In a study published in PNAS, a research team led by Prof. ZHENG Aihua from the Institute of Zoology (IOZ) of the Chinese Academy of Sciences revealed that N6-methyladenosine epigenetic modifications in mosquito-borne flaviviruses (MBFs), orchestrated by the dynamic interplay of SLI-G3BP1, are essential for viral propagation in vertebrates and transmission from vertebrates to mosquitoes.

Through pharmacological inhibition of m6A methylation using the methyltransferase inhibitor STM2457, the researchers observed a significant reduction in viremia, along with alleviated weight loss and decreased mortality in virus-infected mice. Moreover, the treatment almost completely blocked the transmission of the virus from vertebrate hosts to mosquito vectors. These findings indicate that m6A modification directly contributes to viral replication and transmission in vivo.

Mechanistically, the study shows that the stem-loop I (SLI) structure within the viral 3′ untranslated region (3′ UTR) is required for regulating m6A modification in vertebrate cells. The SLI structure interacts with the host protein G3BP1, facilitating the formation of stress granules and thereby promoting m6A modification of the viral genome. Notably, this regulatory pathway is specific to vertebrate cells and does not affect m6A modification in mosquito-derived cells, suggesting a host-dependent regulatory mechanism.

In addition, the researchers investigated the role of m6A modification in viral adaptation. Arboviruses must alternately infect vertebrate hosts and arthropod vectors to sustain transmission. Serial passage in a single host leads to the loss of cross-species infectivity. For example, viruses passaged in vertebrate cells lose N-linked glycosylation on the envelope protein E, impairing their ability to infect mosquitoes, whereas passage in mosquito cells results in the loss of the SLI structure, reducing infectivity in vertebrate hosts.

This study provides in-depth mechanistic detail for a better understanding of the critical role of epigenetic modifications in flavivirus replication, with significant implications for flavivirology, epigenetics, and public health and, importantly, the development of novel strategies to block flaviviral transmission.

https://doi.org/10.1073/pnas.2511164123

Contact:

ZHENG Aihua

Institute of Zoology, Chinese Academy of Sciences

Tel: 86-10-64807178

E-mail: zhengaihua@ioz.ac.cn

Web：http://english.ioz.cas.cn/

Pictured is a blood-feeding Aedes aegypti, the primary vector for the dengue and Zika viruses. (Image by ZHENG Aihua’s Lab)