Immunocompetent mouse models revealed that S100A4+ monocytes/macrophages facilitate long-term Zika virus infection in
Wei Yang1, Chen Zhang1, Li-Bo Liu1
1Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China.
Abstract:
During its global epidemic, Zika virus (ZIKV) attracted widespread attention due to its link with various severe neurological symptoms and potential harm to male fertility. However, the understanding of how ZIKV invades and persists in the male reproductive system is limited due to the lack of immunocompetent small animal models. In this study, immunocompetent murine models were generated by using anti-IFNAR antibody blocked C57BL/6 male mice and human STAT2 (hSTAT2) knock in (KI) male mice. After infection, viral RNA could persist in the testes even after the disappearance of viremia. We also found a population of ZIKV-susceptible S100A4+ monocytes/macrophages that were recruited into testes from peripheral blood and played a crucial role for ZIKV infection in the testis. By using single-cell RNA sequencing, we also proved that S100A4+ monocytes/macrophages had a great impact on the microenvironment of ZIKV-infected testes, thus promoting ZIKV-induced testicular lesions. In conclusion, this study proposed a novel mechanism of long-term ZIKV infection in the male reproductive system.
Insights
Zika virus (ZIKV) can persist in male testes long after infection clears from the blood. Specialized immune cells, S100A4+ monocytes/macrophages, are key to ZIKV
Area of Science:
- Virology
- Immunology
- Reproductive Biology
Background:
- Zika virus (ZIKV) poses risks to male fertility.
- Understanding ZIKV's persistence in the male reproductive system is limited by a lack of suitable animal models.
Purpose of the Study:
- To investigate the mechanism of ZIKV invasion and long-term persistence in the male reproductive system.
- To identify key cellular players involved in ZIKV testicular infection.
Main Methods:
- Generation of immunocompetent murine models (anti-IFNAR antibody blocked C57BL/6 mice and hSTAT2 KI mice).
- Detection of viral RNA in testes post-viremia clearance.
- Single-cell RNA sequencing to analyze cellular responses and identify susceptible cell populations.
Main Results:
- Viral RNA persisted in testes even after viremia resolved.
- ZIKV-susceptible S100A4+ monocytes/macrophages were recruited into testes from peripheral blood.
- These immune cells significantly impacted the testicular microenvironment, exacerbating ZIKV-induced lesions.
Conclusions:
- A novel mechanism for long-term ZIKV infection in the male reproductive system is proposed.
- S100A4+ monocytes/macrophages play a critical role in ZIKV testicular pathogenesis.
- Developed immunocompetent models facilitate further research into ZIKV's effects on male fertility.
