Arboviruses such as dengue and Zika viruses circulate widely across the globe, posing threats to human health and biosecurity. They spread through the bites of arthropod vectors, moving between insects and vertebrate hosts. To sustain their transmission cycle, these viruses must alternately infect both mosquito vectors and vertebrate hosts.
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 (m6A) 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.
The m6A is the most prevalent post-transcriptional modification of RNA in eukaryotes, which plays a key role in regulating RNA stability and translation. Using cell culture systems, researchers discovered that this modification preferentially enhanced flavivirus propagation in vertebrate cells but not in their mosquito vectors.
Through pharmacological inhibition of m6A methylation using the methyltransferase inhibitor STM2457, researchers observed a significant reduction in viremia, along with alleviated weight loss and decreased mortality in virus-infected mice. The treatment almost completely blocked the transmission of the virus from vertebrate hosts to mosquito vectors. These findings indicated that m6A modification directly contributes to viral replication and transmission in vivo.
Mechanistically, researchers found that the stem-loop I (SLI) structure within the viral 3′ untranslated region was required for regulating m6A modification in vertebrate cells. The SLI structure interacted with the host protein G3BP1, facilitating the formation of stress granules and thereby promoting m6A modification of the viral genome. This regulatory pathway was specific to vertebrate cells and did not affect m6A modification in mosquito-derived cells, suggesting a host-dependent regulatory mechanism.
In addition, researchers investigated the role of m6A modification in viral adaptation. They found that arboviruses must alternately infect vertebrate hosts and arthropod vectors to sustain transmission. Serial passage in a single host led to the loss of cross-species infectivity. For example, viruses passaged in vertebrate cells lost N-linked glycosylation on the envelope protein E, impairing their ability to infect mosquitoes, while passage in mosquito cells resulted 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. It has significant implications for flavivirology, epigenetics, and public health and, importantly, the development of novel strategies to block flaviviral transmission.