Single-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation

Wei Yang, Li-Bo Liu, Feng-Liang Liu, Yan-Hua Wu, Zi-Da Zhen, Dong-Ying Fan, Zi-Yang Sheng, Zheng-Ran Song, Jia-Tong Chang, Yong-Tang Zheng (), Jing An () and Pei-Gang Wang ()
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Wei Yang: Capital Medical University
Li-Bo Liu: Capital Medical University
Feng-Liang Liu: Chinese Academy of Sciences
Yan-Hua Wu: Capital Medical University
Zi-Da Zhen: Capital Medical University
Dong-Ying Fan: Capital Medical University
Zi-Yang Sheng: Capital Medical University
Zheng-Ran Song: Capital Medical University
Jia-Tong Chang: Capital Medical University
Yong-Tang Zheng: Chinese Academy of Sciences
Jing An: Capital Medical University
Pei-Gang Wang: Capital Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RT‒qPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.

Date: 2023
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DOI: 10.1038/s41467-023-38223-z

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