Prothymosin α accelerates dengue virus-induced thrombocytopenia

Mei-Lin Yang; Chia-Ling Lin; Yi-Cheng Chen; I-An Lu; Bing-Hua Su; Yen-Hsu Chen; Kuan-Ting Liu; Chao-Liang Wu; Ai-Li Shiau

doi:10.1016/j.isci.2023.108422

Prothymosin α accelerates dengue virus-induced thrombocytopenia

iScience. 2023 Dec 2;27(1):108422. doi: 10.1016/j.isci.2023.108422. eCollection 2024 Jan 19.

Authors

Mei-Lin Yang^{1

2}, Chia-Ling Lin³, Yi-Cheng Chen⁴, I-An Lu⁴, Bing-Hua Su⁵, Yen-Hsu Chen^{6

7

8

9}, Kuan-Ting Liu^{10

11}, Chao-Liang Wu^{1

4}, Ai-Li Shiau^{1

2}

Affiliations

¹ Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.
² Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.
⁴ Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁵ School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁶ Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Tropical Medicine and Infectious Diseases, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
⁹ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan.
¹⁰ Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹¹ School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract

Thrombocytopenia is the hallmark finding in dengue virus (DENV) infection. Prothymosin α (ProT) has both intracellular and extracellular functions involved in cell cycle progression, cell differentiation, gene regulation, oxidative stress response, and immunomodulation. In this study, we found that ProT levels were elevated in dengue patient sera as well as DENV-infected megakaryoblasts and their culture supernatants. ProT transgenic mice had reduced platelet counts with prolonged bleeding times. Upon treatment with DENV plus anti-CD41 antibody, they exhibited severe skin hemorrhage. Furthermore, overexpression of ProT suppressed megakaryocyte differentiation. Infection with DENV inhibited miR-126 expression, upregulated DNA (cytosine-5)-methyltransferase 1 (DNMT1), downregulated GATA-1, and increased ProT expression. Upregulation of ProT led to Nrf2 activation and reduced reactive oxygen species production, thereby suppressing megakaryopoiesis. We report the pathophysiological role of ProT in DENV infection and propose an involvement of the miR-126-DNMT1-GATA-1-ProT-Nrf2 signaling axis in DENV-induced thrombocytopenia.

Keywords: Cell biology; Virology.