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Innate immune surveillance and nucleic acid sensing: Gatekeepers of inflammatory cell death in respiratory infectious diseases.

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Title: Innate immune surveillance and nucleic acid sensing: Gatekeepers of inflammatory cell death in respiratory infectious diseases.
Authors: Thapa N; Department of Biotechnology, Kathmandu University, Dhulikhel 6250, Nepal; Department of Biomedicine and Translational Research, Research Institute for Bioscience and Biotechnology, Kathmandu 44700, Nepal., Jin Y; College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea., Han JH; College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea. Electronic address: joohui.han@chungbuk.ac.kr.
Source: Pharmacological research [Pharmacol Res] 2026 Sep; Vol. 231, pp. 108340. Date of Electronic Publication: 2026 Jul 14.
Publication Type: Journal Article; Review
Language: English
Journal Info: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8907422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-1186 (Electronic) Linking ISSN: 10436618 NLM ISO Abbreviation: Pharmacol Res Subsets: MEDLINE
Imprint Name(s): Publication: Oct. 2015- : Amsterdam ; Elsevier
Original Publication: London ; San Diego : Academic Press, c1989-
MeSH Terms: Nucleic Acids*/immunology , Respiratory Tract Infections*/immunology , Respiratory Tract Infections*/virology , Respiratory Tract Infections*/pathology , Immunity, Innate* , Immunologic Surveillance*, Cell Death/immunology ; Inflammation/immunology ; Receptors, Pattern Recognition/immunology ; Humans ; Animals ; Innate Immunity Recognition ; Signal Transduction
Abstract: Respiratory infections caused by viral pathogens, including influenza A virus, respiratory syncytial virus, and SARS-CoV-2, as well as bacterial pathogens, remain major contributors to global morbidity and mortality. The outcomes of these infections are largely determined by how the host innate immune system detects pathogen-derived nucleic acids and regulates subsequent inflammatory responses. Pattern recognition receptors (PRRs) located in endosomal and cytosolic compartments, including toll-like receptors, RIG-I-like receptors, absent in melanoma 2, and Z-DNA-binding protein 1, as well as the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, recognize viral and bacterial nucleic acids and initiate signaling cascades that promote cytokine production and antimicrobial defense. However, dysregulated PRR activation can trigger inflammatory programmed cell death, including apoptosis, pyroptosis, necroptosis, and PANoptosis. This review summarizes recent advances in understanding how nucleic acid sensing orchestrates inflammatory cell death during respiratory infections, with particular emphasis on pathogen- and cell type-specific mechanisms that shape disease outcomes. We further highlight the dual nature of these pathways, which are essential for pathogen clearance but can drive immunopathology when excessively activated. Defining how nucleic acid-sensing pathways shape inflammatory cell death in respiratory infections may guide host-directed therapies that enhance pathogen clearance while preserving lung function. Overall, the field remains constrained by the predominance of virus-focused and murine preclinical studies, whereas bacterial nucleic acid sensing during respiratory infections remains poorly defined. Future studies should integrate major bacterial infection models with human-relevant respiratory epithelial systems to better translate PRR-mediated immune mechanisms into host-directed therapeutic strategies.
(Copyright © 2026 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors have declared no conflicts of interest.
Contributed Indexing: Keywords: Innate immunity; Nucleic acid sensing; Pattern recognition receptors; Programmed cell death; Respiratory infections
Substance Nomenclature: 0 (Nucleic Acids)
0 (Receptors, Pattern Recognition)
Entry Date(s): Date Created: 20260714 Date Completed: 20260825 Latest Revision: 20260825
Update Code: 20260826
DOI: 10.1016/j.phrs.2026.108340
PMID: 42448011
Database: MEDLINE
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  Data: Innate immune surveillance and nucleic acid sensing: Gatekeepers of inflammatory cell death in respiratory infectious diseases.
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  Data: <searchLink fieldCode="AU" term="%22Thapa+N%22">Thapa N</searchLink>; Department of Biotechnology, Kathmandu University, Dhulikhel 6250, Nepal; Department of Biomedicine and Translational Research, Research Institute for Bioscience and Biotechnology, Kathmandu 44700, Nepal.<br /><searchLink fieldCode="AU" term="%22Jin+Y%22">Jin Y</searchLink>; College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea.<br /><searchLink fieldCode="AU" term="%22Han+JH%22">Han JH</searchLink>; College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea. Electronic address: joohui.han@chungbuk.ac.kr.
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  Data: <searchLink fieldCode="JN" term="%228907422%22">Pharmacological research</searchLink> [Pharmacol Res] 2026 Sep; Vol. 231, pp. 108340. <i>Date of Electronic Publication: </i>2026 Jul 14.
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  Data: <i>Publication</i>: Oct. 2015- : Amsterdam ; Elsevier<br /><i>Original Publication</i>: London ; San Diego : Academic Press, c1989-
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  Data: <searchLink fieldCode="MM" term="%22Nucleic+Acids%22">Nucleic Acids*</searchLink>/<searchLink fieldCode="MM" term="%22Nucleic+Acids+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Respiratory+Tract+Infections%22">Respiratory Tract Infections*</searchLink>/<searchLink fieldCode="MM" term="%22Respiratory+Tract+Infections+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Respiratory+Tract+Infections%22">Respiratory Tract Infections*</searchLink>/<searchLink fieldCode="MM" term="%22Respiratory+Tract+Infections+virology%22">virology</searchLink> <br /><searchLink fieldCode="MM" term="%22Respiratory+Tract+Infections%22">Respiratory Tract Infections*</searchLink>/<searchLink fieldCode="MM" term="%22Respiratory+Tract+Infections+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Immunity%2C+Innate%22">Immunity, Innate*</searchLink> <br /><searchLink fieldCode="MM" term="%22Immunologic+Surveillance%22">Immunologic Surveillance*</searchLink><br /><searchLink fieldCode="MH" term="%22Cell+Death%22">Cell Death</searchLink>/<searchLink fieldCode="MH" term="%22Cell+Death+immunology%22">immunology</searchLink> ; <searchLink fieldCode="MH" term="%22Inflammation%22">Inflammation</searchLink>/<searchLink fieldCode="MH" term="%22Inflammation+immunology%22">immunology</searchLink> ; <searchLink fieldCode="MH" term="%22Receptors%2C+Pattern+Recognition%22">Receptors, Pattern Recognition</searchLink>/<searchLink fieldCode="MH" term="%22Receptors%2C+Pattern+Recognition+immunology%22">immunology</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Innate+Immunity+Recognition%22">Innate Immunity Recognition</searchLink> ; <searchLink fieldCode="MH" term="%22Signal+Transduction%22">Signal Transduction</searchLink>
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  Data: Respiratory infections caused by viral pathogens, including influenza A virus, respiratory syncytial virus, and SARS-CoV-2, as well as bacterial pathogens, remain major contributors to global morbidity and mortality. The outcomes of these infections are largely determined by how the host innate immune system detects pathogen-derived nucleic acids and regulates subsequent inflammatory responses. Pattern recognition receptors (PRRs) located in endosomal and cytosolic compartments, including toll-like receptors, RIG-I-like receptors, absent in melanoma 2, and Z-DNA-binding protein 1, as well as the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, recognize viral and bacterial nucleic acids and initiate signaling cascades that promote cytokine production and antimicrobial defense. However, dysregulated PRR activation can trigger inflammatory programmed cell death, including apoptosis, pyroptosis, necroptosis, and PANoptosis. This review summarizes recent advances in understanding how nucleic acid sensing orchestrates inflammatory cell death during respiratory infections, with particular emphasis on pathogen- and cell type-specific mechanisms that shape disease outcomes. We further highlight the dual nature of these pathways, which are essential for pathogen clearance but can drive immunopathology when excessively activated. Defining how nucleic acid-sensing pathways shape inflammatory cell death in respiratory infections may guide host-directed therapies that enhance pathogen clearance while preserving lung function. Overall, the field remains constrained by the predominance of virus-focused and murine preclinical studies, whereas bacterial nucleic acid sensing during respiratory infections remains poorly defined. Future studies should integrate major bacterial infection models with human-relevant respiratory epithelial systems to better translate PRR-mediated immune mechanisms into host-directed therapeutic strategies.<br /> (Copyright © 2026 The Authors. Published by Elsevier Ltd.. All rights reserved.)
– Name: Abstract
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  Data: Declaration of Competing Interest The authors have declared no conflicts of interest.
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  Data: <i>Keywords: </i>Innate immunity; Nucleic acid sensing; Pattern recognition receptors; Programmed cell death; Respiratory infections
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        Value: 10.1016/j.phrs.2026.108340
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      – Code: eng
        Text: English
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        StartPage: 108340
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      – SubjectFull: Cell Death immunology
        Type: general
      – SubjectFull: Inflammation immunology
        Type: general
      – SubjectFull: Receptors, Pattern Recognition immunology
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      – SubjectFull: Nucleic Acids immunology
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      – SubjectFull: Respiratory Tract Infections immunology
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      – SubjectFull: Respiratory Tract Infections virology
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      – SubjectFull: Immunity, Innate
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      – SubjectFull: Immunologic Surveillance
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      – TitleFull: Innate immune surveillance and nucleic acid sensing: Gatekeepers of inflammatory cell death in respiratory infectious diseases.
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              Text: 2026 Sep
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