Unveiling dual localization of TLRs: a new paradigm in microbial immunology

Toll-like receptors (TLRs) are indispensable sentinels of innate immunity, enabling host cells to detect conserved microbial patterns and coordinate early immune responses. The canonical framework distinguishes between plasma membrane-associated TLRs, including TLR1, TLR2, TLR4, and TLR5, which sense extracellular microbial products, and endosomal TLRs, including TLR3, TLR7, TLR8, and TLR9, which recognize intracellular nucleic acid ligands; however, the mammalian TLR repertoire is evolutionarily divergent, with species-specific receptor expansions, deletions, and pseudogenization events. However, mounting experimental evidence has fundamentally challenged this binary model. Endosomal TLRs are increasingly detected at the plasma membrane, where their surface-expressed forms appear to mediate distinct, non-redundant signaling events that existing frameworks fail to fully account for.

This dual localization, the concurrent presence of a single TLR species at both the cell surface and intracellular endolysosomal compartments, represents a paradigm shift in our understanding of microbial pattern recognition. The molecular determinants governing this dual trafficking, including differential glycosylation states, chaperone-mediated transport via UNC93B1, and receptor proteolytic processing, remain incompletely resolved. Equally, the downstream signaling consequences of compartment-specific TLR activation, particularly regarding NF-κB versus IRF3/IRF7 pathway selectivity, type I interferon induction, and pro-inflammatory cytokine profiles, have yet to be systematically mapped across immune and non-immune cell lineages.

This Research Topic, hosted in the Microbial Immunology section of Frontiers in Immunology, seeks to consolidate and advance understanding of TLR dual localization and its functional significance in host–microbe interactions. By bringing together mechanistic, translational, and systems-level investigations, this collection aims to illuminate how subcellular TLR compartmentalization shapes innate immune discrimination between pathogens and commensals, governs adaptive immune priming, and influences host susceptibility across bacterial, viral, fungal, and parasitic infections.

The scope of this Topic includes, but is not limited to:

-Molecular mechanisms governing TLR trafficking, membrane insertion, and endosomal retention in myeloid and lymphoid cells
-Glycosylation, proteolytic cleavage, and chaperone-dependent regulation of endosomal TLR surface expression
-Compartment-specific signaling: TRIF versus MyD88 pathway selectivity and downstream immune outcomes
-Differential roles of surface-expressed versus endosomal TLR3, TLR7, TLR8, and TLR9 in pathogen-specific responses
-Microbial evasion strategies that exploit or disrupt TLR localization and intracellular trafficking
-Crosstalk between TLR compartmentalization and other pattern recognition systems, including RLRs, NLRs, and cGAS-STING
-Therapeutic implications: vaccine adjuvant design, agonist/antagonist development, and infection control strategies targeting compartment-specific TLR activity

We welcome Original Research Articles, Systematic Reviews, Narrative Reviews, and Perspectives. Studies employing advanced imaging, proteomics, structural biology, and multi-omics approaches are particularly encouraged, as are contributions spanning diverse microbial classes, consistent with the broad mandate of the Microbial Immunology section.

The topic editors declare no conflict of interest

Article types and fees

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

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Editorial
• FAIR² Data
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

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Article types

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

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Editorial
• FAIR² Data
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Toll-like receptors, innate immunity, TLR trafficking, endosomal signaling, UNC93B1, pattern recognition, NF-κB/IRF3 pathways, type I interferons, microbial evasion, vaccine adjuvants

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.