BACKGROUND Heightened surveillance of acute febrile illness in China since 2009 has led to the identification of a severe fever with thrombocytopenia syndrome (SFTS) with an unknown cause. Infection with Anaplasma phagocytophilum has been suggested as a cause, but the pathogen has not been detected in most patients on laboratory testing. METHODS We obtained blood samples from patients with the case definition of SFTS in six provinces in China. The blood samples were used to isolate the causal pathogen by inoculation of cell culture and for detection of viral RNA on polymerase-chain-reaction assay. The pathogen was characterized on electron microscopy and nucleic acid sequencing. We used enzyme-linked immunosorbent assay, indirect immunofluorescence assay, and neutralization testing to analyze the level of virus-specific antibody in patients’ serum samples. RESULTS We isolated a novel virus, designated SFTS bunyavirus, from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. RNA sequence analysis revealed that the virus was a newly identified member of the genus phlebovirus in the Bunyaviridae family. Electron-microscopical examination revealed virions with the morphologic characteristics of a bunyavirus. The presence of the virus was confirmed in 171 patients with SFTS from six provinces by detection of viral RNA, specific antibodies to the virus in blood, or both. Serologic assays showed a virus-specific immune response in all 35 pairs of serum samples collected from patients during the acute and convalescent phases of the illness. CONCLUSIONS A novel phlebovirus was identified in patients with a life-threatening illness associated with fever and thrombocytopenia in China. (Funded by the China Mega-Project for Infectious Diseases and others.)

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified Phlebovirus that causes severe fever with thrombocytopenia syndrome. Our study demonstrated that SFTSV NSs functioned as IFN antagonist mainly by suppressing TBK1/IKKε-IRF3 signaling pathway. NSs interacted with and relocalized TANK-binding kinase 1 (TBK1) into NSs-induced cytoplasmic structures and this interaction could effectively inhibit downstream phosphorylation and dimerization of interferon regulatory factor 3 (IRF3), resulting in the suppression of antiviral signaling and IFN induction. Functional sites of SFTSV NSs binding with TBK1 were then studied and results showed that NSs had lost their IFN-inhibiting activity after deleting the 25 amino acids in N-terminal. Furthermore, the mechanism of Rift Valley fever virus (RVFV) NSs blocking IFN-β response were also investigated. Preliminary results showed that RVFV NSs proteins could neither interact nor co-localize with TBK1 in cytoplasm, but suppressed its expression levels, phosphorylation and dimerization of IRF3 in the subsequent steps, resulting in inhibition of the IFN-β production. Altogether, our data demonstrated the probable mechanism used by SFTSV to inhibit IFN responses which was different from RVFV and pointed toward a novel mechanism for RVFV suppressing IFN responses.

Poor graft function (PGF), characterized by pancytopenia, is a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our prior works (BBMT 2013; BMT 2016; Blood 2016; Haematologica 2022) reported that the decreased and dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs), a crucial cellular component in moderating hematopoietic stem cells (HSCs) in the BM microenvironment, were implicated in the pathogenesis of PGF. Moreover, prophylactic approaches to rescue aberrant BM EPCs in PGF patients could promote hematopoietic reconstitution after allo-HSCT (Blood Advances 2019; BMC Med 2022), further confirming the vital role of BM EPCs in regulating hematopoietic recovery post-allo-HSCT. However, the underlying mechanism by which EPCs mediate HSCs remains to be elucidated. Peroxisome proliferator-activated receptors (PPARs), consisting of three isotypes, PPARα , PPARγ and PPARδ , act as key members of the nuclear receptor superfamily of transcription factors that govern a variety of biological processes, such as cell metabolism, proliferation, differentiation and survival. Recently, PPARδ , but not PPARα or PPARγ , was reported to be the predominant expressed isotype of PPARs in BM HSCs and plays a critical role in regulating HSC activities, including maintenance of stemness and asymmetric division. Although PPARδ plays an essential role in HSCs, its effect on BM EPCs, the indispensable niche for HSCs, is largely unknown.