Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections
Tadaki Suzuki, … , Masayuki Saijo, Hideki Hasegawa
Tadaki Suzuki, … , Masayuki Saijo, Hideki Hasegawa
Published January 6, 2020
Citation Information: J Clin Invest. 2020;130(2):799-812. https://doi.org/10.1172/JCI129171.
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Research Article Infectious disease Virology

Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever caused by a tick-borne banyangvirus and is associated with high fatality. Despite increasing incidence of SFTS and serious public health concerns in East Asia, the pathogenesis of lethal SFTS virus (SFTSV) infection in humans is not fully understood. Numbers of postmortem examinations to determine target cells of the viral infection have so far been limited. Here we showed that B cells differentiating into plasmablasts and macrophages in secondary lymphoid organs were targets for SFTSV at the end stage of lethal infection, and the majority of SFTSV-infected cells were B cell–lineage lymphocytes. In affected individuals, B cell–lineage lymphocytes with SFTSV infection were widely distributed in both lymphoid and nonlymphoid organs, and infiltration of these cells into the capillaries of the organs could be observed occasionally. Moreover, a human plasmablastic lymphoma cell line, PBL-1, was susceptible to SFTSV propagation and had a similar immunophenotype to that of target cells of SFTSV in fatal SFTS. PBL-1 can therefore provide a potential in vitro model for human SFTSV infection. These results extend our understanding of the pathogenesis of human lethal SFTSV infection and can facilitate the development of SFTSV countermeasures.

Authors

Tadaki Suzuki, Yuko Sato, Kaori Sano, Takeshi Arashiro, Harutaka Katano, Noriko Nakajima, Masayuki Shimojima, Michiyo Kataoka, Kenta Takahashi, Yuji Wada, Shigeru Morikawa, Shuetsu Fukushi, Tomoki Yoshikawa, Masayuki Saijo, Hideki Hasegawa

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Figure 7

Expression of DC-SIGN enhances the susceptibility of PBL-1 cells to SFTSV infection.

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Expression of DC-SIGN enhances the susceptibility of PBL-1 cells to SFTS...
(A) Infectivity of SFTSV was compared in PBL-1 and Vero cells (MOI = 1, n = 3). Cells were inoculated with SFTSV, incubated for 24 hours, and then analyzed by flow cytometry with DyLight 488–labeled anti–SFTSV N protein antibody. Data are the mean ± SD of biological replicates. ****P < 0.0001 (unpaired Student’s t test). (B) Infectivity of SFTSV was compared in PBL-1, THP-1, and human monocytic THP-1 cell–derived macrophages with PMA treatment (THP1-Mϕ) (MOI = 10, n = 6). ****P < 0.0001 (1-way ANOVA followed by Holm-Sidak’s multiple-comparisons test). (C) Cell-surface expression of DC-SIGN in THP-1 (left panel) or THP-1 cell–derived macrophages with PMA treatment (THP1-Mϕ, right panel) was analyzed by flow cytometry with anti–DC-SIGN/DC-SIGNR antibody. (D) Cell-surface expression of DC-SIGN in PBL-1, TY-1, Raji, or LCL-K cells transfected with lentivector encoding fCD2 or DC-SIGN, or in parent PBL-1 cells, was analyzed by flow cytometry with anti–DC-SIGN/DC-SIGNR antibody (left panel). SFTSV infectivity in PBL-1 cells, TY-1, Raji, or LCL-K cells expressing DC-SIGN or fCD2, or in parental cells, was determined by flow cytometry using DyLight 488–labeled anti–SFTSV N antibody 24 hours after SFTSV inoculation (MOI = 3, right panel). (E) Relationship between expression of DC-SIGN on cell surface and SFTSV infectivity in PBL-1 cells, TY-1, Raji, or LCL-K cells expressing DC-SIGN was examined by simultaneous staining with anti–DC-SIGN/DC-SIGNR antibody and DyLight 488–labeled anti–SFTSV N antibody. (F) Comparison of SFTSV infectivity between DC-SIGN− (blue) and DC-SIGN+ (red) PBL-1, TY-1, Raji, and LCL-K cells demonstrated that expression of DC-SIGN significantly enhanced the susceptibility of these B cell lines to SFTSV infection, and infectivity of DC-SIGN–expressing PBL-1 cells was significantly higher than that of DC-SIGN–expressing TY-1, Raji, or LCL-K cells. Data are the mean ± SD of 3 biological replicates. ****P < 0.0001 (2-way ANOVA followed by Sidak’s multiple-comparisons test).