Overview of the immunological mechanism underlying severe fever with thrombocytopenia syndrome (Review)

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) has been acknowledged as an emerging infectious disease that is caused by the SFTS virus (SFTSV). The main clinical features of SFTS on presentation include fever, thrombocytopenia, leukocytopenia and gastrointestinal symptoms. The mortality rate is estimated to range between 5‑30% in East Asia. However, SFTSV infection is increasing on an annual basis globally and is becoming a public health problem. The transmission cycle of SFTSV remains poorly understood, which is compounded by the pathogenesis of SFTS not being fully elucidated. Since the mechanism underlying the host immune response towards SFTSV is also unclear, there are no effective vaccines or specific therapeutic agents against SFTS, with supportive care being the only realistic option. Therefore, it is now crucial to understand all aspects of the host‑virus interaction following SFTSV infection, including the antiviral states and viral evasion mechanisms. In the present review, recent research progress into the possible host immune responses against SFTSV was summarized, which may be useful in designing novel therapeutics against SFTS.

Keywords: adaptive immune response; immunological; innate immune response; severe fever with thrombocytopenia syndrome; severe fever with thrombocytopenia syndrome virus.

Figure 1

SFTSV activates IFN production and cytokine storm to evade the innate immune response. SFTSV RNAs bind to TLR-3 and RIG-1 to activate TRIF, TBK1 and IKK, which in turn activate the NF-κB signaling pathway whilst phosphorylating IRF3 and IRF7. This induces the expression of cytokine, type I and type III IFN genes, promoting the production of inflammatory cytokines, type I and III IFNs. Type I and III IFNs can share the same JAK/STAT pathway by binding to their receptors, which activate the expression of ISGs and antiviral proteins that inhibit viral replication. SFTSV NSs can bind several host proteins to form inclusion bodies, such as RIG-I, TBK1, IKK, IRF3, IRF7, TRIM25, STAT1 and STAT2, leading to severe clinical implications. Red lines indicate inhibition. SFTSV, severe fever with thrombocytopenia syndrome virus; NSs, nonstructural protein; TLR, Toll-like receptor; RIG-I, retinoic acid-inducible gene I; TRIF, TIR-domain-containing adaptor inducing interferon-β; IKK, inhibitor of NF-κB kinase; IPS-1, IFN-β promoter stimulator 1; TBK, TANK-binding kinase 1; IRF, IFN regulatory factor; JAK, Janus kinase; ISGs, IFN-stimulated genes, TRIM, tripartite motif.

Figure 2

Innate immune response and the adaptive immune response against SFTSV. The antigen is presented to adaptive immune cells after recognizing the SFTSV by monocytes/macrophages, dendritic cells and NK cells. In addition, monocytes/macrophages can engulf the virus to induce apoptosis, whereas NK cells can release perforin and granzyme to lyse lean virus-infected cells. CD8⁺ T cells can directly kill virus-infected cells by removing cytotoxic particles. Naïve CD4⁺ T cells can differentiate into Th1, Th2, Th17 and Tregs under different cytokine environments. These helper T cells secrete various cytokines that provoke an inflammatory storm, leading to harmful outcomes and possibly to lymphopenia. T cells recognize virus-antigens presented by major histocompartibility complex II and stimulate the proliferation and differentiation of B cells by secreting cytokines. A portion of B cells differentiates into Ig-secreting plasma cells, which secrete anti-SFTSV antibodies. SFTSV, severe fever with thrombocytopenia syndrome virus; NK, natural killer.