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 February 3, 2020; First 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 4

Class-switched IgG+ B cells are more susceptible to SFTSV infection than class-unswitched IgM+ B cells in lymphoid and nonlymphoid organs.

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Class-switched IgG+ B cells are more susceptible to SFTSV infection than...
(A) Representative images of chromogenic IHC staining for SFTSV N protein (left panel) or multiplex IHC staining for immunoglobulin heavy chains (IgA, brown; IgM, purple; IgG, green; right panel) on serial tissue sections of lymph node from an individual with fatal SFTS. The arrowhead in the right panel indicates an IgM+ cell. Scale bars: 50 μm. (B) Representative images of chromogenic multiplex IHC staining for SFTSV (green) with activated lymphocyte marker (CD38, brown; left panel); plasmablast-lineage marker (MUM1, brown; middle panel); and IgG (brown; right panel). Arrowheads indicate colocalization of staining in cells. Scale bars: 10 μm. (C) Comparison between immunoglobulin heavy chain (IGH) mRNA levels (IGHG and IGHM) and SFTSV viral RNA levels in tissue sections of lymph nodes (n = 58, left panel) and nonlymphoid organs (n = 36, right panel) including the liver, adrenal gland, kidney, heart, and bladder, quantified by real-time RT-PCR. The SFTSV RNA load was positively correlated with the IGHG mRNA level in lymph node (Spearman’s coefficient = 0.6027, P < 0.0001) and nonlymphoid organs (Spearman’s coefficient = 0.8025, P < 0.0001). To compare regression lines, the P values were calculated with nonlinear regression analysis with a straight-line model. **P = 0.0045, ****P < 0.0001.