vaccine research and development (23). Despite progress in SFTS prevention and management, challenges persist due to the virus's high genetic variability, geographically restricted transmission patterns and the absence of effective vaccines or specific antiviral therapies. It emphasizes its continuous threat to public health. This review summarizes current advances in virology, epidemiology, pathogenic mechanisms, vaccine development and therapeutic strategies for SFTS, while proposing future research directions to enhance disease control and improve clinical and public health outcomes.

2. Etiological characteristics of SFTSV

Virus structure

SFTSV is a single-stranded, negative-sense, enveloped, segmented circular RNA virus (24) (Fig. 1A). The virus is composed of 110 hexagons and 12 pentamers, forming a symmetrical icosahedron with a diameter of ~80-120 nm (25). It has a unit membrane envelope covered by a 5-7 nm thick lipid bilayer. The lipid bilayer envelope contains a heterodimer of glycoproteins Gn and Gc, which are further assembled into penton and hexon peplomers (26). The interior of the virus particle is filamentous or coiled, consisting of three viral segments (L, M, S) enclosed within a circular viral nucleoprotein (NP) (27). The SFTSV genome exhibits high conservation in terminal sequences. The complementary 3′ and 5′ends form a hairpin structure, with each segment forming a closed loop (28). The viral genome consists of three segments (Fig. 1B). The genome of the L segment comprises 6,368 nucleotides and contains a 6,255-nt open reading frame (ORF), which encodes a 2,804-amino acid RNA-dependent RNA polymerase (RdRp). It is responsible for viral RNA replication and mRNA synthesis, making it the primary target of nucleoside analogue antiviral drugs (29). The M segment, composed of 3,378 nucleotides, contains an ORF from positions 19 to 3,240, encoding a 1,073-amino acid (aa) membrane protein precursor (Gp) (30). This precursor is transported to the endoplasmic reticulum (ER), where it is cleaved by cellular proteases into two distinct glycoproteins: Gn (516aa) and Gc (511aa) (31). These glycoproteins mediate viral entry into host cells and are primary targets for neutralizing antibodies (32). The S segment, belonging to the ambisense RNA family, has 1,744 nucleotides and contains two ORFs in opposite directions (882nt/738nt), separated by a ~54 bp intergenic region (33). The 3′end sequence encodes a 245-amino acid NP, which encapsidates the three RNA genome segments of SFTSV and forms a ribonucleoprotein complex (RNP) with the RdRp, protecting the virus from nucleases and the host immune system (34). The RNP occupies this volume as densely packed filamentous structures, filling the interior (25). The 5′end sequence encodes a 293aa non-structural protein (NSs), which is the major virulence factor of SFTSV and can inhibit the host's innate antiviral immune response (35). The L, M and S segments have short non-coding sequences at their 5′ and 3′ends (36). The 5′non-coding regions are 16nt (L), 18nt (M) and 42nt (S), while the 3′non-coding regions are 100nt (L), 141nt (M) and 28nt (S) (36). The relative levels of self-replication of the three segments are M>L>S, occurring in the host cell matrix, with transcription and translation happening simultaneously (37). The terminal ends of the three segments of the SFTSV genome, like other Bunyaviruses, are untranslated regions (UTRs), which are short and highly conserved. In fact, the 5′ and 3′UTRs of these three segments are widely complementary, forming a roughly slender structure (38).

Figure 1.

Structure and genome of SFTSV. (A) SFTSV is a spherical RNA virus, with its surface covered by spikes composed of Gn and Gc glycoproteins. The virus contains three single-stranded genomes (L, M and S fragments) inside, which are wrapped by NPs and form ribonucleoprotein complexes with RdRp. (B) L fragment (6,368bp): Encodes RdRp. M fragment (3,378 bp): Encodes glycoproteins Gn and Gc. S fragment (1,174 bp): Encodes the structural protein NP and the non-structural protein NSs. SFTSV, severe fever with thrombocytopenia syndrome virus; RdRp, RNA polymerase; NP, nucleoprotein.

Genetic diversity and evolution

The genotype classification of SFTSV is still rather complex at present and there are multiple classification systems based on phylogenetic analysis. Fu et al (39) initially classified SFTSV into six genotypes (A-F) through a comprehensive study of 205 virus strains. Their research found that the genetic distance within the same genotype was 0.001-0.026 substitutions per point and the genetic distance between different genotypes was 0.035-0.062 substitutions (39). Subsequent research refined this classification. Genotype B was subdivided into subseries B-1, B-2 and B-3, and genotype A was further divided into subseries A1 and A2 based on the geographical isolation of the Taebaek Mountains in South Korea (40,41). In China, genotypes A, D and F are dominant, among which F is the most prevalent. However, all six genotypes have been detected so far (42). Still, regional differences exist. Yun et al (40) found genotype B (especially B-2, at 36.1%) to be dominant in Japan, similar to South Korea, but genotypes A and F are the disadvantageous genotypes there. This highlights the geographically specific distribution (40).

Evolutionary studies have shown that the three segments of SFTSV genome have different replacement rates. Liu et al (42) reported that the M segment evolves fastest with a nonsynonymous to synonymous substitution rate ratio (dN/dS) of 0.14, but other studies identified the NSs gene in the S segment as a mutation hotspot, possibly due to regional sampling bias (39,40,43,44). Despite the differences, the L segment remains the most conserved (45). Positive selection in the M segment may reflect its role in host-cell interactions and immune evasion, and the RdRp's strong purifying selection (dN/dS=0.048) aligns with its essential replication function (46,47).

SFTSV's genetic plasticity is further increased by frequent rearrangements and homologous recombination. Various rearrangement types have been documented, including seven variants (e.g., AFA, DFD) described by Fu et al (39) and nine recombinants (R-1 to R-9) identified by Yun et al (48). Genotype B is prominent in these events; for example, Wen et al (49) identified a new B-4 sub-lineage. Homologous recombination, initially confirmed in the L and M segments, has further driven viral diversification, with Korean strains showing active recombination-mediated evolution (48).

From a clinical perspective, genotype-related virulence differences are significant. Pure genotype B, particularly B-2, is linked to high case fatality rates (43.8% in ferrets) (48). Genotype F, despite its lower incidence, has a higher mortality rate (44.4%) (48). Recombinants R-1 and R-5 show high lethality (80%), contrasting sharply with the 20% case fatality rate of R-8/R-9 (48). This variability underscores genotype distribution as a key factor in regional case fatality rate differences. Differences in classification systems (e.g., A-F and A-E, China-specific C1-C6 and Japan's J1-J4) complicate cross-study comparisons, making a standardized genotyping framework urgently needed (43,50,51). Mortality differences among SFTSV genotypes may result from viral traits like replication efficiency and immune escape, alongside host responses such as inflammatory storms or antibody deficiency. Genotype B-2, for example, could heighten mortality via elevated viral loads, early immunosuppression and organ damage. Regional genotype variations and host factors like age also impact outcomes. Further research is essential to clarify these associations.

3. Epidemiological characteristics

SFTS distribution

Time distribution

From 2010 to 2023, the incidence of SFTS in China showed a significant upward trend. In the early years (2010-2016), the number of cases rose rapidly, peaking in 2016. There was a temporary decline in certain regions between 2017 and 2019, but the incidence increased again in recent years. By 2023, the national incidence had increased by 35 times compared to 2010 (52) (Table I). SFTS cases occur throughout the year but are seasonal, primarily from April to October, with a peak from May to July, coinciding with tick activity (53,54). Japan and South Korea, like China, have temperate and subtropical monsoon climates, leading to similar SFTS seasonality (55,56). Most Japanese cases occur from April to October, while in South Korea, they are seen from May to October (55). Interestingly, compared with 2019, the incidence of SFTS in China suddenly increased in 2020. The reason might be that due to the impact of the novel coronavirus pneumonia epidemic, local residents were unable to work in other places. To make a living, more people participated in outdoor labor such as tea picking in the local area, increasing the chances of exposure to vectors such as ticks and the risk of infection (57). Furthermore, both COVID-19 and SFTS have symptoms such as fever, thrombocytopenia, gastrointestinal symptoms and fatigue, to a certain extent. Hospitals have strengthened the monitoring and detection of these symptoms, enabling the diagnosis of more mild or asymptomatic infections that might have been overlooked (58).

Table I.

Reported annual incidence of severe fever with thrombocytopenia syndrome in China from 2010 to 2023.

Year	Number of cases	Annual incidence rate (/100,000)
2010	71	0.01
2011	547	0.04
2012	681	0.05
2013	878	0.06
2014	1,387	0.10
2015	2,073	0.15
2016	2,601	0.19
2017	1,900	0.14
2018	1,848	0.13
2019	1,841	0.13
2020	2,503	0.18
2021	2,638	0.19
2022	3,418	0.24
2023	5,061	0.36
Total	27,447	0.14 (average)

Data adapted from a previous epidemiological study (52).

Regional distribution

Globally, SFTS primarily affects East and Southeast Asia. Since 2010, the disease has spread across China, with a rising number of annual cases (59). Recently, 27 provinces in mainland China have reported cases, mostly in Shandong, Henan, Anhui, Hubei, Liaoning, Zhejiang and Jiangsu (52) (Table II). Cases are highly sporadic but show regional clustering. Spatial trend surface analysis has identified four distinct ecogeographic clusters in China: Cluster I is in the Changbai Mountains of northeastern China; Cluster II is on the Jiaodong Peninsula in northern Shandong; Cluster III is around Mount Tai; the largest cluster, Cluster IV, is centered on the Huaiyang Mountains in central China and spans five provinces: Henan, Anhui, Hubei, Jiangsu and Zhejiang (9). Cluster II has the highest average annual incidence. Within each cluster, SFTS spreads from the center to the periphery (9). Despite being in different ecogeographic areas, all four clusters share similarities: They are densely forested or mountainous, with temperate humid or subtropical climates (9). From 2010 to 2018, these clusters accounted for 94.7% of confirmed SFTS cases (9). In Japan, most cases are concentrated in the western part of the country, particularly in Shikoku and Kyushu, which represent the main endemic regions (60). In South Korea, cases are concentrated in central and southern regions, particularly in the North Chungcheong and North Jeolla Provinces (61).

Table II.

Number of severe fever with thrombocytopenia syndrome cases reported in high-incidence areas of China from 2010 to 2023.

Province	Cumulative number of reported cases
Shandong	7,894
Henan	6,275
Anhui	5,715
Hubei	3,939
Liaoning	1,421
Zhejiang	990
Jiangsu	957

The cumulative number of reported cases was estimated based on reported deaths and case fatality rates extracted from an epidemiological study (52).

Population distribution

An epidemiological analysis in China (2010-2018) shows that, while SFTSV affects all age groups, its distribution has significant age dependence (9). The median age of confirmed cases was 63 years (interquartile range: 53-71 years), with 93.3% of cases in the 40-84 age group (53,62). Notably, those aged ≥60 had a significantly higher incidence than other age groups, and children under 10 years of age accounted for only 0.41% of cases, highlighting the disease's age-specific pattern (63). In Japan, patients had a higher median age of 78 years, compared to 63 years in China and 69 years in South Korea, linked to Japan's aging population (25.1% aged ≥65 in 2013) (56).

Occupational exposure analysis indicated that 87.91% of confirmed cases were agricultural workers (64). This phenomenon is closely related to the current changes in the rural population structure in China. The accelerated urbanization process has led to the migration of young and middle-aged labor force to cities, making the elderly population >60 years of age the main bearers of agricultural activities like plowing, weeding and animal husbandry (65,66). This intergenerational labor shift likely increases older adults' exposure to tick vectors, creating an age-related infection risk gradient (67).

The incidence and case fatality rates of SFTS show significant differences between genders. Overall, the incidence rate is higher in females, with national data showing that females account for ~52.6% of cases (68). However, gender ratios vary among different provinces; Jiangsu, Liaoning and Shandong have more male cases, while Henan and Hubei have a higher proportion of female cases (68). This gender disparity may be related to exposure scenario specificity. In tea-producing areas dominated by hilly landscapes, women's outdoor working hours significantly increase during the tea-picking season from April to June, leading to a higher incidence rate among females during this period. Interestingly, the case fatality rate is significantly higher in males than in females (69). National data indicate a male case fatality rate of 7.76% compared to 5.76% for females (68). However, more research is needed to explore the reasons behind this.

Source of infection, route of transmission

Source of infection

The ecological cycle of SFTSV remains unclear and may involve arthropod vectors and mammalian hosts (70). Ticks are the main reservoir hosts and vectors of SFTSV (71). Common tick species include Haemaphysalis longicornis, Amblyomma testudinarium, Ixodes nipponensis and Rhipicephalus microplus (72). The animal hosts of SFTSV are not fully identified, but specific antibodies have been detected in livestock such as sheep, goats, cattle, dogs, cats, pigs, chickens, ducks, geese and deer, with the highest seropositivity in goats (66.8-83.0%), followed by cattle (28.2-60.5%), dogs (7.4-52.1%) and chickens (1.2-47.4%) (63,73). Besides livestock, numerous wild animals, including wild boars, hedgehogs, sambar deer, ferrets, foxes and certain birds also serve as reservoir hosts (74). Humans are accidental hosts and play a minimal role in the virus's lifecycle (75).

Transmission route

1. Tick-to-human transmission. SFTSV primarily spreads to humans through the bites of infected ticks. Haemaphysalis longicornis is the main vector and the virus can be transmitted vertically through eggs transstadially across different tick life stages (24,71). This tick can reproduce asexually, facilitating widespread population expansion and pathogen dissemination (76,77). Other ticks like the Haemaphysalis flava, Ixodes nipponensis and Rhipicephalus microplus have also tested positive for SFTSV (78-80). However, detecting the virus in ticks only indicates their infection status and doesn't confirm their vector competence, which depends on complex factors like species differences and virus-vector coevolution.

2. Animal-to-human transmission. SFTSV can spread to humans through bites or scratches from infected animals (81-87). Cats, for instance, have been documented to transmit SFTSV to humans (88,89). Recent ecological studies suggest that migratory birds may play a role in the spread of SFTSV, as their migration routes align with the virus's distribution (90,91). Molecular analyses show that viral genotypes from different regions overlap, indicating that the virus may spread over long distances via host species movements (92). Evidence from coastal provinces in East Asia and regions in Japan and Korea supports this hypothesis (93). Haemaphysalis longi-cornis, a key vector, not only feeds on terrestrial mammals but has also been found on migratory birds such as the Zoothera aurea, Turdus shortulorum, Halcyon coromanda and Pitta nympha (94). It has been suggested that these birds may carry infected ticks during their long flights across Asia and the Pacific, potentially aiding viral spread (77). However, the exact mechanisms and efficiency of this spread remain elusive and more research is needed to confirm the role of migratory birds in SFTSV transmission.

3. Human-to-human transmission. Current evidence indicates that human-to-human transmission of SFTSV primarily occurs through direct contact with infected individuals, particularly when adequate protective measures are not taken (95,96). The main risk factor is exposure to infectious bodily fluids (particularly blood or bloody secretions from severe cases) and excreta (97). Epidemiological observations highlight an increased risk of iatrogenic infections in settings such as home care, healthcare facilities and during corpse handling, where close contact is more likely (98-100).

Regarding non-contact transmission, several studies have explored the possibility of aerosol transmission (101,102). Wei et al (103) demonstrated that mice exposed to SFTSV aerosols at specific concentrations in a controlled environment could become infected via the nasal, oral and conjunctival routes. However, there is currently no direct evidence confirming aerosol transmission in human cases, and further rigorous clinical studies are needed to validate this potential route.

4. Pathogenic mechanism

Viral entry and replication

C-C motif chemokine receptor 2 (CCR2) is one of the key receptors for SFTSV entry into cells (104) (Fig. 2). Research shows that CCR2 interacts directly with the Gn glycoprotein of SFTSV through its N-terminal extracellular domain, mediating viral attachment and cell entry (104). Since CCR2 is primarily expressed in monocytes, this explains why monocytes are a target cell for SFTSV (105). Additionally, dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), heparan sulfate (HS) and non-muscle myosin heavy chain IIA (NMMHCIIA) have been found to facilitate SFTSV entry (106-108). Interestingly, DC-SIGN functions as both a receptor and an adhesion molecule, while HS and NMMHCIIA serve solely as adhesion molecules (107,109). SFTSV recruits grid proteins onto the cell membrane to form grid protein-coated pits and further separates them from the plasma membrane to form discrete vesicles (110). These vesicles transport the virus particles to early endosomes marked by Rab5, and then to late endosomes marked by Rab7 (110). The intracellular transport of endocytic vesicles carrying the virus initially relies on actin filaments near the cell periphery, followed by movement along microtubules from the cell periphery toward the interior (110). Within 15-60 min of entry, membrane fusion occurs in the acidic environment (pH=5.6) of the late endosome (110). The extracellular domain of SFTSV Gc undergoes a conformational change at low pH to form a trimeric structure (111). A key feature of the class II fusion glycoprotein Gc is the hydrophobic fusion loop at the top of domain II, which inserts into the host membrane and brings the viral and host membranes together during fusion (111). The viral RNP is then released into the cytoplasm, providing the basis for subsequent replication and assembly (112). In the ER, Gn and Gc undergo N-linked glycosylation at their N-termini, which helps maintain their stability (113). Properly folded Gn and Gc form non-covalent heterodimers with the assistance of molecular chaperones such as binding immunoglobulin protein, protein disulfide isomerase and calnexin in the ER. They are subsequently transported to the Golgi apparatus for budding (113,114). The virus uses the host cell's endomembrane system to form replication complexes, completing genome replication and transcription of subgenomic mRNA (115). Tsuda et al (116) have shown that the amino acid at position 624 of the G protein is crucial for inducing low-pH-dependent cell fusion. GPs with tryptophan, serine, glycine or aspartic acid at position 624 can induce cell fusion, while those with basic amino acids (e.g., arginine or lysine) cannot (116).

Figure 2.

Life cycle of SFTSV. The SFTSV life cycle starts when viral surface glycoproteins interact with host cell surface receptors (CCR2, DC-SIGN) and adhesion factors (HS, NMMHCIIA) to bind to target cells. The virus then enters the cell via clathrin-mediated endocytosis, forming a coated vesicle that transports the virus sequentially to Rab5-positive early endosomes and Rab7-positive late endosomes. As the endosomal pH drops to ~5.6, it triggers a conformational change in the viral surface glycoproteins. In late endosomes, the Gc glycoprotein undergoes conformational rearrangement to form a trimeric structure, and its fusion loop inserts into the host membrane, triggering membrane fusion and releasing the viral ribonucleoprotein complex RNP into the cytoplasm. The viral glycoproteins Gn and Gc undergo N-glycosylation and proper folding mediated by molecular chaperones (PDI/Bip/CNX) in the endoplasmic reticulum, forming a heterodimer that is transported to the Golgi apparatus for assembly. The virus uses the host's endomembrane system to establish replication complexes, completing genome replication and transcription, and is finally secreted out of the cell through exocytosis. SFTSV, severe fever with thrombocytopenia syndrome virus. SFTSV, severe fever with thrombocytopenia syndrome virus; CCR2, C-C motif chemokine receptor 2; DC-SIGN, dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin; HS, heparan sulfate; NMMHCIIA, non-muscle myosin heavy chain IIA; Rab5/7, Ras-related proteins 5/7; Gn/Gc, envelope glycoproteins N and C; RNP, ribonucleoprotein complex; PDI, protein disulfide isomerase; BiP, binding immunoglobulin protein; CNX, calnexin.

Innate immune evasion by SFTSV

Once the genome of SFTSV, an RNA virus, is released into the host cell's cytoplasm, the virus is primarily recognized by the host cell through three pattern recognition receptors that identify pathogen-associated molecular patterns: Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and NOD-like receptors (NLRs) (37) (Fig. 3). Interferons (IFNs) play a crucial role in the innate antiviral immune response, including IFN-α and IFN-β, which are produced by infected cells such as macrophages, dendritic cells and epithelial cells, through autocrine and paracrine actions (117). Studies have found that RNA sensors like TLR3, TLR7 and TLR8 can identify viral single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA). It can activate TLRs that recruit specific adapter molecules like Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and myeloid differentiation primary response 88 (MyD88) and then trigger the production of inflammatory factors and IFN-I (117). After secretion, IFN-I binds to specific membrane receptors within the cell (homologous receptors composed of IFNA-R1 and IFNA-R2), activating and forming dimers that trigger downstream signaling pathways, including the JAK-STAT, MAPK and PI3K-AKT pathways (117-119). Activation of these pathways leads to the expression of IFN-stimulated genes (ISGs), producing various biological effects such as antiviral, immunomodulatory and antitumor activities (120). Additionally, IFN-I can activate surrounding cells through paracrine signaling, enhancing IFN-I production and further amplifying the immune response (118). Other studies have also shown that RLRs, including RIG-I and melanoma differentiation-associated protein 5 (MDA5), can recognize dsRNA and ssRNA (121,122). Activated RLRs then interact with mitochondrial antiviral signaling protein (MAVS), leading to MAVS oligomerization (123). Activated MAVS recruits various proteins like TNF receptor-associated factor and TANK-binding kinase 1 (TBK1) to form a MAVS signaling complex, activating the NF-κB and interferon regulatory factor 3 (IRF3) pathways to promote IFN-I gene expression (115). NLR proteins typically contain a nucleotide-binding oligomerization domain (NOD), leucine-rich repeat domain and effector domain (124). It has been shown that SFTSV infection induces the upregulation of BCL2 antagonist/killer protein 1 (BAK) and the activation of BCL2-associated X protein (BAX) on the mitochondrial membrane. Typically, BAK/BAX activation leads to the release of cytochrome c into the cytoplasm, a hallmark of apoptosis. However, Li et al (125) discovered that in the context of SFTSV infection, BAK/BAX activation preferentially triggers the release of mitochondrial DNA (mtDNA), initiating the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway rather than classical apoptosis. This process increases mitochondrial membrane permeability and promotes mtDNA oxidation, resulting in its release into the cytoplasm. The cytosolic mtDNA subsequently binds to and activates the NLRP3 inflammasome, playing a key role in the innate immune response (124,125). Additionally, other pathways can activate the innate immune response, such as nuclear scaffold attachment factor A (SAFA), a nuclear matrix protein considered a novel RNA sensor. Liu et al (126) found that cytoplasmic SAFA can recognize SFTSV genomic RNA through the RGG domain and form a homodimer. This process recruits and promotes the activation of the stimulator of IFN genes-TANK-binding kinase 1 (STING-TBK1) signaling axis to combat SFTSV infection (126). Furthermore, SFTSV infection significantly upregulates the expression of the host cell's DNA sensor cyclic GMP-AMP synthase, leading to IFN-I production through STING-mediated IRF3 phosphorylation (127).

Figure 3.

Innate immune evasion by SFTSV. During replication and translation, SFTSV's ssRNA, dsRNA and proteins activate and evade innate immunity through various pathways. i) Viral RNA is sensed by TLR3 and TLR7, activating MyD88, TRAF and TRIF. This leads to IRF3, IRF7 and NF-κB phosphorylation and nuclear translocation, driving IFN and pro-inflammatory cytokine secretion. ii) Viral RNA is detected by RIG-I, MDA5 and SAFA, which interact with MAVS to activate TRAF3 and phosphorylate IRF3 and IRF7. However, NSs sequesters MAVS, IRF3 and IRF7 into viral IBs, blocking their activation and suppressing IFN production. iii) IFNAR on the cell membrane recognizes secreted IFN, activating the JAK-STAT pathway. This forms ISRE with IRF9 to induce ISG expression. NSs counteracts this by sequestering STAT1 and STAT2 into IBs, reducing IFN synthesis. iv) BAK/BAX disrupt mitochondria, releasing oxidized mtDNA. This activates the NLRP3 inflammasome, releasing IL-1β and IL-18, and is sensed by cGAS, which activates IRF pathways to boost IFN production. v) NSs interacts with autophagy proteins like mTOR and Beclin1 to promote viral autophagy. vi) NP inhibits the BECN1-BCL2 interaction, inducing BECN1-dependent autophagy. Solid arrows indicate activation, dashed arrows with a line at the end indicate inhibition and scissors indicate cleavage. SFTSV, severe fever with thrombocytopenia syndrome virus; IB, inclusion body. SFTSV, severe fever with thrombocytopenia syndrome virus; ssRNA, single-stranded RNA; dsRNA, double-stranded RNA; TLR3/7, toll-like receptor 3/7; MyD88, myeloid differentiation primary response 88; TRAF, TNF receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing IFN-β; IRF3/7/9, IFN regulatory factor 3/7/9; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; IFN, interferon; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; SAFA, scaffold attachment factor A; MAVS, mitochondrial antiviral signaling protein; NSs, nonstructural protein of SFTSV; IB, inclusion body; IFNAR, IFN-α/β receptor; JAK, Janus kinase; STAT1/2, signal transducer and activator of transcription 1/2; ISRE, IFN-stimulated response element; ISG, IFN-stimulated gene; BAK/BAX, Bcl-2 homologous antagonist/killer/Bcl-2-associated X protein; mtDNA, mitochondrial DNA; NLRP3, NOD-like receptor family pyrin domain-containing 3; IL-1β/IL-18, interleukin 1β/18; cGAS, cyclic GMP-AMP synthase; mTOR, mammalian target of rapamycin; BECN1, Beclin-1; BCL2, B-cell lymphoma 2; NP, nucleoprotein.

However, SFTSV has developed various strategies to counteract the innate immune response (Fig. 3). The nonstructural protein NSs induces autophagy to inhibit the IFN signaling pathway, helping the virus evade the immune response (128,129). Studies have found that SFTSV NSs can capture important antiviral protein molecules in the IFN signaling pathway, such as TBK1, tripartite motif-containing protein 25, inhibitor of nuclear factor кB kinase ε, IRF3 and IRF7, MAVS, and signal transducer and activator of transcription 1 (STAT1) and STAT2, by forming inclusion bodies (IBs) and prevent the production of IFN. Blocking the JAK-STAT signaling pathway means that even in the presence of IFN, cells cannot effectively express downstream ISG, thereby reducing the antiviral effect of IFN (120). In addition, IBs can also form a structure similar to a 'replication factory' by aggregating key replication components such as viral RNA, NP and RdRp, relying on the microenvironment provided by lipid droplets. Thus, it provides a platform for SFTSV RNA replication (130,131). Zhang et al (132) found that NSs interacts with LSm14 homolog A to effectively inhibit downstream phosphorylation and dimerization of IRF3, thus suppressing antiviral signaling and IFN induction in several human-derived cells. The virus can regulate the host cell autophagy pathway through various mechanisms. It has been shown that the NSs protein targets the mTOR kinase domain, capturing it within viral IBs to activate the UNC-51 like autophagy activating kinase 1 pathway and initiate autophagy (133). Liu et al (134) further confirmed that the NSs protein interacts with vimentin, degrading it through the K48-linked ubiquitin-proteasome pathway, inhibiting the formation of the Beclin1-vimentin complex, and thereby enhancing autophagy activity. Sun et al (135) found that during SFTSV infection, the NSs protein colocalizes with autophagy-related proteins such as light chain 3B, p62 and Lamp2b, and by binding to the coiled-coil domain of beclin 1 (BECN1), promotes the assembly of the autophagy complex BECN1-PIK3C3, initiating the complete autophagy process. Notably, in addition to the NSs protein, the SFTSV NP also has the function of regulating autophagy. Yan et al (136) revealed that SFTSV activates the classical autophagy pathway dependent on RB1-inducible coiled-coil 1/FAK family-interacting protein of 200 kDa-beclin 1 (BECN1)-autophagy-related 5, with its nucleoprotein inducing BECN1-dependent autophagy by dissociating the BECN1-BCL2 complex. In terms of cell cycle regulation, the NSs protein specifically binds to cyclin-dependent kinase 1 (CDK1), causing cell cycle arrest at the G2/M phase. This interaction inhibits the formation and nuclear transport of the cyclin B1-CDK1 complex, creating a microenvironment conducive to viral replication and synthesis, ultimately exacerbating the infection process (137).

Adaptive immunity

During the body's response to viral infections, innate immunity, although rapid in response, is nonspecific and short-lived, making it difficult to completely eliminate the virus. In contrast to innate immunity, adaptive immunity works through the coordinated action of humoral and cellular immunity, demonstrating a more precise and enduring antiviral effect. Humoral immunity, mediated by antibodies secreted by plasma cells, has significant clinical implications in SFTS infection. It has been shown that specific IgM antibodies of SFTSV can undergo seroconversion in the early stages of infection (within three days of symptom onset), peak at 2-3 weeks post-onset and then begin to decline at three months, essentially disappearing after six months (138). In contrast, specific IgG antibodies can be detected at 5-9 days into the disease course, with titers continuing to rise and maintaining peak levels for 6 months to 1 year, gradually declining from the second year onwards (138,139). However, there is a significant difference in antibody response patterns between severe and mild cases. The time for IgG to turn negative in severe cases was delayed (average, 17 days vs. earlier in mild cases), and the overall antibody level increased with a reduced rate of attenuation (138,140,141). This may be related to sustained immune activation due to high viral loads (142). Neutralizing antibodies primarily target the Gn/Gc complex on the surface of SFTSV (143). Wu et al (144) have confirmed that the α6 helix in domain III of Gn is a critical epitope. Non-neutralizing antibodies primarily recognize the nucleocapsid protein (145). There is a significant difference in neutralizing antibody levels between survivors and fatal cases. A serological epidemiological analysis showed that survivors and healthy individuals have significantly higher antibody titers than those who died, and these titers persist for a longer time (146). This aligns with the findings of Song et al (147). Although the proportion of plasmablasts was significantly increased in fatal cases, these cells failed to secrete effective antibodies, indicating a failure in antibody class switching and a deficiency in humoral immune response (147). This suggests that the absence of neutralizing antibodies may be a key marker of fatality in SFTS.

Regarding cellular immunity, CD4⁺ and CD8⁺ T lymphocytes jointly mediate the core antiviral response. Research has found that the differentiation dynamics of CD4⁺ T cells determine the direction of the immune response; a shift towards type 1 T-helper (Th1), Th2 or Th17 phenotypes can lead to excessive inflammatory responses, while abnormal proliferation of regulatory T cells may result in immunosuppression (148,149). This immune imbalance is closely related to the severity of the disease. Sun et al (150) further confirmed that CD3⁺ and CD4⁺ T lymphocytes in acute and severe cases are significantly lower than in recovery and mild cases. Since the Th1 subset is the main effector cell mediating anti-SFTSV cellular immunity, a decrease in their numbers will impair immune defense functions (148). CD8⁺ T cells in patients with SFTS exhibit a highly activated state during viral infection, including significantly increased expression of CD69 and CD25, and stronger proliferative capacity (151). It is speculated that these cells, once activated, can migrate to sites of viral infection to participate in the immune response. Furthermore, CD8⁺ T cells directly mediate the clearance of virus-infected cells by secreting higher levels of cytotoxic substances such as interferon-γ and granzyme B, playing an antiviral role (37,151).

Pathogenic mechanism of tissue and organ injury

SFTSV infection causes organ damage with distinct stages (Fig. 4). In the early phase of infection (<14 days), the pathological damage is mainly restricted to the bone marrow and spleen. There is a significant increase in megakaryocytes in the bone marrow, indicating a compensatory hematopoietic response. Meanwhile, the virus replicates in splenic red pulp macrophages and adheres to platelet surfaces, triggering macrophage phagocytosis and clearance of virus-platelet complexes, which directly leads to a decrease in peripheral blood platelets and leukocytes (27,152). During this period, splenic lymphocyte density decreases, while megakaryocyte proliferation and extramedullary hematopoiesis are active, reflecting the compensatory mechanism of blood cell production after severe infection (27). In the later phase of infection (≥14 days), secondary damage appears in the liver and kidneys. Liver pathology shows hepatocyte ballooning degeneration and focal necrosis, while the kidneys exhibit glomerular cell proliferation and Bowman's capsule congestion. It suggests that this organ damage may be related to virus-induced microvascular permeability abnormalities or metabolic imbalance, rather than direct viral replication (27,152). Laboratory tests found significant increases in serum transaminases (ALT/AST), lactate dehydrogenase and blood urea nitrogen, along with elevated levels of inflammatory cytokines such as IL-6, IL-10 and TNF-α (153,154). Cytokine storms have been confirmed to be associated with disease worsening in severe SFTS cases. Histopathological evidence shows that liver and kidney damage is mainly caused by inflammatory cell infiltration or cytokine-mediated vascular endothelial damage and coagulation dysfunction leading to necrotic lesions (3,155). Therefore, organ damage caused by SFTSV has significant spatiotemporal heterogeneity. Early blood cell abnormalities stem from the virus's direct effect on splenic macrophages, while later liver and kidney dysfunctions are likely the result of multiple pathological mechanisms (including endothelial damage, coagulation disorders and metabolic toxicity) acting together (152,156). Additionally, SFTSV can cause neurological complications. SFTSV can cross the blood-brain barrier (BBB) into the central nervous system (CNS), infect neurons and replicate (157). Animal experiments show that SFTSV has direct neuroinvasive capabilities, can infect neurons and brain macrophages, damage the BBB, induce activation of neurotoxic A1-type reactive astrocytes, release pro-inflammatory cytokines and exacerbate neuronal death (158). However, certain studies have not detected the virus in the CNS, supporting the hypothesis that cytokine storms or reduced cerebral blood flow may indirectly cause disease (5,159). Further research is needed in the future to explore the potential mechanisms of neurological complications.

Figure 4.

Tissue and organ damage caused by severe fever with thrombocytopenia syndrome virus. The virus enters the bloodstream, forming viremia. At this point, macrophages and dendritic cells carry the virus and cytokines into various tissues and organs, leading to immune cell infiltration and cytokine storms, which cause damage to these tissues and organs. In the early stage (<14 days): The virus infects splenic red pulp macrophages and adheres to platelet surfaces, forming virus-platelet complexes that trigger macrophage phagocytosis and clearance, resulting in a decrease in peripheral blood platelets and leukocytes; compensatory proliferation of megakaryocytes in the bone marrow occurs. In the later stage (≥14 days): The liver shows hepatocyte ballooning degeneration and focal necrosis, while the kidneys exhibit glomerular cell proliferation and Bowman's capsule congestion. Neurological complications: The virus crosses the blood-brain barrier, infecting neurons and activating microglia and reactive astrocytes, releasing pro-inflammatory factors and inducing neurotoxicity; some damage may be indirectly mediated by cytokine storms. Created with BioGDP.com.

5. Vaccine research and development

DNA vaccine

In recent years, research on DNA vaccines targeting SFTSV has continued to deepen, mainly focusing on the refined design of antigen combinations and delivery systems. Kang et al (160) constructed a single plasmid, pSFTSV-IL12, which simultaneously encodes the immunomodulatory factor IL-12 and the key antigens of SFTSV (Gn, Gc and NP-NS fusion protein) within the same vector. It was then delivered to IFN-α/β receptor (IFNAR) knockout mice through using muscle electroporation technology. The experimental results showed that this vaccine can significantly enhance the specific response of CD4⁺ and CD8⁺ T cells and achieve complete protection against lethal doses of SFTSV. However, the control vaccine that removes the co-expression of IL-12 can only provide partial protection. It fully demonstrates the significant role of IL-12 in regulating cellular immunity (160). Kwak et al (161) adopted a multi-plasmid strategy, expressing all structural proteins of SFTSV (Gn, Gc, NP, NSs and RdRp), respectively. They also combined in vivo electroporation administration. After two doses of inoculation in an elderly ferret model, all animals survived, exhibiting high levels of neutralizing antibodies and multifunctional T-cell responses, with no detectable viral load in the serum. Further comparison revealed that the plasmid strain expressing only Gn/Gc was sufficient to provide comprehensive protection, while the expression of non-envelope proteins (NP, NSs, RdRp) alone was ineffective. This also indicates that Gn/Gc is the most effective antigen for inducing protective immunity (161).

mRNA vaccine

mRNA vaccines have become an emerging direction in the development of SFTSV vaccines due to their rapid preparation, avoidance of vector pre-stored immune interference and ease of large-scale production (162). Kim et al (163) were the first to report an mRNA Gn vaccine encoding SFTSV Gn glycoprotein, which was encapsulated in lipid nanoparticles. Significant neutralizing antibody production was detected within 24 h after inoculation in BALB/c mice, accompanied by strong Th1-type cellular immunity. Under the lethal dose challenge, all inoculated mice achieved a stable body weight and 100% survival (163). Subsequently, the researchers respectively designed mRNA candidate vaccines in the form of soluble Gn head (sGN-H) and its ferritin nanoparticle fusion (sGN-H-FT) (164). Both of them could maintain high-titer neutralizing antibodies for 12-15 weeks in BALB/c mice and also achieved complete protection in the A129 IFNAR-deficient mouse model. The serum viral RNA decreased significantly and the body regained weight rapidly (163,164). A mechanistic study has shown that the self-assembly structure of ferritin nanoparticles helps enhance antigen presentation and the activation of germinal centers, thereby amplifying the humoral immune effect (164). Lu et al (165) further verified that the full-length Gn mRNA vaccine can continuously activate the Th1 response and provide long-term protection at an ultra-low dose of 1 µg.

Protein subunit vaccine

Protein subunit vaccines focus on the important neutralizing epitopes of glycoproteins on the surface of SFTSV. Kim et al (166) previously have fused sGn-H with self-assembled ferritin 24 polymer (FT) to construct sGN-H-FT nanoantigens, which have been used in the form of recombinant proteins for the development of protein subunit vaccines. This vaccine, when administered at low doses in mouse and elderly ferret models, can induce high-titer neutralizing antibodies and achieve 100% survival in the lethal challenge. Kang et al (160) fused the extracellular domain of the glycoprotein Gn or Gc of SFTSV with the Fc fragment of human IgG to form recombinant proteins Gn-FC and GC-FC. Although the Gn/Gc-Fc fusion protein vaccine can induce specific antibodies, due to its inability to fully simulate the conformation of natural viruses and the lack of cellular immune support, it only provides partial protection (Gn-FC) or no protection (Gc-Fc) in animal models (160). However, traditional subunit vaccines are prone to requiring multiple booster doses during a single immunization due to their low antigen presentation efficiency and limited T-cell immune response (162). To address this, researchers have explored several strategies. One approach is combining antigens with aluminium hydroxide or MF59 adjuvants. Another is using adenovirus vectors for primary immunization, followed by a boost with purified proteins. These methods aim to activate dendritic cells and promote germinal center formation, thereby achieving a Th1/Th2 balance and enhancing both humoral and cellular immune responses (145,167). Although subunit vaccines have good safety and tolerability, certain studies suggest that their antibody levels decline over time. It indicates the need to ensure long-term and durable immune protection by optimizing adjuvant combinations, adjusting immunization schedules or combining with other platforms (145).

Viral vector vaccine

Strategies based on both replicating and non-replicating viral vectors have demonstrated significant advantages in the development of SFTSV vaccines, among which rVSV, Ad5, LC16m8 vaccinia strains and the AAV9 platform have attracted considerable attention. Researchers used rVSV to express SFTSV Gn/Gc. The prepared rVSV SFTSV/AH12 GP vaccine could induce high-titer cross-neutralizing antibodies in immune-healthy and IFNAR gene knockout mice after a single intramuscular injection. It also achieves comprehensive protection in the HRTV lethal challenge and is not affected by existing VSV antibodies (168). The Ad5 vector vaccine Ad5 Gn achieves Th1/Th2 immune balance by efficiently activating dendritic cells and B cells, and has a neutralizing effect superior to that of Ad5 Gc or the combined expression of Ad5 Gn/Gc. It also demonstrates better protective efficacy in IFNAR defect models (169). The recombinant vaccine constructed using the highly attenuated LC16m8 vaccinia virus strain generated virus-like particles in dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin transgenic mice. After immunization, the animals revealed persistent neutralizing antibodies and passive serum transfer confirmed that protection mainly relied on anti-Gn/Gc antibodies (170). The latest research has applied the non-replicating vector AAV9 to Gn delivery. A single dose can not only induce high-titer neutralizing antibodies but is also considered to have excellent safety and immune persistence due to its long-term gene expression characteristics (171).

Attenuated live vaccine

At present, the development of attenuated live vaccines for SFTSV mainly involves modifying viral virulence factors through reverse genetics technology, particularly for the modification of non-structural proteins NSs. Yu et al (172) constructed two recombinant viruses: rHB2912aaNSs (lacking amino acids 2-282 inside the NSs protein and retaining only the head and tail structure) and rHB29NSsP102A (with a conserved proline mutation at position 102 of the NSs to alanine). Both of these mutants lose the ability to induce the tumor progression locus 2 signaling pathway and IL-10, thereby significantly reducing pathogenicity (171). In ferret models, a single dose of vaccination can induce a potent humoral immune response and completely defend against lethal doses (10^7.6 50% tissue culture infectious dose) of allogeneic genotypes (such as the CB1/2014 strain), confirming its cross-protective potential (172). In addition, Bopp et al (173) verified the protective effect of the NSs complete deletion strain (delNSs SFTSV) in IFNAR⁻/⁻ mice. The serum passive transfer experiment after a single dose of immunization showed that the neutralizing antibody was sufficient to mediate a 100% survival rate, highlighting its immunogenicity advantage (173). These vaccines achieve attenuation by disrupting the immune escape function of NSs and preserve antigenic integrity, providing a candidate strategy with both safety and broad-spectrum protective potential for high-risk populations.

Inactivated vaccine

Current studies on inactivated SFTSV vaccines primarily focus on the development of vaccines using formalin-inactivated SFTSV. In a canine model, the vaccine was administered three times with two adjuvants (Alhydrogel and Alhydrogel^® adjuvant or AddaVax^® nanoemulsion) with a two-week interval. Two weeks after the final immunization, the SFTSV strain KCD46 was used for challenge. The results showed that the control group dogs presented with viriemia (2-4 days after infection) and pathological damage to the spleen (atrophy of the white pulp and high TUNEL-positive areas), while in the inactivated vaccine group, not only was no viral load detected, but also the apoptotic areas of the spleen were significantly reduced and pathological changes were rare. The vaccine induced potent neutralizing antibodies, confirming its effectiveness in preventing the pathogenicity and viremia of SFTSV (174).

However, several scientific and technical issues remain to be addressed. The segmented genome of the virus increases the likelihood of reassortment and mutation, posing potential challenges for vaccine coverage. Despite the low genetic variability of Gn/Gc glycoprotein sequences across different SFTSV genotypes, which theoretically supports cross-protective immunity, current experimental data are insufficient to confirm this (162). Furthermore, existing animal models do not fully replicate the clinical manifestations of human infection, complicating preclinical evaluation (173). Special consideration is also required for elderly populations, who are particularly vulnerable to severe outcomes. Vaccine design must therefore maintain immunogenicity while optimizing dosing schedules and ensuring safety in this high-risk group (166). Looking forward, future vaccine development should focus on enhancing the breadth of protection, refining animal models to better mimic human pathophysiology, improving platform technologies and addressing production cost, thermostability and delivery challenges.

6. Progress of clinical treatment

Currently, the clinical management of SFTS is centered on comprehensive supportive care, including platelet transfusion, intravenous immunoglobulin and blood purification (175-177). Due to the lack of specific and effective antiviral drugs, severe cases can rapidly progress to multiple organ failure, particularly in older patients, with significantly increased mortality rates (178). The disease course is typically divided into three stages: The fever stage (lasting 3-7 days), the multiple organ dysfunction stage (starting around day 7) and the recovery stage (after about day 13), with high viral loads (>10⁶ copies/ml) closely associated with disease worsening and death risk (179).

In terms of antiviral treatment, various compounds have been shown to have effects against SFTSV. Ribavirin was once promising, but its efficacy is virus load-dependent, reducing mortality only in early cases with low viral loads (<10⁶ copies/ml), and is ineffective in those with high loads (180,181). Favipiravir (T-705) has shown potential in clinical studies, shortening the disease course by inhibiting viral replication, but it also requires early intervention and is more effective in patients with low viremia, with limited improvement in critical cases (182,183). Additionally, immunomodulatory treatments like corticosteroids are used to suppress excessive inflammatory responses, but their timing and dosage remain controversial and there is a lack of randomized controlled trials to support their use (184). The efficacy of convalescent plasma is still unclear. It may involve neutralizing antibodies and immunomodulatory effects, but plasmapheresis treatment has shown clinical effects in reducing the risk of cytokine storms by quickly clearing circulating viral particles and inflammatory mediators (185).

In recent years, monoclonal antibodies have become a research focus. For instance, the monoclonal antibody 40C10 targeting the viral surface glycoprotein Gn can neutralize different genotypes of SFTSV and related viruses in mouse models, significantly reducing tissue damage and accelerating viral clearance, and is still effective when administered within four days after infection (186). Bispecific antibodies, by targeting different antigenic epitopes synergistically, show stronger neutralizing capabilities (187). However, these biological agents are still in the experimental stage and require further verification of their safety and clinical applicability.

7. Conclusion

SFTS is a tick-borne disease that has received increasing attention in recent years. In China, the complexity and severity of SFTS have gradually emerged through ongoing research and clinical observations. In this review, recent advances in the knowledge of virological characteristics, epidemiological trends, pathogenic mechanisms, vaccine development and clinical treatment of SFTS in China were systematically summarized. These findings reveal core scientific challenges and highlight potential breakthroughs for future research and public health interventions. Based on existing evidence, future efforts should integrate basic research with clinical practice, promote optimization of precise prevention and treatment strategies through multidisciplinary cooperation and provide a scientific basis for public health decision-making.

Funding Statement

The present study was supported by the National Natural Science Foundation of China (grant nos. 82273695 and 82073618), Henan Province Science and Technology Research Project (grant no. 242102311147) and Xinyang Soft Science Research Project (grant no. 20240044).

Availability of data and materials

Not applicable.

Authors' contributions

SC and GD conceptualized the study. HS, QH, SL, YY, LZ, JL, YJ and HY performed the literature search. HS wrote the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.