Wolbachia outcompetes mosquito-borne viruses by reprogramming host ATPSβ1-driven ATP metabolism toward symbiotic proliferation
9 affiliations
- 1Department of Medical Laboratory Science, School of Medical Technology and Translational Medicine, Hunan Normal University Health Science Center, Changsha, Hunan, P. R. China
- 2Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P. R. China
- 3Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, Hunan, P. R. China
- 4Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan, P. R. China
- 5School of Life Sciences and Medicine, Shandong University of Technology, Zibo, P. R. China
- 6Kunming Medical University, Kunming, Yunnan, P. R. China
- 7Guangzhou Wolbaki Biotech Co., Ltd., Guangzhou, Guangdong, P. R. China
- 8Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, P. R. China
- 9Department of Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, Michigan, United States of America
Abstract
Wolbachia endosymbionts confer broad-spectrum resistance to mosquito-borne viruses. While the antiviral metabolites in Wolbachia-Aedes have been identified during viral replication, the core metabolic gene underlying this defense across the entire viral infection cycle remains undefined. Here, we demonstrated for the first time that Wolbachia strongly suppressed the emerging alphavirus Venezuelan equine encephalitis virus, extending its known antiviral spectrum. Transcriptomic and functional analyses revealed ATP synthase beta subunit 1 (ATPSβ1) as a key metabolic hub hijacked by both MBV and the symbiont. Without Wolbachia symbiosis, dengue virus and VEEV induced ATPSβ1 to promote viral binding via the viral envelope protein and increased intracellular ATP production for viral replication. Conversely, Wolbachia overrode ATPSβ1-mediated viral binding and redirected ATPSβ1-driven ATP synthesis to fuel its proliferation, strengthening antiviral activity. Pharmacologically, adenosine increased Wolbachia wAlbB density and potently suppressed viral infection in Ae. aegypti and Ae. albopictus cells. Oligomycin reduced intracellular ATP and inhibited viral infection in Wolbachia-free Ae. aegypti cells. Collectively, Wolbachia repurposes dual-functional ATPSβ1, which governs MBV binding and replication, into a potent antiviral effector through a metabolic tug-of-war over host ATP during symbiont-virus competition. Moreover, we highlight interventions targeting the ATPSβ1-driven metabolism as promising strategies to curb MBV transmission. Author summary: Mosquito-borne viruses (MBVs), such as dengue virus (DENV) and Venezuelan equine encephalitis virus (VEEV), pose serious threats to global public health. The endosymbiotic bacterium Wolbachia has been developed as a powerful tool for blocking virus transmission. However, the core metabolic mechanisms underlying Wolbachia-induced broad-spectrum antiviral resistance, especially across the complete viral infection cycle, remain unclear. In this study, we uncover ATP synthase beta subunit 1 (ATPSβ1) as a previously unrecognized metabolic hub that governs both viral infection and Wolbachia symbiosis. Importantly, we demonstrate that pharmacological modulation of ATPSβ1-driven metabolism potently suppresses MBV infection. Furthermore, we establish ATPSβ1 as a novel molecular target for developing small-molecule interventions that could recapitulate Wolbachia’s antiviral effect, even in the absence of the symbiont. Collectively, this work shifts the paradigm from viewing Wolbachia only as a blocker of viral transmission to understanding it as an active metabolic competitor. It also opens a new avenue for developing broad-spectrum antiviral strategies targeting host ATP metabolism, offering a transformative approach to mitigating the global public health burden of mosquito-borne diseases.
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BibTeX
@article{yuan2026wolbachia,
title = {{Wolbachia outcompetes mosquito-borne viruses by reprogramming host ATPSβ1-driven ATP metabolism toward symbiotic proliferation}},
author = {Hao Yuan and Yalan Zhang and Yaqi Zhao and Chaojun Wang and Yuanyuan Zhou and Qian Ni and Xiaodan Li and Bo Zhang and Yong Wang and Liang Cai and Hong Liu and Jinglin Wang and Juntao Gong and Meichun Zhang and Zhiyong Xi and Xiaoling Pan},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014692},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014692},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Wolbachia outcompetes mosquito-borne viruses by reprogramming host ATPSβ1-driven ATP metabolism toward symbiotic proliferation
AU - Hao Yuan
AU - Yalan Zhang
AU - Yaqi Zhao
AU - Chaojun Wang
AU - Yuanyuan Zhou
AU - Qian Ni
AU - Xiaodan Li
AU - Bo Zhang
AU - Yong Wang
AU - Liang Cai
AU - Hong Liu
AU - Jinglin Wang
AU - Juntao Gong
AU - Meichun Zhang
AU - Zhiyong Xi
AU - Xiaoling Pan
PY - 2026
DA - 2026/10/21
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014692
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014692
AB - Wolbachia endosymbionts confer broad-spectrum resistance to mosquito-borne viruses. While the antiviral metabolites in Wolbachia-Aedes have been identified during viral replication, the core metabolic gene underlying this defense across the entire viral infection cycle remains undefined. Here, we demonstrated for the first time that Wolbachia strongly suppressed the emerging alphavirus Venezuelan equine encephalitis virus, extending its known antiviral spectrum. Transcriptomic and functional analyses revealed ATP synthase beta subunit 1 (ATPSβ1) as a key metabolic hub hijacked by both MBV and the symbiont. Without Wolbachia symbiosis, dengue virus and VEEV induced ATPSβ1 to promote viral binding via the viral envelope protein and increased intracellular ATP production for viral replication. Conversely, Wolbachia overrode ATPSβ1-mediated viral binding and redirected ATPSβ1-driven ATP synthesis to fuel its proliferation, strengthening antiviral activity. Pharmacologically, adenosine increased Wolbachia wAlbB density and potently suppressed viral infection in Ae. aegypti and Ae. albopictus cells. Oligomycin reduced intracellular ATP and inhibited viral infection in Wolbachia-free Ae. aegypti cells. Collectively, Wolbachia repurposes dual-functional ATPSβ1, which governs MBV binding and replication, into a potent antiviral effector through a metabolic tug-of-war over host ATP during symbiont-virus competition. Moreover, we highlight interventions targeting the ATPSβ1-driven metabolism as promising strategies to curb MBV transmission. Author summary: Mosquito-borne viruses (MBVs), such as dengue virus (DENV) and Venezuelan equine encephalitis virus (VEEV), pose serious threats to global public health. The endosymbiotic bacterium Wolbachia has been developed as a powerful tool for blocking virus transmission. However, the core metabolic mechanisms underlying Wolbachia-induced broad-spectrum antiviral resistance, especially across the complete viral infection cycle, remain unclear. In this study, we uncover ATP synthase beta subunit 1 (ATPSβ1) as a previously unrecognized metabolic hub that governs both viral infection and Wolbachia symbiosis. Importantly, we demonstrate that pharmacological modulation of ATPSβ1-driven metabolism potently suppresses MBV infection. Furthermore, we establish ATPSβ1 as a novel molecular target for developing small-molecule interventions that could recapitulate Wolbachia’s antiviral effect, even in the absence of the symbiont. Collectively, this work shifts the paradigm from viewing Wolbachia only as a blocker of viral transmission to understanding it as an active metabolic competitor. It also opens a new avenue for developing broad-spectrum antiviral strategies targeting host ATP metabolism, offering a transformative approach to mitigating the global public health burden of mosquito-borne diseases.
SN - 1553-7374
SN - 1553-7366
ER -