Interferon performs various roles in innate and acquired immunity, exhibiting potent and universal antiviral activity (26). After infecting epithelial cells, fibroblasts, and pDCs surround the bite location, the immune system responds by secreting interferon-α (IFN-α) and IFN-β. IFN-γ is produced by activated macrophages and NK cells in the early stages or by activated Th1 cells in the later stages, thus inducing an antiviral state. DBV binds to pattern recognition receptors on the cell surface and activates critical kinases that initiate type I interferon (IFN-I) production (27). Secreted IFN then binds to IFNARs on the cell surface, activating JAK-STAT signaling and increasing the expression of antiviral interferon-stimulated genes (ISGs) (28). However, the nonstructural proteins (NSs) of DBV can hinder the production and response of intracellular IFN by encapsulating the STAT heterodimer and TBK1/IKKϵ (29, 30) that are integral molecules of the IFN-I production pathway to form viral inclusion bodies. NSs can also block the phosphorylation of STAT2 and nuclear translocation of STAT, ultimately leading to a complete blockade of the IFN response (4, 31, 32) ( Figure 1B ). Recently discovered a higher prevalence of exacerbated IFN-I signaling pathways and increased ISGs expression in patients with fatal SFTS, and a direct correlation between enhanced ISGs expression and disease severity. Therefore, an increased IFN-I response may be detrimental rather than beneficial (33, 34). The blockade of the interferon response seems to occur only in DBV-infected cells, whereas the majority of cells in SFTS patients still show a high enrichment of the IFN-I signaling pathway, which may contribute to the exacerbation of the disease.

Peripheral monocytes are derived from bone marrow and express a variety of receptors that exert strong phagocytosis and pathogen-clearing abilities. They are believed playing pivotal role during expansion of DBV replication via being directly infected by the virus (22, 35, 36). In the early stages of infection, monocytes suffer extensive apoptosis and result in viral particle release (37), which might be contributed by immune surveillance to clear virus-infected target cells. Previous analysis has revealed that intermediate monocytes are more prone to DBV infection than classical monocytes. In vitro, transition of monocytes from the classical to the intermediate phenotype was observed by DBV stimulated peripheral blood mononuclear cells of patients with SFTS, especially in deceased patients (33). The expression of RNA virus infection acquired gene CTSL and CTSB was found significantly increase in intermediate monocytes (33, 38, 39), which may explain why intermediate monocytes are more susceptible to DBV infection. Meanwhile, intermediate monocytes exhibit enhanced expression of ISGs and IFN-dependent chemokines, as well as complement activation. Overactivation of type I IFN response and complement cascade reaction by intermediate monocytes is the hallmark of DBV induced organism injury and indicator of poor prognosis (33). Furthermore, monocytes isolated from individuals with acute SFTS produce significantly lower TNF-α levels by LPS stimulation. This might indicate that monocytes are not major source of TNF-α in SFTS patients (35).

Circulating monocytes can migrate to inflammatory tissues for differentiating to macrophages during viral infections, which further activate and release proinflammatory mediators. The function of macrophages could be significantly promoted by IFN-γ with expressing iNOS enzyme and NO to kill virus-infected cells. Based on the specific staining of DBV-positive macrophages of spleen, macrophages are hypothesized to be one of important target cells for DBV infection. Consistently, replication of DBV is observed in primary mouse macrophages in vitro infection model, without affecting phagocytic activity to platelets (40). Another study reported that DBV infection significantly increased the expression of miR-146a and miR-146b in macrophages and facilitated their differentiation into M2 phenotypes (41). M2 macrophages can enhance phagocytic activity but suppress the production of proinflammatory cytokines and reduce pathogen-killing capability (42), which may promote the expansion of DBV (4, 43). In the early stage of DBV infection, elevated expression of IFN-γ encourages macrophages M1 phenotype transition with proinflammatory role via STAT1 pathway, while the elevated DBV replication and IL10 levels promote macrophage M2 differentiation in the late stage of infection (4, 41, 44).

NK cells are one of primary responders of innate immunity to viral infections (4). The surface expression of major histocompatibility complex class I molecules on infected host cells is generally downregulated during viral infection, which can be recognized by NK cells, leading to the direct elimination of infected cells. In addition, NK cells secrete proinflammatory cytokines and aid in the early elimination of the virus. Recent studies have highlighted a negative association between NK cell depletion and severe SFTS, particularly during the early stages of infection (45, 46). CD56^dimCD16⁺ NK cells are the primary subset of cytotoxic NK cells and their decrease in patients with SFTS may impair the clearance of virus-infected cells and immunomodulation. Furthermore, the activation and functional enhancement of CD56^dimCD16⁺ NK cells have also been observed in the acute phase of SFTS, with high expression of Ki-67 and GZMB and relatively low expression of NKG2A (47, 48).

Activation of the complement system and coagulation disorders can increase the risk of infection caused by various pathogens (49). Complement activation is well known in patients with disseminated intravascular coagulation, and there is a connection between the complement and coagulation systems (50). A recent study examining serum proteins in SFTS patients found a decrease in complement system proteins in those who passed away, except for MASP2. Conversely, complement proteins C4a, C4b, C1s, and C1R were elevated, while C6 and C7 proteins were reduced in recovering patients (51, 52). Therefore, the fatal patients are thought to have deficiencies in their innate immune responses, including the down-regulation of the complement system that leads to the progression of DIC characterized by coagulation dysfunction. Interestingly, another study reported upregulated expression of complement-related genes in patients who died of SFTS (33). This phenomenon may be caused by excessive activation of the complement system and subsequent depletion of complement components. Complement-dependent cytotoxicity undoubtedly assists the body in clearing viruses.

Pathological examination of fatal SFTS cases revealed that large hematopoietic cells in lymphoid organs (lymph nodes, spleen, and bone marrow) comprise the majority of the cells infected by the virus. Additionally, mature lymphocytes are particularly sensitive to DBV infection in fatal cases, with a notable presence of DBV⁺ mononuclear cells found in the capillaries of non-lymphoid organs in deceased patients. The infected cells can be recognized through the detection of plasmablast markers (MUM1 and CD38). However, unlike B cells infected with DBV, DBV⁺ cells in these capillaries do not express CD20 (54). CD20 is a familiar marker for B cells that starts to express in late pre-B lymphocytes (but not in pre-B lymphocytes) and is absent from terminally differentiated plasmablasts and plasma cells (55). Another study showed that most mature B cells infected with DBV in the lymph nodes were activated and had immunophenotypes similar to those of plasmablasts (54, 56). Based on these findings, it can be inferred that B cells at different stages of plasma cell differentiation serve as sites for DBV replication and spread the virus to non-lymphoid organs (54, 57). Elevated proportions of plasmablasts with functional impairments have also been observed (33), resulting in the absence of DBV-specific IgG antibodies against glycoprotein and nucleocapsid protein. Various factors, including impaired DC differentiation and antigen presentation function, failed follicular helper T cell differentiation and B cell antibody class switching, lead to comprehensive impairment of humoral immunity and affect virus clearance (37, 58).

Although DBV infection can activate B cells and cause them to replicate at a low level, most activated B cells are not infected with DBV. Despite limited viral infection and replication efficiency in peripheral blood B cells, the B cell lineage contributes to B cells activation (56). The sirtuin and IFN signaling pathways exhibit broad induction in the whole B cell population of patients who die of the disease, whereas the infected B cell population shows a specific reduction in these pathways compared to the uninfected population (57). This may be due to uninfected immune cells attempting to activate the IFN and sirtuin pathways to against virus. DBV infection of B cells induces uninfected B cells to produce cytokines and chemokines, such as IL-6 in vitro ( 56). However, DBV-infected B cells can block their signaling pathways and hamper paracrine effects on neighboring uninfected cells in vivo ultimately allowing high viral replication (33, 57). This may help DBV evade the host immune system (59).

DBV infection impairs DCs differentiation and function (58) hindering the development of T follicular helper cells and compromising the effectiveness of virus-specific humoral response (37). T-cell depletion is prevalent during the initial stages of DBV infection, particularly in patients with severe underlying conditions (46). Moreover, changes in T lymphocytes are similar to the overall dynamics of lymphocytes. CD4+ T cell deficiency and Th2 and Th17 bias are strongly correlated with SFTS severity (60). The significant decrease of peripheral T cells is revealed as its apoptosis via the Fas/FasL pathway in patients with SFTS (53). High levels of PD-1 expression are detected in exhausted T cells (61–63) in some chronic viral infections. Approximately 20% of CD4+ and CD8+ T cells display increased PD-1 expression, enhanced cytotoxicity, and effector functions in the early stages of DBV infection (53, 64). Additionally, CD8+ T cells that are similar to the response of antigen-specific T cells during acute viral infections exhibit a stronger response than CD4+ T cells (65). They can be activated rapidly and are recruited mainly by intermediate monocytes via CXCL10 (66). The differentiation from classical to intermediate monocytes in SFTS patients may lead to enhanced CD8+ T cell recruitment and an extensive immunological response. Cellular immunity is critical for virus clearance on antiviral immunity. However, T cell apoptosis, exhaustion, and decreased numbers occur with disease progression, indicating potential impairment of cellular immunity (64).