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.

Keywords: SFTS; SFTSV; epidemio­logical characteristics; etiological characteristics; pathogenic mechanism; treatment; vaccine.

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.

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.

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.

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.