Infection Meets Inflammation: N6-Methyladenosine, an Internal Messenger RNA Modification as a Tool for Pharmacological Regulation of Host–Pathogen Interactions

Abstract

The significance of internal mRNA modifications for the modulation of transcript stability, for regulation of nuclear export and translation efficiency, and their role in suppressing innate immunity is well documented. Over the years, the molecular complexes involved in the dynamic regulation of the most prevalent modifications have been characterized—we have a growing understanding of how each modification is set and erased, where it is placed, and in response to what cues. Remarkably, internal mRNA modifications, such as methylation, are emerging as an additional layer of regulation of immune cell homeostasis, differentiation, and function. A fascinating recent development is the investigation into the internal modifications of host/pathogen RNA, specifically N6-methyladenosine (m6A), its abundance and distribution during infection, and its role in disease pathogenesis and in shaping host immune responses. Low molecular weight compounds that target RNA-modifying enzymes have shown promising results in vitro and in animal models of different cancers and are expanding the tool-box in immuno-oncology. Excitingly, such modulators of host mRNA methyltransferase or demethylase activity hold profound implications for the development of new broad-spectrum therapeutic agents for infectious diseases as well. This review describes the newly uncovered role of internal mRNA modification in infection and in shaping the function of the immune system in response to invading pathogens. We will also discuss its potential as a therapeutic target and identify pitfalls that need to be overcome if it is to be effectively leveraged against infectious agents.