Multidimensional mechanisms of SFTSV-host interactions: viral protein functions, m⁶A modification, tick saliva factors, and platelet regulation

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV), officially designated as Dabie bandavirus by the International Committee on Taxonomy of Viruses (ICTV), is an emerging zoonotic pathogen belonging to the order Bunyavirales and the family Phenuiviridae. First isolated and identified in 2010 from the serum of patients with severe fever with thrombocytopenia syndrome (SFTS) in China, SFTSV has since been reported in multiple provinces across China, as well as in South Korea, Japan, Vietnam, the United Arab Emirates (including Dubai), and Pakistan. With a case fatality rate of up to 30%, SFTSV poses a serious threat to public health and carries the potential for broader global spread. In nature, SFTSV is primarily transmitted through tick bites, although direct human-to-human or animal-to-human transmission can also occur through exposure to the blood, respiratory secretions, or other bodily fluids of infected individuals or animals. The pathogenic mechanisms of SFTSV are complex and multifaceted, involving the coordinated actions of multiple viral proteins, host epigenetic regulation, and virus–vector interactions. In this review, we take tick bites as the starting point to describe how SFTSV achieves cross-species transmission through ticks, summarize the viral life cycle, including internalization, replication, assembly, and egress, and discuss the antagonistic interplay between the viral life cycle and host defense responses, with the aim of providing a solid theoretical foundation for understanding the infection and pathogenesis of SFTSV.

1. Introduction

SFTSV is a segmented negative-sense RNA virus with spherical or pleomorphic virions approximately 80–100 nm in diameter, characterized by a 5–7 nm-thick lipid bilayer envelope bearing 5–10 nm-long surface spikes composed of the glycoproteins Gn and Gc (Jia et al., 2024), and an internal ribonucleoprotein (RNP) complex formed by genomic RNA tightly encapsidated by the nucleoprotein (Np) (Li, 2024). During the infection process, the virus releases the RNP into the host cell cytoplasm via membrane fusion, and its key life-cycle events, including genome transcription, translation, and virion assembly, are all concentrated and completed within the cytoplasm. The SFTSV genome consists of three RNA segments, designated large (L), medium (M), and small (S), which encode the RNA-dependent RNA polymerase (RdRp), the envelope glycoprotein precursor (Gn/Gc), and both the nucleoprotein (Np) and nonstructural protein (NSs), respectively (Liu et al., 2014; Lee et al., 2023). Collectively, these virus-encoded proteins construct a regulatory network for SFTSV infection across three major stages: host cell entry, genome amplification, and immune evasion, thereby creating an immune-sheltered microenvironment for viral replication (Figure 1).

Figure 1.

Overview of SFTSV-host interactions and the viral life cycle. (A) Tick bite and cross-species transmission. Haemaphysalis longicornis serves as the primary vector for SFTSV transmission. Upon tick attachment to the host's skin, the virus and tick salivary factors are co-released into the localized microenvironment. Host macrophages participate in viral recognition via pattern recognition receptors such as TLRs; however, in cells with low TLR4 expression, the virus more readily establishes infection and activates relevant signaling pathways (e.g., p38 MAPK) to promote viral dissemination. (B) Viral attachment. SFTSV initially binds to the host cell via surface receptors or attachment factors, including C-type lectins, lipid rafts, CCR2, and AXL, which collectively mediate viral attachment and initiate the entry process. (C) Endocytosis and replication. The virus undergoes receptor-mediated endocytosis to enter the host cell. Driven by endosomal acidification (pH change), the virus completes membrane fusion and uncoating, releasing the viral ribonucleoprotein (vRNP) complex into the cytoplasm for subsequent genome replication and transcription. (D) Interactions between virus-encoded proteins and the host. Distinct SFTSV proteins modulate host antiviral responses through multiple mechanisms: Np interacts with host factors to promote viral replication and inhibits the cGAS-STING signaling pathway. NSs induces the formation of inclusion bodies (IBs) to sequester or suppress key molecules, including TBK1, NF-κB, STAT1/2, IRF3/7, SAFA, MAVS, and RIG-I, thereby effectively abrogating the type I interferon signaling pathway. Gn impedes the activation and translocation of STING and facilitates the degradation of related components. The L protein executes viral RNA transcription via a "cap-snatching" mechanism and extensively associates with host pathways, such as the WNT-CTNNB1 pathway. (E) Autophagy and viral release. SFTSV intricately regulates the host autophagic flux. By exploiting molecules such as NSs, NP, BECN1, BCL2, vimentin, Beclin1, and MAVS, the virus promotes autophagosome formation, viral assembly, and maturation, ultimately orchestrating the egress of progeny virions via autophagy-dependent pathways.

2. Role of tick salivary factors in SFTSV

Arboviruses are a group of viruses transmitted by blood-sucking arthropods, with mosquitoes and ticks serving as the primary vectors. Representative pathogens include dengue virus, Chikungunya virus, Japanese encephalitis virus, West Nile virus, and severe fever with thrombocytopenia syndrome virus (SFTSV) (Harsh and Eleftherianos, 2020; Laureti et al., 2020). In recent years, climate change and ecological alterations have continuously expanded the geographical distribution of these vectors, increasing the risk of cross-regional pathogen transmission and thereby making arboviral diseases one of the major public health threats worldwide (Cholvi et al., 2024).

During the establishment of early infection, a complex and dynamic interplay exists between ticks, tick-borne pathogens, and the host immune system. The host skin serves as both the primary barrier against viral invasion and the principal portal of entry for these pathogens (Hermance and Thangamani, 2020). Mechanical injury caused by tick attachment rapidly triggers the host’s wound-healing programs, predominantly characterized by hemostasis and inflammation, which can impede sustained tick feeding (Esteves et al., 2025). Consequently, ticks have evolved sophisticated regulatory strategies mediated by salivary components to counteract these repair responses and remodel the local microenvironment at the bite site. This modulation creates favorable conditions for both blood-feeding and pathogen dissemination, thereby facilitating successful viral colonization within the host.

Current studies indicate that active components in tick saliva facilitate pathogen transmission primarily through two distinct pathways: anti-hemostasis and immunomodulation (Tirloni et al., 2017). For instance, regarding anti-hemostatic functions, apyrase hydrolyzes ATP and ADP to inhibit platelet aggregation (Perumalsamy et al., 2024); tick salivary gland protein 3 (TSGP3) suppresses collagen-platelet binding and its interaction with thromboxane A2, thereby preventing both platelet aggregation and vasoconstriction; meanwhile (Beaufays et al., 2008), TIX-5 targets coagulation-related factors to hinder the coagulation cascade (Šimo et al., 2017). In terms of immunomodulation, Salp15, lipocalin proteins, and other salivary gland-derived proteins can dampen dendritic cell signaling, thereby attenuating the host immune response (Carvalho-Costa et al., 2015; Pham et al., 2021). Concurrently, an IL-2-binding protein suppresses T cell proliferation, while B-cell inhibitory factor (BIF) halts B cell activation and expansion (Pham et al., 2021). Furthermore, during tick feeding and pathogen transmission, salivary gland extract (SGE) can antagonize local angiogenesis and immune responses by inhibiting TGF-β and ERK signaling pathway-mediated fibroblast migration (Bartíková et al., 2020). SGE also directly impairs the motility of macrophages and monocytes and alters cytokine production, further facilitating tick feeding and pathogen dissemination (Schneider et al., 2021). Similarly, in the context of mosquito-borne viruses, SGE has been shown to downregulate inflammasome activation induced by Dengue and Zika virus infections, effectively suppressing innate immunity and promoting viral replication (Shrivastava et al., 2024). Collectively, these effects contribute to the establishment of a localized immune-privileged microenvironment highly conducive to pathogen colonization. It is worth noting, however, that while the aforementioned factors represent the general paradigm of how tick saliva modulates host hemostasis and immunity, the precise mechanisms linking specific salivary components directly to the transmission of select pathogens remain incompletely resolved. Importantly, a recent study has revealed that HIDfsin2, a salivary factor derived from SFTSV-infected ticks, plays a pivotal role in mediating SFTSV transmission.

Specifically, The tick salivary factor HIDfsin2 exerts a bidirectional regulatory effect during SFTSV infection. Upon recognition of HIDfsin2, Toll-like receptor 4 (TLR4) on the surface of macrophages triggers a robust innate immune response, effectively suppressing SFTSV replication. Mechanistically, this process hinges on the interaction between HIDfsin2 and lipopolysaccharide (LPS), where HIDfsin2 disrupts the micellar structure of LPS, thereby upregulating TLR4 expression and activating downstream signaling cascades. Specifically, it induces the activation of the NF-κB signaling pathway and the nuclear translocation of the p38 protein. This intricate regulation culminates in the explosive release of downstream inflammatory cytokines and type I interferons (IFNs), collectively forging a robust barrier against viral infection (Wang L. et al., 2024). However, in stark contrast to this TLR4-mediated antiviral mechanism, in cells with low TLR4 expression (such as A549 and Huh7), HIDfsin2 aberrantly amplifies p38 MAPK activation via the upstream MKK3/6 kinase pathway (Wang et al., 2023). This creates a highly permissive environment for SFTSV replication, elegantly illustrating how the virus exploits the complexity of host signaling pathways to facilitate its own propagation. This phenomenon indicates that tick salivary factors do not exert a strictly unilateral promotive or suppressive effect on SFTSV infection; rather, their ultimate impact is highly contingent upon the host cell type and the specific expression profile of pattern recognition receptors (PRRs). Taken together, tick saliva functions not merely as an accessory tool for vector blood-feeding, but acts as a crucial regulatory node bridging the tick, the virus, and the host immune response.

3. Interactions between SFTSV-encoded proteins and host cells

3.1. Mechanisms of receptor recognition and membrane fusion mediated by Gn/Gc glycoproteins

SFTSV cellular entry is initiated by the binding of Gn/Gc to the cell surface receptor (DC-SIGN) and attachment factors (HS, NMMHCIIA) (Hicks et al., 2024). Both glycoproteins are derived from a glycoprotein precursor (GP) encoded by the viral M segment. Within the endoplasmic reticulum (ER) lumen, GP is cleaved and processed by host proteases to generate two functionally complementary mature subunits: the N-terminal glycoprotein (Gn) and the C-terminal glycoprotein (Gc). On the viral envelope surface, they exist as heterodimers (Moming et al., 2021), and further assemble into pentamers and hexamers (Sun Z. et al., 2023).

The type I transmembrane protein Gn serves as the primary spike structure on the virion surface, mediating viral attachment and endocytosis by specifically binding to host receptors via its highly glycosylated N-terminal domain (Ren et al., 2024). Beyond the previously reported receptor DC-SIGN, subsequent investigations into alternative entry pathways have identified C-C motif chemokine receptor 2 (CCR2) and pro-low-density lipoprotein receptor-related protein 1 (LRP1) as additional critical factors for viral entry. Regarding the former, CCR2 exists as two splice isoforms, CCR2A and CCR2B, which differ in their C-terminal lengths and localize to the plasma membrane. Both isoforms interact directly with Gn through tyrosine sulfation at the Y26 residue of the N-terminal domain (Zhang L. et al., 2023). This interaction is particularly significant because CCR2 is highly expressed in monocytes and macrophages, identifying these as primary target cells for SFTSV infection (Ahmad et al., 2022); furthermore, as a chemokine receptor, CCR2 facilitates the recruitment of inflammatory monocytes, where its binding with Gn triggers pro-inflammatory effects that may correlate with clinical severity (Park and Kim, 2026). In parallel, LRP1 has also been demonstrated as a crucial host factor during the viral entry stage, binding directly to Gn via its CLI and CLII motifs (Xing et al., 2025). Together, these receptor-mediated mechanisms provide clarity to the long-standing debate regarding the target organs and cells of SFTSV. While traditional views attributed multi-organ damage to systemic inflammation induced by B-lineage lymphocyte infection, recent evidence reveals that SFTSV can directly infect pancreatic tissue via CCR2 and LRP1. This direct infection triggers localized immune responses and tissue damage (Liu et al., 2026), offering a new perspective on SFTSV-induced multi-organ dysfunction and suggesting that similar direct infection mechanisms may occur in other organs.

In addition to the aforementioned traditional receptors, recent studies have identified AXL as another critical entry receptor for SFTSV. Identified through genome-wide CRISPRa screening, AXL significantly enhances SFTSV infection and can synergistically facilitate viral entry into host cells when co-expressed with DC-SIGN. Unlike CCR2 and LRP1, which primarily rely on the direct recognition of Gn, AXL-mediated viral entry depends more on an “apoptotic mimicry” mechanism. Specifically, phosphatidylserine (PS) on the viral envelope binds to AXL via the bridging ligand GAS6, forming a “PS-GAS6-AXL” complex. This complex subsequently induces the autophosphorylation of intracellular tyrosine residues on AXL, recruiting PI3K and PLC to activate the PI3K/PLC-dependent macropinocytosis pathway, thereby accelerating viral internalization. Notably, this mechanism remains effective in DC-SIGN-negative cells, such as HUVECs, suggesting that AXL might serve as a crucial entry factor for the early dissemination of SFTSV in tissues like skin and endothelium. Furthermore, these findings indicate that SFTSV is capable of adopting distinct receptor recognition and endocytic strategies depending on diverse cellular contexts (Jin et al., 2025).

Following the initial binding of Gn to cell surface receptors, SFTSV can be internalized into host cells via multiple endocytic mechanisms, including clathrin-mediated endocytosis, lipid raft/caveolin-dependent pathways, and macropinocytosis (Yu Y. et al., 2025). Among these mechanisms, lipid rafts play a well-documented role in facilitating the cellular entry of numerous enveloped viruses, such as influenza virus (IV), herpes simplex virus type 1 (HSV-1), human immunodeficiency virus (HIV), Ebola virus (EBOV), Marburg virus (MARV), and Epstein-Barr virus (EBV) (Takahashi and Suzuki, 2011; Amini-Bavil-Olyaee et al., 2013). During SFTSV infection, upon binding to lipid rafts, the viral glycoprotein Gn recruits the TALIN1 protein into these lipid rafts. This leads to a specific interaction between TALIN1 and Gn, thereby mediating the viral internalization process (Cheng et al., 2024).

Once internalized via endocytosis, SFTSV is encapsulated within vesicular structures and sequentially transported to Rab5+ early endosomes and Rab7+ late endosomes. As the late endosomes gradually acidify (pH ≈ 5.6) (Shen et al., 2022), the class II fusion protein Gc undergoes a pH-dependent conformational rearrangement, thereby driving the fusion of the viral envelope with the host endosomal membrane (Du et al., 2023). During the membrane fusion stage, the fusion peptide of the Gc protein is inserted into the target host membrane; under acidic conditions, the protein shifts from a dimer to a trimer (Jeon et al., 2024). This conformational change shortens the distance between the viral envelope and the endosomal membrane, forcing the two membranes to fuse and thereby releasing the viral genome into the cytoplasm (Jeon et al., 2024). Furthermore, an increasing number of studies indicate that Gn/Gc are not solely involved in viral entry processes—such as attachment, endocytosis, and membrane fusion—but also participate in immune evasion by interfering with host innate immune signaling pathways.

3.2. Mechanisms of immune evasion mediated by Gn/Gc

SFTSV infection of host cells leads to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which is subsequently captured by the DNA sensor cyclic GMP-AMP synthase (cGAS), thereby activating the innate immune response mediated by the cGAS-STING signaling pathway (Sun et al., 2025a). The molecular mechanism of this pathway primarily involves the following key steps: upon binding to mtDNA via its N-terminal domain, cGAS undergoes a conformational change to form a 2:2 dimeric configuration and exposes its enzymatic active site. It subsequently catalyzes the synthesis of the second messenger cGAMP from ATP and GTP; cGAMP then specifically binds to the ligand-binding domain of the endoplasmic reticulum (ER) membrane protein STING (Jiang et al., 2024). In the resting state, STING is anchored to the ER membrane as a dimer via its C-terminal transmembrane domain, with its carboxy-terminal dimerization domain (DD) forming the ligand-binding pocket (Guimarães et al., 2021; Zheng and Gao, 2023). The binding of cGAMP induces the oligomerization of STING and triggers its translocation across the ER-Golgi-perinuclear membrane system. During this translocation process, STING recruits TANK-binding kinase 1 (TBK1) via its C-terminal tail (CTT) domain, forming the STING-TBK1 signaling complex (Sun C. et al., 2023). The activation of TBK1 triggers its kinase activity, which activates the IRF3 transcription factor through a cascade of phosphorylation and ubiquitination modifications. Following nuclear translocation, phosphorylated IRF3 synergizes with nuclear factor-kappa B (NF-κB) to act on the promoter region of type I interferon genes, ultimately mediating the secretion of antiviral cytokines (Wang B. et al., 2022). The SFTSV glycoproteins Gn/Gc can antagonize this pathway through multiple mechanisms: after completing dimerization in the ER, Gn translocates to the Golgi apparatus, where its C-terminal domain (amino acids 1-200) interacts with the CTT domain of STING (amino acids 196-340) (Jiang et al., 2024). This interaction directly interferes with the formation of STING dimers, thereby blocking its oligomerization and subsequent translocation process. Additionally, Gn specifically inhibits the K27 ubiquitination of STING, significantly reducing its ability to recruit TBK1. Furthermore, during the late stages of infection, Gn further attenuates the host antiviral response by promoting the autophagic degradation of STING (Jiang et al., 2024) (Figure 2).

Figure 2.

Mechanisms of SFTSV immune evasion. Regulatory mechanisms of Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) on innate immune recognition, interferon production, and downstream antiviral effector pathways following host cell infection. Under conditions of mitochondrial damage or infection-induced stress, mitochondrial DNA (mtDNA) is released into the cytoplasm and recognized by cGAS, activating the STING-TBK1-IRF3 signaling axis to induce the expression of type I interferons (IFNs) and related antiviral genes. Concurrently, the RIG-I-MAVSTBK1/ IKK-IRF7 pathway is involved in viral RNA recognition and the activation of consecutive immune responses. SFTSV proteins intervene in host antiviral responses via multiple cellular targets. NP interacts with host factors such as A2B1 and SAFA to suppress cGAS-STING signaling and promote viral ribonucleoprotein (RNP) replication. Additionally, the virus modulates the WNTDVL- CTNNB1 pathway to influence host transcriptional responses. On the other hand, NSs induces the formation of inclusion bodies (IBs) to suppress host immune responses, and impacts autophagy as well as RNA interference (RNAi) processes by regulating molecules such as vimentin, Beclin1, and AGO2. Meanwhile, the virus interferes with PRR-IFN-JAK-STAT signal transduction, suppressing the expression of antiviral effector genes such as MxA, IFITM3, and NF-κB. Overall, SFTSV achieves robust immune evasion and facilitates viral replication and release by dampening pathogen recognition, intercepting interferon signaling, and remodeling intracellular homeostasis.

3.3. The role of L protein in viral replication

After entering host cells via endocytosis, the virus completes membrane fusion under the influence of late endosomal acidification and releases its genome into the cytoplasm. Subsequently, SFTSV rapidly initiates the transcription and replication processes. This process is primarily mediated by the RNA-dependent RNA polymerase (RdRp) encoded by the L segment, namely the L protein, whose function relies on the synergistic coordination of multiple domains, including the core catalytic domain, the cap-binding (CapB) domain responsible for recognizing the 5’ cap structure of host mRNAs, and the Endo domain with endonuclease activity (Kim and Park, 2023; Kim D. et al., 2024). During genome replication, the virus first uses the negative-sense genomic RNA (vRNA) as a template to synthesize positive-sense complementary RNA (cRNA), and subsequently uses the cRNA as a template to generate new progeny vRNAs (Williams et al., 2023).

Viral genome replication primarily proceeds via two pathways, namely replicating from both termini or initiating from the internal generation of short primers (Williams et al., 2024). Current structural data on how the SFTSV L protein facilitates viral genome replication indicate that SFTSV genome replication tends towards the realignment of short primers, initiating replication via a mechanism known as”cap-snatching” (Vogel et al., 2020). The CapB domain of the L protein binds and cleaves host capped RNAs to serve as viral replication primers; related studies show that RNAs associated with the WNT-CTNNB1 signaling pathway in host cells may become an important “reservoir” for viral transcription initiation primers, thereby triggering the downregulation of this signaling pathway (Jiang et al., 2023). This phenomenon is not limited to SFTSV; a similar downregulation trend in the WNT-CTNNB1 signaling pathway has also been observed during infections with other segmented negative-sense RNA viruses, such as Lassa virus (LASV) and influenza A virus (IAV) (Jiang et al., 2023). In the context of viral infection, the L protein interacts with WNT pathway-associated RNAs, utilizing CapB to capture host mRNAs, while the Endo domain cleaves short RNA fragments at the 5’ ends of host cell mRNAs, snatching the host mRNA caps to serve as primers for transcription initiation. Subsequently, the cap-snatched WNT pathway-associated RNAs undergo degradation, ultimately causing a decline in overall CTNNB1 levels and thereby affecting the activation of downstream transcription factors (Jiang et al., 2023), a cascade of events that ultimately leads to disease exacerbation or even death. Studies indicate that the WNT-CTNNB1 pathway exerts a certain regulatory role in platelet function, including aspects such as platelet adhesion, aggregation, and activation (Woldeamanuel et al., 2025), whereas alterations in platelet function and reductions in platelet count are typical hallmarks of human SFTSV infection, and this pathway along with its downstream transcription factors may contribute to impaired T cell responses (Dai et al., 2016). The expression level of this pathway holds promise as a biomarker for evaluating disease prognosis, possessing value for further investigation.

After completing cap-snatching, the viral genome then begins to initiate viral replication dependent on the conformational changes of the L protein. Cryo-electron microscopy (cryo-EM) further resolved five conformational states of the L protein during the replication process from pre-initiation to the late-elongation stage (Williams et al., 2023). In the initiation stage, the L protein binds with the 5’cRNA and undergoes conformational change; in the dynamic conformations of the viral polymerase, the vRNA-binding lobe (vRBL) coordinately rearranges with the adjacent fingers domain and the PA-C-like core lobe, forming a binding interface rich in positive charges to specifically capture the 5’ end RNA, namely the 5’ hook structure, and subsequently the L protein enters the elongation stage. The elongation stage can be divided into three subtypes based on differences in endonuclease conformations: “Early-elongation”, “Early-elongation-endo”, and “Late-elongation”. Therein, the Endo domain completes the terminal stage of elongation through a “protruding” conformational transition, at which point the distal double strand forms a stable 3’RNA and guides it into the RdRp active center of the L protein, accommodating a 10bp product-template duplex structure within the RdRp core, thereby starting the replication process. Finally, the 3’ and 5’ ends of the cRNA bind with the hook binding site and the secondary binding site, respectively; this stage does not form a distal duplex structure, and the L protein enters a resting conformation (Figure 2).

3.4. Viral RNA protection and immune evasion functions of the Np

Upon the release of the viral genome into the cytoplasm, the nucleocapsid protein Np wraps the viral RNA in an exquisite hexameric/pentameric ring structure and forms a functional conjugate with the L protein, jointly constituting the viral ribonucleoprotein complex (vRNP) (Wang et al., 2025). This unique morphology serves not only as a protective shell for the viral genetic material, but also as a core architecture actively participating in the viral replication and assembly processes. This encapsulation strategy of the Np protein can effectively resist degradation by host cellular nucleases and attacks from the host immune system, thereby ensuring the integrity and stability of the viral genome (Park et al., 2025). This encapsulation strategy possesses evolutionary conservation among viruses of the Phenuiviridae family; further analysis of this phenomenon helps to deepen the understanding of viral immune evasion mechanisms and propel the development of new antiviral drugs.

Np can hijack host factors to promote replication. Heterogeneous ribonucleoprotein A2B1 (hnRNP A2B1), as a core member of the eukaryotic hnRNP complex, participates in the replication process of various RNA viruses through a nucleocytoplasmic transport reprogramming mechanism, and its function possesses significant evolutionary conservation (Zhang et al., 2024). For example, during infections with Sendai virus (SeV), vesicular stomatitis virus (VSV-GFP), enterovirus 71 (EV71), and Zika virus (ZIKV), it exhibits translocation from the nucleus to the cytoplasm (Zhang et al., 2024). In SFTSV infection, Np directly interacts with the RRMs domain of A2B1, competitively blocking its nuclear localization signal (NLS) function and mediating the retention of hnRNP A2B1 in the cytoplasm; the latter interacts with the 5’ UTR of SFTSV RNA segments to enhance SFTSV replication (Zhang et al., 2024).

Np Participates in Virus-Host Interactions Through the Type I Interferon Response. Studies have shown that the host heterogeneous ribonucleoprotein A2B1 (hnRNP A2B1) is involved in sensing mitochondrial DNA (mtDNA) leakage during SFTSV infection and triggers the STING-TBK1 axis to enhance the type I interferon response (Huang et al., 2025). By capturing newly synthesized hnRNP A2B1 in the cytoplasm, SFTSV NP recognizes mitochondrial mtDNA leakage, and subsequently mediates the activation of the STING-TBK1 signaling pathway to promote IFN-β production. These findings reveal the role of hnRNP A2B1 in sensing SFTSV infection in the cytoplasm and activating innate immunity. This suggests that by targeting hnRNP A2B1, novel antiviral therapies against SFTSV and other RNA viral infections can potentially be developed.

Recent studies have also revealed that nuclear scaffold attachment factor A (SAFA) is involved in host innate immune recognition during SFTSV infection. In the resting state, SAFA is primarily localized in the nucleus; however, following SFTSV infection, its expression level is upregulated, and it is retained in the cytoplasm mediated by the viral nucleocapsid protein Np (Amurri et al., 2023). This process relies on the binding of the viral nucleocapsid protein Np to the nuclear localization signal (NLS) domain of SAFA. The cytoplasm-retained SAFA recognizes exogenous SFTSV RNA, binding specifically to the viral S- and M-segment RNAs; on this basis, SAFA further recruits and promotes the activation of the STING-TBK1 signaling axis, enhancing the phosphorylation levels of TBK1, IRF3, and NF-κB related pathways, thereby inducing the expression of type I interferons and various pro-inflammatory cytokines, and ultimately inhibiting SFTSV replication (Amurri et al., 2023). Furthermore, host cell Myxovirus Resistance Protein A (MxA) specifically targets the N-terminal domain of Np in an RNA-independent manner, blocking the Np-RdRp interaction and interfering with RNP activity, which in turn inhibits viral replication (Chang et al., 2024; Li, 2024). However, Np is not merely a passive target of host antiviral recognition; it also possesses significant immune evasion functions. Studies have demonstrated that Np specifically binds to the 161–382 domain of cyclic GMP-AMP synthase (cGAS) to form an Np-cGAS-LC3 ternary complex. This complex is directionally transported to the lysosomal system for degradation via the autophagy pathway, successfully inhibiting the activation of the cGAS-STING signaling pathway and significantly weakening the host type I interferon response, thereby facilitating the establishment of an intracellular microenvironment conducive to the virus (Jiang et al., 2024).

Np as a Crucial Diagnostic Target and Protective Vaccine Immunogen. Owing to its high conservation across diverse RNA viruses, the nucleocapsid protein Np serves as the premier diagnostic target for SFTSV, underpinning the successful development of various Np-specific monoclonal antibodies, ELISA assays, and S-segment-targeted PCR tools (Kim S. et al., 2024; Stamper et al., 2025). Beyond its diagnostic utility, Np exhibits robust immunogenicity, eliciting potent Np-specific humoral and cellular immune responses following viral infection. Notably, recent subunit vaccine evaluations in IFNAR-KO mouse models demonstrated that a single-dose Np vaccination yielded a remarkable 66.7% survival rate against lethal SFTSV challenge, vastly outperforming the Gn subunit vaccine (which offered only a 16.7% survival rate), while concurrently and significantly boosting antigen-specific T-cell responses. Although Np-specific antibodies lack direct in vitro neutralizing activity, they play an indispensable collective role in in vivo antiviral immunity, likely acting in synergy with Np-specific T-cell responses to robustly enhance the overall protective efficacy (Kim S. et al., 2024). This paradigm of non-neutralizing yet protective Np-mediated immunity represents a conserved feature shared with other bunyaviruses; previous investigations have established that active or passive immunization targeting Np confers at least partial protection in animal models against lethal challenges of Rift Valley fever virus (RVFV) and Crimean-Congo Hemorrhagic Fever Virus(CCHFV) (Jansen van Vuren et al., 2011; Tipih and Burt, 2020). Consequently, although the detailed humoral mechanisms of these non-neutralizing antibodies remain to be fully elucidated, Np has emerged as an indispensable protective immunogen for the design of future SFTSV vaccines (Figure 2).

3.5. Immune evasion and viral RNA protection by the non-structural protein NSs

The Non-structural Protein NSs Inhibits Host Antiviral Immunity. As a crucial SFTSV virulence factor, its strategic mechanism lies in inducing the formation of a specialized lipid-body structure—the inclusion body (IB)—to hijack a series of key immune signaling molecules. These hijacked molecules include TANK-binding kinase 1 (TBK1), inhibitor of nuclear factor-κB (IκB) kinase subunit epsilon (IKKϵ), retinoic acid-inducible gene I (RIG-I), transcription factors STAT1 and STAT2, and interferon regulatory factors IRF3 and IRF7, thereby effectively suppressing the host immune response (Ning et al., 2019; Lee and Shin, 2021; Li et al., 2022). Studies have demonstrated that heat shock protein 90 beta (HSP90β) is involved in the formation and stabilization of NSs-mediated inclusion bodies (IBs) (Wang B. et al., 2024). Given the critical roles of the HSP90 family in protein folding, complex assembly, and functional maintenance across various viral life cycles (e.g., during dengue virus entry and herpes simplex virus transcription) (Kamal et al., 2004; Kubota and Hashiguchi, 2021; Ben Abdallah et al., 2024), focusing on the connection between HSP90 and SFTSV infection is of great significance. Particularly, interfering with the NSs-HSP90β interaction holds promise as a potential antiviral strategy to inhibit IB formation and restore the host immune response. Furthermore, NSs interacts with SAFA to mediate its nucleocytoplasmic translocation. By enhancing the interactions among SAFA, LC3, and SQSTM1, NSs subsequently drives the autophagic degradation of SAFA, downregulates the phosphorylation of TBK1 and p65, and thereby suppresses the host innate immune response (Yu TM. et al., 2025). Concurrently, the formation of IBs allows the Np-SAFA complex to be sequestered within these structures, effectively blocking the STING signal transduction pathway through spatial isolation to facilitate immune evasion (Huang et al., 2026). Nevertheless, whether the signaling mechanisms underlying the retention of SAFA by Np and NSs predominantly represent a viral immune evasion strategy or a host antiviral defense mechanism requires further investigation.

In addition to suppressing innate immune responses by sequestering pattern recognition receptor (PRR)-associated molecules within IBs and blocking subsequent signal transduction, NSs also protects viral RNA and promotes replication by antagonizing the RNA interference (RNAi) mechanism. As a core eukaryotic antiviral defense mechanism, RNAi utilizes small RNAs to mediate complementary sequence recognition, leading to target mRNA degradation or translational inhibition (Ying et al., 2007; Chable-Bessia et al., 2009). This pathway is initiated by the recognition of viral double-stranded RNA (dsRNA) by DICER, which processes it into multiple small interfering RNA (siRNA) duplexes (Bocos-Asenjo et al., 2022). NSs can interact with several components of the RNAi pathway, including AGO2, DICER, TNRC6A, and PRKRA, with a particularly noteworthy interaction with AGO2. NSs competitively binds to AGO2, primarily in an RNA-independent manner, thereby inhibiting the degradation of viral RNA by the RNAi machinery and facilitating viral replication (Javaid et al., 2025) (Figure 2).

4. Dual regulatory roles of m⁶A modification in SFTSV infection

Beyond direct viral-host protein interactions, epitranscriptomic regulation mediated by RNA chemical modifications represents another vital mechanism by which viruses intricately fine-tune gene expression and modulate host antiviral responses. With the continuous advancement of high-throughput sequencing technologies, over 170 distinct types of RNA chemical modifications have been identified in eukaryotic cells (Zhang et al., 2020). Collectively, these modifications construct a highly intricate epitranscriptomic regulatory network; by dynamically governing fundamental processes such as RNA splicing, nuclear export, transcript stability, translational efficiency, and immune evasion/recognition, this network plays an essential role in driving development, immune responses, and disease progression (Shi et al., 2020; Yang et al., 2024). Multiple studies have shown that many chemical modifications, originally found in eukaryotic cell RNAs, also exist in viral genomic RNAs and viral transcripts (Lichinchi et al., 2016; Courtney et al., 2017; Shen and Zhang, 2023). After the virus enters host cells, viral RNA can not only utilize the host’s chemical modifications to regulate its life cycle, but can also regulate the expression levels of host chemical modifications, greatly affecting viral replication and the host innate immune response (Gokhale et al., 2016; Lichinchi et al., 2016; Iwanami et al., 2020). In the exploration of the interactions between viruses and chemical modifications to date, researchers have found that only a very few chemical modifications play a role in virus-host interactions, such as N⁷-methylguanosine (m⁷G), 2′-O-methylated ribonucleosides (Nm), m⁶A, and 5-methylcytidine (m⁵C) (Williams et al., 2019; Furuse, 2021; Ma et al., 2021; Zhang et al., 2021).

N⁶-methyladenosine (m⁶A), as the most abundant dynamic and reversible post-transcriptional modification in mRNA, is coordinately regulated by methyltransferases (methylases), demethylases (demethylases), and reader proteins, forming a “Writer-Eraser-Reader” tripartite molecular regulatory axis (Yang et al., 2018; Ma et al., 2021). It plays an important role in the specific gene expression and replication of various pathogenic viruses, as well as the innate immune responses generated after viral infection of the host.

Multiple studies have shown that m⁶A modification is a dynamic and variable process, and there exist multiple modification patterns for m⁶A (Zhang et al., 2022). While m⁶A modification exerts a promotive effect on the replication of viruses such as SARS-CoV-2, IAV, HIV-1, EBV, and EV71, it exhibits inhibitory effects on the replication of HSV, KSHV, and various viruses within the Flaviviridae family (Zhang et al., 2021; Yanagi et al., 2022; Cao et al., 2024). Taking HBV as an example: on one hand, YTHDF2/YTHDF3 proteins reduce the stability of HBV RNA by binding to m⁶A modification sites at the 3′ stem-loop end, thereby affecting its protein expression; on the other hand, m⁶A modification at the 5′ end of HBV pgRNA positively regulates the reverse transcription process of pgRNA, promoting viral replication (Imam et al., 2018; Kim and Siddiqui, 2021; Lv et al., 2023).

m⁶A modification also exhibits a complex spatio-temporal specific regulatory pattern in SFTSV. SFTSV recruits the host methyltransferase complex METTL3-METTL14 via Np, prompting the translocation of this complex to the cytoplasm. By utilizing its C-lobe domain (P112-L245) to interact with the METTL3 zinc finger domain (ZFD) (aa 258-336), Np catalyzes the m⁶A modification of viral RNA (Chen et al., 2024). Simultaneously, Np synergistically recruits the RNA-binding protein family GF2BP1/2/3, which binds to m⁶A modification sites to significantly enhance the stability of viral genomic RNA and the translational efficiency of Np mRNA, thereby driving efficient viral replication (Chen et al., 2024). This is similar to the mechanism found in SARS-CoV-2 infection, where RdRp appears to regulate the synthesis and ubiquitination of METTL3 through unknown mechanisms, altering its distribution and enhancing viral replication (Li et al., 2021). This demonstrates that m⁶A modification plays a crucial role in viral replication.

Furthermore, the m⁶A reader protein YTHDF1 exhibits functional duality during SFTSV infection. On one hand, YTHDF1/2/3 proteins recognize the A273 site to promote viral translation efficiency (Liu et al., 2024). On the other hand, YTHDF1 recognizes the A63 and A343 sites to negatively regulate SFTSV mRNA translation efficiency; specifically, YTHDF1 reduces the RNA stability and protein translation efficiency of the SFTSV S segment in an m⁶A-dependent manner (Liu et al., 2024). To dismantle the negative regulatory effect of host YTHDF1, SFTSV has evolved a dual strategy. The first layer of this strategy is that, after SFTSV infection, total cellular lactate levels rise, promoting lysine lactylation (Klac) modification of YTHDF1, which leads to increased ubiquitination levels and decreased YTHDF1 stability. The second layer of the strategy involves the virulence factor NSs, which induces the nuclear translocation of the deacylase Sirt6 and interacts with it to downregulate the formation of the Sirt6-YTHDF1 complex. This weakens the removal of lysine lactylation (Klac) from the YTHDF1 protein by Sirt6, thereby affecting YTHDF1 protein stability and subsequently promoting viral replication (Liu et al., 2024). Consequently, SFTSV not only utilizes the host m⁶A writing and reading systems to enhance its own RNA stability and translation efficiency but also lifts host restrictions by regulating the post-translational modification status of m⁶A reader proteins, reflecting the virus’s sophisticated utilization of the host epitranscriptomic regulatory network (Figure 3).

Figure 3.

Bidirectional regulation of m⁶A modification in viral infection. This image compares the differential regulatory roles of SFTSV in host RNA epitranscriptomic modifications and viral replication in the context of mutational backgrounds at the A273 site versus the A63/A343 sites. The left panel illustrates that at the A273 site, the viral nucleocapsid protein (Np) interacts with the host methyltransferase complex METTL3/METTL14 to promote the m⁶A modification of viral RNAs. The m⁶A-modified viral RNAs are subsequently recognized and bound by reader proteins such as YTHDF1/2/3 and IGF2BP1/2/3. This process significantly enhances RNA stability and translational efficiency, thereby promoting viral protein synthesis and viral replication. The right panel reveals that at the A63 and A343 sites, viral infection induces lactic acidification and alters the lysine lactylation (Kla) levels of host proteins, which directly affects the modification status of YTHDF1 and its ability to recognize m⁶A-marked RNAs. Meanwhile, Sirt6 is involved in removing the lactylation marks, a regulatory process that is also modulated by the viral NSs protein. Collectively, these alterations decrease viral mRNA stability and suppress related post-transcriptional regulation. This suggests that variations at distinct sites can alter SFTSV replication efficiency and the pathogenic process by modulating m⁶A recognition, RNA fate, and host translational regulatory networks.

5. Programmed cell death and pathogenesis of SFTSV-infected host cells

By suppressing host antiviral responses, viruses create a microenvironment conducive to their own replication, completing gene transcription and translation and proceeding to the assembly and release of viral particles. Simultaneously, the host utilizes various programmed cell death (PCD) pathways to restrict infection and eliminate infected cells. PCD includes modes such as apoptosis, necroptosis, pyroptosis, autophagy-dependent cell death, and ferroptosis, which are not only involved in maintaining tissue homeostasis but also serve as key components of the innate immune defense system (Lamkanfi and Dixit, 2010). The interaction between the virus and the host leads to a complex bidirectional regulation of cell death. On one hand, the host limits viral dissemination and promotes tissue repair by inducing programmed death; conversely, viruses can selectively regulate or exploit specific death pathways to facilitate replication or evade immune clearance. Emerging research demonstrates that SFTSV possesses the capability to modulate host cell death through multiple pathways. At the inflammatory level, SFTSV can activate the NLRP3 inflammasome to drive the cleavage and maturation of caspase-1, promoting the release of IL-1β and IL-18 (Liu et al., 2021; Li et al., 2022; Liu PP. et al., 2025). This pyroptotic mechanism shares pathological features with SARS-CoV-2 infection in monocytes and HIV-induced pyroptosis in CD4+ T cells (Chen et al., 2022; Lokupathirage et al., 2025). Beyond pyroptosis, SFTSV also participates in inflammatory pathogenesis via RIPK3-MLKL-mediated necroptosis (Li S. et al., 2025). The viral non-structural protein NSs directly binds to the kinase domain of RIPK3 and forms condensate-like “viral necrosomes,” which promote RIPK3 autophosphorylation and MLKL activation. By inducing inflammatory necroptosis while inhibiting RIPK3-mediated antiviral apoptosis in a kinase-independent manner, the virus amplifies the inflammatory response and facilitates its own replication (Li S. et al., 2025). This suggests that SFTSV may reshape RIPK3-downstream cell death programs via NSs, suppressing antiviral apoptosis while driving more pro-inflammatory necroptosis to achieve a pathogenic outcome where viral replication thrives alongside host damage. Regarding metabolic regulation, SFTSV utilizes m⁶A epigenetic modifications to regulate the ATG5-dependent ferritinophagy pathway, triggering hepatocyte ferroptosis and hepatic dysfunction (Liu B. et al., 2025); simultaneously, SFTSV coordinates pyroptosis, apoptosis, and autophagy to cause multifaceted damage to platelets, accelerating the clinical progression of thrombocytopenia (Ding et al., 2026). To date, the dynamic regulatory network of SFTSV-modulated host cell programmed death—particularly the synergistic or antagonistic interactions between various death modes within the infection microenvironment—remains a critical scientific challenge to be addressed.

Among the above-mentioned multiple programmed cell death pathways, the most systematically researched is the regulation of the viral life cycle by autophagy. Autophagy is a highly conserved intracellular metabolic regulatory mechanism, which transports intracellular damaged proteins, organelles, or pathogens to lysosomes for degradation through the formation of double-membrane enclosed vesicles, thereby achieving the recycling of cellular components and the maintenance of homeostasis (Zhou et al., 2025). The invasion of exogenous pathogens is the trigger for autophagy initiation. The interaction between viruses and cell surface receptors induces autophagy, such as inducing autophagy through the CD46-Cyt-1/GOPC pathway, TOLL-like receptors recognizing viruses and then stimulating adaptor proteins to interact with Beclin1 to induce autophagy, and integrins can activate autophagy by interacting with LIR motifs or inhibiting the mTOR pathway (Yang, 2023; Zhang J. et al., 2023). There are complex interactions between viruses and autophagy. As a protective mechanism of the body, it induces innate immune responses through antigen presentation and the induction of interferon production during viral infection, achieving the effect of clearing pathogens. However, in order to antagonize this effect, viruses have evolved multiple evasion strategies. Viruses disrupt the formation of autophagosomes through interference with various stages of autophagosome formation, can also hijack autophagosomes as sites for their own assembly and maturation, and complete the release of viral particles through autophagy. For example, SARS-CoV-2 inhibits autolysosomal degradation through NSP6, preventing recognition and degradation by the body’s defense system (Ivanova et al., 2023), and viruses such as HCV, ZIKV, and DENV have been confirmed to be able to induce autophagy, utilizing autophagy to promote their own replication (Ming et al., 2016). Therefore, depending on the differences in viruses and viral replication cycles, autophagy has both the function of promoting viral replication and anti-viral function.

SFTSV controls the viral life cycle by regulating autophagic flux. SFTSV assembles progeny SFTSV particles through phagocytic vesicles formed by the endoplasmic reticulum-Golgi intermediate compartment (Chen et al., 2023). In this process, Np/NSs encoded by the S segment induce complete autophagic flux (i.e., the entire process from autophagosome formation to lysosomal degradation) to promote viral replication (Feng et al., 2023).

Research has demonstrated that Np antagonizes the innate immune response by inducing mitophagy. After SFTSV invades host cells, viral RNA is recognized by RIG-I-like receptors, subsequently RIG-I translocates to the mitochondrial outer membrane and interacts with MAVS, the latter of which transmits signals to downstream kinases TBK1 and the IKK complex. IRF3, IRF7, and NF-κB are further activated and translocated into the nucleus, leading to the induction of type I interferons (IFN-I), IFN-stimulated genes (ISGs), and pro-inflammatory cytokines, thereby exerting antiviral effects. Np causes the RLR downstream pathway to be unable to activate by degrading MAVS through autophagy, thus antagonizing the antiviral response. Np induces TUFM (Tu translation elongation factor, mitochondrial)-dependent mitophagy, upregulates the expression of TUFM and interacts with it to translocate to the mitochondria, then mediates mitochondrial sequestration into autophagosomes through interaction with LC3, thereby inducing mitophagy for the degradation of MAVS (Zhang WK. et al., 2025). In addition, Np can also inhibit the association between BECN1 and BCL2, inhibiting its binding with BCL2 to promote PIK3C3-BECN1 complex-dependent autophagy (Wang T. et al., 2022).

In addition to Np, NSs utilizes autophagy to promote viral replication. NSs interacts with vimentin and induces the degradation of vimentin through the K48-linked ubiquitin-proteasome pathway, which hinders the formation of the negatively regulatory Beclin1-vimentin complex and promotes complete autophagic flux, thereby facilitating viral replication and release (Liu et al., 2023). Np and NSs not only regulate autophagy through single proteins, but can also interact with each other to jointly participate in the regulation of autophagy. Research has found that NSs W61Y (substitution of tryptophan with tyrosine at position 61) can inhibit the interaction between Np and NSs, thereby affecting the lipidation process of LC3-I, inhibiting the formation of phagophores, and ultimately affecting replication; moreover, viral components such as Np and NSs can also promote autophagy by inhibiting the phosphorylation of MTOR and suppressing the activation of its downstream pathways (Park et al., 2024) (Figure 2).

6. Interaction between SFTSV and platelets

6.1. Role of platelets in SFTSV infection

Platelets, as an important component of the blood system, play an important role in thrombosis and hemostasis. At the same time, platelets also play an important role in immune responses; their surfaces possess a variety of receptors related to immune functions, such as Toll-like receptors, NOD-like receptors, and the major histocompatibility complex, etc., and these surface receptors and proteins interact with invading pathogens to exert innate immune functions (Wolny et al., 2023; Sun et al., 2025b). Activated platelets release various chemokines and cytokines, participating in the regulation of inflammatory and immune responses (Tian et al., 2025).

In SFTSV infection, platelets, with their unique identity, become the key link connecting the virus and the host’s immune response. Activated platelets can regulate the phagocytic function of phagocytes and promote the release of multiple cytokines such as IL-6, IL-10, and TNF-α; while clearing the virus, this can lead to a cytokine storm and exacerbate disease severity (Liu et al., 2017). SFTSV adheres to platelets, utilizing platelets as carriers to enter phagocytes for replication, which can lead to the overactivation of phagocytes and the release of large amounts of inflammatory factors and chemokines (Li, 2013; Nakano et al., 2017; Du et al., 2024). Clinical studies show that the levels of inflammatory factors and chemokines in SFTS patients are significantly higher than those in healthy controls, and are often accompanied by lymphopenia and the inhibition of adaptive immune responses (He et al., 2021; Hou et al., 2025). In SARS virus infection, research has shown that T cell numbers are negatively correlated with serum IL-6, IL-10, and TNF-α; combined with the fact that the same phenomenon of the aforementioned cytokine elevation and T cell reduction exists in SFTSV infection (Li et al., 2023; Chen et al., 2025), it suggests that SFTSV may also partially through inflammatory factor imbalance indirectly inhibit T cell function, promote T cell exhaustion, ultimately weaken host antiviral immunity and drive the formation of cytokine storms, diminish the host’s ability to respond to the virus, seriously damage host immune function, cause the occurrence of host immunodeficiency diseases, increase the occurrence of opportunistic infections, and exacerbate the progression of the disease.

Beyond their role in mediating inflammatory amplification and viral transport, platelets are also direct targets of SFTSV damage, leading to functional impairment and a reduction in counts. SFTSV-induced platelet activation and apoptosis are the primary causes of thrombocytopenia, the severity of which correlates with that of SFTS. Recent studies indicate that platelet surface glycoproteins recognize and interact with SFTSV glycoproteins GN/GC through hydrogen bonds and electrostatic interactions, activating the GPVI signaling pathway and triggering downstream spleen tyrosine kinase (Syk), signal transducer and activator of transcription 3 (STAT3), and phospholipase Cγ2 (PLCγ2) (Fang et al., 2023). This series of reactions enhances the expression of P-selectin on the platelet surface and the exposure of phosphatidylserine (PS), causing platelets to be overactivated and aggregate at endothelial cells, increasing their risk of being cleared and the possibility of thrombosis. At the same time, the activated platelets release various chemokines, which not only may initiate immune responses and enhance phagocytosis, but also affect functions such as platelet aggregation, apoptosis, ATP release, spreading, and clot retraction, collectively promoting the loss and reduction in the number of platelets during SFTSV infection (Fang et al., 2025).

In parallel, SFTSV can internalize into platelets, exploiting their active metabolism to replicate within organelles such as mitochondria, the Golgi apparatus, and the endoplasmic reticulum (Cox, 2023). Platelets with viral adhesion or internalization are more likely to become targets for phagocytes. Transcriptomic analysis of SFTSV infection reveals that the virus can downregulate the expression of calcium signaling pathway-related genes GNA13 and ARHGEF12, thereby modulating genes such as ROCK1 and MYL12A to inhibit the calcium signaling pathway (Fu et al., 2023). Calcium signaling transduction plays a central role in platelet activation, granule release, adhesion, aggregation, and cytoskeletal remodeling; its dysregulation directly leads to abnormalities in platelet morphology and function (Mojzisch and Brehm, 2021). Newly released virions then interact with uninfected platelets, further exacerbating the depletion of platelets and adding a new dimension of complexity to the pathological mechanisms of SFTSV infection.

Concurrently, the interaction between SFTSV and platelets can induce a pronounced oxidative stress response. The adhesion of SFTSV triggers the generation of large amounts of reactive oxygen species (ROS) within platelets; an excess of ROS disrupts the platelet redox balance and, by upregulating Bax/Bak proteins, decreasing mitochondrial membrane potential, and activating MAPK pathways (p38, ERK, and JNK), promotes the release of cytochrome C and its binding with Apaf-1 (Zhou and Yu, 2021; Newman and Shadel, 2023; Zhou et al., 2024; Liao et al., 2025). This, in turn, activates the mitochondrial caspase apoptosis pathway, ultimately inducing platelet apoptosis. In this process, the activation of MAPK is a pivotal link; it not only enhances the activation state of platelets but also promotes platelet aggregation and clot retraction. Antioxidants exhibit a significant inhibitory effect on the elevated phosphorylation levels of MAPK family members (including ERK, p38, and JNK) caused by SFTSV infection, confirming that SFTSV induces apoptosis by utilizing the ROS-MAPK signaling pathway (Zhou et al., 2024).

In addition to oxidative stress, SFTSV infection can also induce extensive changes in the transcriptomic and functional states of platelets. Particularly notable among these are the mediation of neutrophil activation, type I interferon (IFN) signaling, and the fine regulation of the viral life cycle. In this series of complex biological responses, three differentially expressed genes (DEGs)—LYZ (lysozyme C), USP1 (ubiquitin carboxyl-terminal hydrolase 1), and CTSS (cathepsin S)—play crucial roles, suggesting their potential involvement in the aforementioned processes (Fang et al., 2025). Although the specific roles of these three genes in SFTSV infection are not yet fully elucidated, existing studies have shown that they possess potential functions in other viral infections or immune regulation. Among them, USP1 can stabilize cGAS and enhance type I interferon responses through the UAF1-USP1 deubiquitinase complex, thereby promoting host antiviral immunity, which suggests that USP1 may play an important immunoregulatory role in SFTSV infection-related platelet responses (Yu et al., 2017). LYZ is an antimicrobial enzyme involved in innate immunity that primarily exerts antibacterial effects; in the context of porcine epidemic diarrhea virus (PEDV), it was found that LYZ downregulates the transcriptional level of RIG-I via YTHDF2, thereby affecting the degradation of endogenous RIG-I protein and inhibiting innate immunity (Zhang Y. et al., 2025). Meanwhile, CTSS is associated with neuroinflammation caused by human herpesvirus 6 (HHV-6) and multiple sclerosis (Shao et al., 2016). However, the specific functions of these three genes in SFTSV infection require further exploration. In addition, SFTSV infection leads to platelet activation and functional abnormalities, where activated platelets express a variety of receptors on their membrane surfaces that participate in platelet adhesion, aggregation, and the release of bioactive substances (such as growth factors, chemokines, and cytokines), playing important roles in thrombosis, hemostasis, and immunomodulation. For instance, the most abundant integrin on the platelet surface, αIIbβ3, binds to multiple ligands (e.g., fibrinogen, von Willebrand factor, and fibronectin) to activate integrin signaling involved in mediating platelet adhesion and aggregation to form thrombi (Son et al., 2017); GPVI is a key collagen receptor on the platelet surface that can also interact with fibrin and fibrinogen, whose activation can further mediate the activation of adhesion receptors such as integrins αIIbβ3 and α2β1, inducing downstream signal transduction and platelet granule release, thereby promoting thrombosis (Li R. et al., 2025); platelet P-selectin (CD62P) is stored in platelet α-granules and is exposed on the cell surface upon platelet activation through degranulation, and its interaction with the P-selectin glycoprotein ligand-1 (PSGL-1) on the neutrophil surface mediates the formation of neutrophil extracellular traps (Bautista-Becerril et al., 2021); furthermore, platelets can release extracellular vesicles expressing molecules such as GPIIb/IIIa, GPIbα, and P-selectin to participate in inflammatory regulation and angiogenesis. SFTSV typically results in reduced platelet membrane protein trafficking and impaired intracellular vesicle-related structures and transport functions, while platelet-derived vesicles themselves carry a procoagulant phenotype and participate in thrombus maintenance, inflammatory amplification, and angiogenesis; therefore, these abnormalities in lethal SFTS patients may hinder the transport and release of cytokines and bioactive molecules, thereby leading to the suppression of platelet activation and correlating with poor outcomes (Yan et al., 2023). PLA2G4A, as a key enzyme in the arachidonic acid metabolic pathway, mediates the release of arachidonic acid (AA) from membrane phospholipids; AA is further metabolized to produce bioactive thromboxane A2 (TXA2), and TXA2 is an important mediator for promoting platelet activation (Fu et al., 2023). SFTSV infection downregulates PI3-AKT pathway-related genes (GP1BA, PIK3CA, PIK3CB, AKT3, PRKG1, PRKG2), inhibiting the activation of PLA2G4A, thus suppressing TXA2 production and inhibiting platelet activation (Fu et al., 2023). RAP1 is an important intersection in platelet signaling pathways, which can activate integrin αIIbβ3 through Talin1 to mediate platelet attachment and adhesion (Lagarrigue et al., 2020). In patients infected with SFTSV, the activation of RAP1A, ACTB, and VAMP8 is suppressed, thereby inhibiting RAP1 signaling activation and subsequently affecting platelet attachment and adhesion (Fu et al., 2023; Shi et al., 2025). Histone methylation levels influence the outcomes of lethal SFTS patients (Fang et al., 2025). Relevant studies have shown that the reduction of histone trimethylation increases the binding of von Willebrand factor (vWF) to NF-κB and drives its transcription, enhancing platelet adhesion (Ghani and Pepke-Zaba, 2023). Increased histone methylation in lethal patients may disrupt this balance. Although platelets are anucleate cells, they possess a variety of functional coding or non-coding RNAs and translational mechanisms inherited from megakaryocyte precursors that have important biological significance, participating in platelet aggregation and adhesion and serving as one of the sources for synthesizing proteins adapted to their functions (Noh, 2021); as histone methylation is involved in regulating gene expression, alternative splicing, and the accessibility of transcription factors or regulatory complexes (Xu et al., 2024), an increase in histone methylation may also lead to platelet dysfunction, potentially correlating with disease severity (Figure 4).

Figure 4.

SFTSV interaction with platelets. (A) Interaction between SFTSV Gn/Gc and Circulating Platelets. (B) Platelet Death Pathway. (C) SFTSV Infection Alters Platelet Function, Primarily by Regulating the Viral Life Cycle, Mediating Neutrophil Activation, Participating in Type I Interferon Release, and Influencing Platelet Aggregation, Adhesion, and Thrombus Formation. (D) SFTSV induces platelet activation and apoptosis via the ROS-MAPK pathway, simultaneously upregulating Bax/Bak expression and altering platelet membrane potential, leading to thrombocytopenia. (E) SFTSV interacts with platelets to downregulate transcription levels of genes associated with P13- AKT, RAP1, and Ca signaling pathways, thereby inhibiting platelet activation.

7. Conclusion

This review summarizes the multidimensional mechanisms of the interaction between SFTSV and the host, delving into the complex network across multiple distinct levels, including viral protein functions, m⁶A modification, tick salivary factors, and platelet regulation. Viral proteins, as key effectors of SFTSV pathogenesis, not only directly participate in the viral life cycle but also influence disease progression by modulating host cell signaling pathways. As an emerging epigenetic regulatory mechanism, m⁶A modification has been found to affect SFTSV gene expression and virus-host interactions, playing a bidirectional regulatory role during infection and providing a new perspective for understanding viral pathogenic mechanisms. Furthermore, as ticks serve as the primary transmission vector for SFTSV, HIDfsin2 in their saliva plays an important role in viral transmission and host immune responses. Moreover, platelets, as a core component of the host immune and coagulation systems, are both targets of viral attack and participants in antiviral defense during SFTSV infection, and the elucidation of their regulatory mechanisms provides potential targets for the development of therapeutic strategies. In summary, the interaction between SFTSV and the host is a complex process involving multiple factors and levels; future research needs to further explore the fine regulatory networks of these mechanisms, laying a solid foundation for the development of targeted therapeutic drugs and preventive vaccines.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Education Department Foundation of Jilin Province (“13th Five-Year Plan” Science and Technology Project; Grant No. JJKH20200452KJ) and Jilin Provincial Department of Science and Technology’s Outstanding Team for Young and Middle-aged Innovation and Entrepreneurship (20240601008RC).

Author contributions

TW: Writing – original draft, Writing – review & editing. MZ: Writing – review & editing, Writing – original draft. WZ: Writing – review & editing. XF: Writing – review & editing, Supervision.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer DL declared a past collaboration with the author WZ.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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