Lethal severe fever with thrombocytopenia syndrome virus infection causes systemic germinal centre failure and massive T cell apoptosis in cats

Yusuke Sakai; Serina Mura; Yuko Kuwabara; Saya Kagimoto; Masashi Sakurai; Masahiro Morimoto; Eun-Sil Park; Masayuki Shimojima; Noriyo Nagata; Yasushi Ami; Tomoki Yoshikawa; Naoko Iwata-Yoshikawa; Shuetsu Fukushi; Shumpei Watanabe; Takeshi Kurosu; Akiko Okutani; Masanobu Kimura; Koichi Imaoka; Masayuki Saijo; Shigeru Morikawa; Tadaki Suzuki; Ken Maeda

doi:10.3389/fmicb.2023.1333946

Lethal severe fever with thrombocytopenia syndrome virus infection causes systemic germinal centre failure and massive T cell apoptosis in cats

Front Microbiol. 2024 Jan 5:14:1333946. doi: 10.3389/fmicb.2023.1333946. eCollection 2023.

Authors

Yusuke Sakai¹, Serina Mura², Yuko Kuwabara², Saya Kagimoto², Masashi Sakurai², Masahiro Morimoto², Eun-Sil Park³, Masayuki Shimojima⁴, Noriyo Nagata¹, Yasushi Ami⁵, Tomoki Yoshikawa⁴, Naoko Iwata-Yoshikawa¹, Shuetsu Fukushi⁴, Shumpei Watanabe⁶, Takeshi Kurosu⁴, Akiko Okutani³, Masanobu Kimura³, Koichi Imaoka³, Masayuki Saijo⁴, Shigeru Morikawa⁶, Tadaki Suzuki¹, Ken Maeda³

Affiliations

¹ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
² Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan.
³ Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan.
⁴ Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
⁵ Management Department of Biosafety and Laboratory Animal, National Institute of Infectious Diseases, Tokyo, Japan.
⁶ Faculty of Veterinary Medicine, Okayama University of Science, Ehime, Japan.

Abstract

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is a fatal viral disease characterized by high fever, thrombocytopenia, leukopenia, and multi-organ haemorrhage. Disruption of the humoral immune response and decreased lymphocyte numbers are thought to contribute to the disease severity. These findings have been obtained through the analysis of peripheral blood leukocytes in human patients, whereas analysis of lymph nodes has been limited. Thus, in this study, we characterized the germinal centre response and apoptosis in the lymph nodes of cats with fatal SFTS, because SFTS in cats well mimics the pathology of human SFTS.

Methods: Lymph node tissue sections collected during necropsy from seven fatal SFTS patients and five non-SFTS cases were used for histopathological analysis. Additionally, lymph node tissue sections collected from cats with experimental infection of SFTS virus (SFTSV) were also analysed.

Results: In the lymphoid follicles of cats with SFTS, a drastic decrease in Bcl6- and Ki67-positive germinal centre B cells was observed. Together, the number of T cells in the follicles was also decreased in SFTS cases. In the paracortex, a marked increase in cleaved-caspase3 positivity was observed in T cells. These changes were independent of the number of local SFTS virus-positive cell. Furthermore, the analysis of cats with experimental SFTSV infection revealed that the intrafollicular Bcl6- and CD3-positive cell numbers in cats with low anti-SFTSV antibody production were significantly lower than those in cats with high anti-SFTSV antibody production.

Discussion: These results suggest that dysfunction of the humoral response in severe SFTS was caused by the loss of germinal centre formation and massive apoptosis of T cells in the lymph nodes due to systemically circulating viruses.

Keywords: cats; germinal centre reaction; histopathology; lymph nodes; severe fever with thrombocytopenia syndrome.

Copyright © 2024 Sakai, Mura, Kuwabara, Kagimoto, Sakurai, Morimoto, Park, Shimojima, Nagata, Ami, Yoshikawa, Iwata-Yoshikawa, Fukushi, Watanabe, Kurosu, Okutani, Kimura, Imaoka, Saijo, Morikawa, Suzuki and Maeda.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by JSPS KAKENHI grant numbers 20K06412 and 23K18229.