Broadening Our View on Nucleic Acid Sensing: Novel Sensors, Signaling Pathways, and involvement in Non-Infectious Diseases

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Background

The nucleic acid content of pathogens constitutes a prime target for host defence mechanisms. Indeed, the biochemical properties of nucleic acid sequences are not subjected to (or capable of) rapid evolution to escape detection mechanisms and are in consequence evolutionarily conserved. The host has thus evolved foreign nucleic acid sensing pathways to quickly detect and respond to virus infection. Activation of these pathways triggers the type 1 interferon response as well as proinflammatory and antiviral states in the cell. Those well-conserved nucleic acid detection machineries constitute the core of nucleic acid immunity. As such, the essential role of the DNA-sensing cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, and the RNA-sensing Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), in protection from different pathogen infections are well established.

However, recent work is increasingly challenging this linear view of pathogen recognition, as new roles are emerging for nucleic acid sensing pathways in non-communicable diseases, and non-canonical functions are being revealed. Furthermore, we continue to discover other proteins and receptors that are involved in nucleic acid sensing or their downstream signalling pathways. This highlights that we are only beginning to understand the extent to which nucleic acid sensing is involved in other disease states, and the role they play in surveillance and maintenance of homeostasis. There is also great therapeutic potential for exploiting nucleic acid sensors in disease treatment strategies, such as in cancer. This has been heavily pursued for the cGAS-STING pathway in particular, but remains in its infancy, as underscored by mitigated results in preclinical trials. We need to better understand the multifaceted signalling pathways that are induced by nucleic acid sensing, beyond the canonical type 1 interferon responses, to truly harvest their therapeutic potential. While several hypotheses have been put forward, notably in the cancer research field, the source/nature of the nucleic acid agonists in other non-communicable diseases remains largely unknown. Understanding these will broaden the scope of approaches that can be investigated to treat diseases that involve nucleic acid sensing pathways.

For this research topic, we welcome the submission of Original Research, Review, Mini Review articles focusing on novel aspects of nucleic acid sensing. These topics can include, but are not limited to:

- Nucleic acid sensing beyond viral infection, e.g. in sterile inflammation, autoimmunity, cancer
- Novel nucleic acid sensors or modulators of nucleic acid sensing pathways
- Profiling of the types and sources of nucleic acids that activate receptors, in particular, endogenous nucleic acids
- New routes of signalling transmission, e.g. extracellular/intracellular second messengers
- Non-canonical nucleic acid sensing pathways, including roles beyond type 1 interferon induction, e.g. roles in autophagy or cellular metabolism

Keywords: Infection, Immunity, Nucleic acids, non-infectious diseases, signaling

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