Decreased monocyte subsets and TLR4-mediated functions in patients with acute severe fever with thrombocytopenia syndrome (SFTS).

The role of a newly discovered bunyavirus, the severe fever with thrombocytopenia syndrome virus (SFTSV), in the pathogenesis of severe fever with thrombocytopenia syndrome (SFTS) is poorly understood. In this study, it was hypothesized that peripheral monocytes, which are constantly exposed to viral infection in the blood, are likely targeted by the causative virus in SFTS patients. Fifty-three patients and 25 healthy volunteers were enrolled in the study. Monocyte counts in the peripheral blood of all human subjects were monitored throughout the progress of the disease. SFTSV viral load and the expression of monocyte genes were investigated by real-time RT-PCR. Cytokine production of monocytes in SFTS patients upon lipopolysaccharide (LPS) stimulation was examined by ELISA. In comparison to SFTS patients in the convalescent stage and healthy controls, monocyte cell counts and percentages in patients at the acute stage were significantly lower. Decreased monocyte cell counts and subsets were positively correlated with SFTSV viral loads in the serum samples from SFTS patients. Despite their higher basal toll-like receptor 4 (TLR4) expression, monocytes from patients in the acute phase were shown to be compromised regarding the production of tumor necrosis factor alpha, but not interleukin 10, upon LPS stimulation. These data strongly suggest that monocytes could be a major target during SFTSV infection. The decreased population and dysfunction of monocytes in acute SFTS patients may contribute to the disease severity.

Peng C ，Wang H ，Zhang W ，Zheng X ，Tong Q ，Jie S ，Yang D ，Zhou Y ... -  《-》

Detection of SFTS virus RNA and antibodies in severe fever with thrombocytopenia syndrome surveillance cases in endemic areas of China.

Huang X ，Ding S ，Jiang X ，Pang B ，Zhang Q ，Li C ，Li A ，Li J ，Liang M ，Wang S ，Li D ... -  《BMC INFECTIOUS DISEASES》

Dynamic changes of laboratory parameters and peripheral blood lymphocyte subsets in severe fever with thrombocytopenia syndrome patients.

The aim of this study was to dynamically investigate laboratory parameters and peripheral blood lymphocyte subsets in severe fever with thrombocytopenia syndrome (SFTS) patients at different stages, to evaluate the significance of these changes in the infection process and its influence on prognosis. Case-control study was used in the research. Sixty-nine confirmed thrombocytopenia syndrome virus(SFTSV) infected patients were enrolled. They were divided into two groups, recovery group and poor prognosis group, according to the clinical prognosis of the diseases. The laboratory parameters were measured by matched fully-automatic detector. The dynamic lymphocyte subsets of each group were tested by flow cytometry. Independent-group Student's t-test, Bonferroni test and Nemenyi test were used to compare the mean value of every group. The clinical manifestations typically became worse on about the 7th day. Most of them had multi organ dysfunction, and part of them had hemophagocytic lymphohistiocytosis histiocytosis (HLH). The characteristic laboratory findings in the early stage were the drop of platelets (PLT), while the increase of alanine aminotransferase (ALT), aspartate amino transferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH). SFTSV viral loads reached the highest on Days 7-10 after onset of fever in SFTS patients. CD3+, CD3+CD4+ T cell counts were significantly reduced in poor prognosis group, more so on Days 7-10 after onset of fever. CD3-CD19+ (B cell) counts in SFTS patients were significantly higher than that of healthy controls. 11 days after illness onset, symptoms were improved, accompanied by resolution of laboratory abnormalities. These results indicated that SFTS had an acute onset and self-limited course. It was a systemic infection. The host immune response caused tissues and organs injury. The improvement of symptoms and laboratory tests was consistent with the elimination of the virus and recover of immune response. Further investigation should be done in order to reveal the mechanisms of SFTSV pathogenesis and guide the clinical treatment.

Liu J ，Wang L ，Feng Z ，Geng D ，Sun Y ，Yuan G ... -  《-》

RIG-I-Like Receptor and Toll-Like Receptor Signaling Pathways Cause Aberrant Production of Inflammatory Cytokines/Chemokines in a Severe Fever with Thrombocytopenia Syndrome Virus Infection Mouse Model.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a tick-borne phlebovirus of the family Bunyaviridae, SFTS virus (SFTSV). Wild-type and type I interferon (IFN-I) receptor 1-deficient (IFNAR1-/-) mice have been established as nonlethal and lethal models of SFTSV infection, respectively. However, the mechanisms of IFN-I production in vivo and the factors causing the lethal disease are not well understood. Using bone marrow-chimeric mice, we found that IFN-I signaling in hematopoietic cells was essential for survival of lethal SFTSV infection. The disruption of IFN-I signaling in hematopoietic cells allowed an increase in viral loads in serum and produced an excess of multiple inflammatory cytokines and chemokines. The production of IFN-I and inflammatory cytokines was abolished by deletion of the signaling molecules IPS-1 and MyD88, essential for retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and Toll-like receptor (TLR) signaling, respectively. However, IPS-1-/- MyD88-/- mice exhibited resistance to lethal SFTS with a moderate viral load in serum. Taken together, these results indicate that adequate activation of RLR and TLR signaling pathways under low to moderate levels of viremia contributed to survival through the IFN-I-dependent antiviral response during SFTSV infection, whereas overactivation of these signaling pathways under high levels of viremia resulted in abnormal induction of multiple inflammatory cytokines and chemokines, causing the lethal disease.IMPORTANCE SFTSV causes a severe infectious disease in humans, with a high fatality rate of 12 to 30%. To know the pathogenesis of the virus, we need to clarify the innate immune response as a front line of defense against viral infection. Here, we report that a lethal animal model showed abnormal induction of multiple inflammatory cytokines and chemokines by an uncontrolled innate immune response, which triggered the lethal SFTS. Our findings suggest a new strategy to target inflammatory humoral factors to treat patients with severe SFTS. Furthermore, this study may help the investigation of other tick-borne viruses.

Yamada S ，Shimojima M ，Narita R ，Tsukamoto Y ，Kato H ，Saijo M ，Fujita T ... -  《-》

Seroprevalence of severe fever with thrombocytopenia syndrome (SFTS) virus antibodies in humans and animals in Ehime prefecture, Japan, an endemic region of SFTS.

Severe fever with thrombocytopenia syndrome (SFTS) was first identified as an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) in China and has also been found to be endemic to Japan and South Korea, indicating that SFTS is of great concern in East Asia. The aim of the present study was to determine the seroprevalence of SFTSV antibodies in humans and animals in SFTS-endemic regions of Japan. One of 694 (0.14%) healthy persons over 50 years of age and 20 of 107 (18.7%) wild and domestic animals in Ehime prefecture of western Japan were determined to be seropositive for SFTSV antibodies by virus neutralization test and ELISA, respectively. The seropositive person, a healthy 74-year-old woman, was a resident of the southwest part of Ehime prefecture engaged in citriculture and field work. This woman's sample exhibited neutralizing activity against SFTSV although she had neither a clear experience with tick bites nor SFTS-like clinical illness. These findings indicate that most people living in the endemic regions are not infected with SFTSV and suggest that most of the SFTS patients reported so far do not reflect the tip of an iceberg of people infected with SFTSV, but at the same time, that SFTSV infection does not always induce severe SFTS-associated symptoms. These findings also suggested that SFTSV has been maintained in nature within animal species and ticks.

Kimura T ，Fukuma A ，Shimojima M ，Yamashita Y ，Mizota F ，Yamashita M ，Otsuka Y ，Kan M ，Fukushi S ，Tani H ，Taniguchi S ，Ogata M ，Kurosu T ，Morikawa S ，Saijo M ，Shinomiya H ... -  《-》