Innate Immune Sensing of Viral Persistence and Remnant RNA in Long-COVID: Mechanisms of Dysregulated Inflammation and Cellular Homeostasis

Persistent viral antigens or remnant SARS-CoV-2 RNA have been implicated in sustaining innate immune activation in a subset of individuals with post-acute sequelae of SARS-CoV-2 infection (PASC, “Long-COVID”). This Research Topic calls for mechanistic studies that interrogate how microbial products—intact virus, defective viral genomes, replication intermediates, or extracellular vesicle–associated RNA—are sensed and processed by innate immune pathways, and how these signals modulate macrophage, neutrophil, epithelial, and endothelial functions. We seek work that dissects the cellular choreography linking pattern recognition (TLR/RLR/NLR/cGAS-STING) to downstream signaling, inflammasome dynamics, autophagic flux, mitochondrial stress, and programmed cell death, as well as the consequences for immune training, tolerance, and tissue homeostasis. Studies should prioritize direct microbe–host interactions or microbe-derived ligands, maintaining a clear line from microbial sensing to cellular phenotype.

We encourage submissions that leverage primary human cells, patient-derived samples, organoids, and relevant animal or zebrafish models to map cell-intrinsic processes following exposure to SARS-CoV-2 persistence or RNA remnants. Cutting-edge imaging, single-cell multi-omics, spatial transcriptomics, and systems immunology approaches are welcome, especially when paired with functional perturbations (CRISPR, genetic knockouts/knock-ins, pharmacologic inhibitors) that causally link microbial sensing to effector outcomes. Interdisciplinary work connecting viral reservoirs (e.g., gut, lung, lymphoid tissue) with local innate immune microenvironments, and studies examining how microbial co-infections or microbiome-derived ligands shape these pathways, are particularly relevant. Ultimately, this Topic aims to define actionable mechanisms that can guide targeted interventions to restore immune equilibrium, supporting SDG 3: Good Health and Well-being.

We welcome articles addressing, but not limited to, the following themes:

-Innate sensing of persistent SARS-CoV-2 components in macrophages, neutrophils, and barrier epithelia
-Differential activation of TLR3/7/8, RIG-I/MDA5, NLRs, and cGAS-STING by defective genomes, subgenomic RNA, dsRNA, and RNA–protein complexes
-Kinetics, compartmentalization, and post-translational control of innate sensing pathways across cell types
-NLRP3 and non-canonical inflammasome activation by viral RNA/proteins, driven by K+ efflux, mitochondrial ROS, and cardiolipin exposure
-Gasdermin pore formation, pyroptosis versus hyperactivation, and IL-1β/IL-18 maturation
-Autophagy/mitophagy/xenophagy in viral RNA clearance and how viral factors subvert initiation, flux, lysosomes, and MAVS–mitochondrial dynamics
-Selective autophagy determining antigen persistence and chronic innate signaling
-Immediate evasion responses: endolysosomal remodeling, stress granules, RNA-binding protein sequestration, and NETs with feedback on RNA sensing
-Tissue context: reservoirs (gut, lung, lymphoid), myeloid–stromal crosstalk, and endothelial/perivascular drivers of microvascular dysfunction
-Systems and translation: single-cell/spatial multi-omics and functional perturbations (CRISPR, inhibitors) to identify druggable nodes that rebalance innate signaling without global immunosuppression

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review

Keywords: Long-COVID, innate immunity, viral persistence, remnant RNA, inflammasome, cGAS-STING, RIG-I/MDA5, autophagy, neutrophil extracellular traps, macrophage training

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.