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 1

Secondary lymphoid organs are the primary viral targets in human fatal SFTS.

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Secondary lymphoid organs are the primary viral targets in human fatal S...
(A) Representative pathological images of lymph nodes, spleen, and bone marrow of individuals who died from SFTS, with H&E staining (upper panels) or immunohistochemistry (IHC) for SFTSV N protein (lower panels). Pie charts show the number of individuals whose tissues were analyzed and the percentage in whose tissues SFTSV antigen was detected by IHC. Scale bars: 100 μm. (B) SFTSV IHC scores for tissue sections of lymphoid organs. When multiple FFPE blocks of an organ from 1 individual were available, only the section with the highest number of SFTSV+ cells was analyzed. The IHC score for lymph nodes (LNs) was significantly higher than for bone marrow (BM). Scatter plots show the mean ± SD (n = 20, 21, and 19 for LNs, spleen, and BM, respectively). The P values were calculated with 1-way ANOVA followed by Holm-Sidak’s multiple-comparisons test. (C) SFTSV viral RNA loads in the tissues of lymphoid organs. Scatter plots show the relative levels of RNA in tissue sections, quantified by real-time quantitative RT-PCR for SFTSV S segment and human ACTB mRNA (for normalization of RNA extraction). Geometric means ± 95% confidence intervals are also shown (n = 17, 19, and 11 for LNs, spleen, and BM, respectively). The P values were calculated with nonparametric 1-way ANOVA (Kruskal-Wallis test) followed by Dunn’s multiple-comparison test. Relative SFTSV RNA copy numbers in LNs were significantly higher than in BM.