Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections
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
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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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 6

SFTSV propagates in the PBL-1 human plasmablastic lymphoma cell line.

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SFTSV propagates in the PBL-1 human plasmablastic lymphoma cell line. (A...
(A) SFTSV infectivity in human B cell lines LCL-K, LCL-6, Raji, Ramos, PCM6, Bjab, TY-1, BCBL-1, and PBL-1. The cell lines were inoculated with SFTSV (MOI = 10) and incubated for 24 hours. Infectivity in each cell line was determined by flow cytometry using DyLight 488–conjugated anti–SFTSV N protein antibody. Data are expressed as the mean ± SD of 3 biological replicates. ****P < 0.0001 (1-way ANOVA followed by Holm-Sidak’s multiple-comparisons test to compare the SFTSV infectivity of PBL-1 with that of other B cell lines). (B) Kinetics of viral replication in PBL-1 cells was examined by serial sampling of cells and culture supernatants. SFTSV RNA loads in cells (upper panel) and culture supernatants (middle panel) at each time point were estimated by quantitative real-time RT-PCR. The quantity of infectious virions in culture supernatants at each time point was also estimated using Vero cells (SFTSV titer, lower panel). Data are expressed as the mean ± SD of 3 biological replicates. (C) Electron microscopy of SFTSV-infected PBL-1 cells. Virus-like particles of 85- to 90-nm diameter, with moderately to highly dense centers can be seen attached on the cell surface (upper panel), budding into the vacuoles (upper-middle panel), accumulating in intracellular vesicles (lower-middle panel), and egressing from the vacuoles in the cytoplasm of PBL-1 (lower panel). Scale bars: 200 nm and 50 nm (inset).