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Cited by 655interferon and immune responsesRespiratory viral infections researchImmune Response and Inflammation

The airway epithelium: soldier in the fight against respiratory viruses

Open access
Vareille, Marjolaine, Kieninger, Elisabeth, Edwards, Michael R., Regamey, Nicolas·2011·Clinical Microbiology Reviews
DOI 10.1128/cmr.00014-10PMC PMC3021210
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Abstract

SUMMARY: The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions. It initiates multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses. The interaction between respiratory viruses and airway epithelial cells results in production of antiviral substances, including type I and III interferons, lactoferrin, β-defensins, and nitric oxide, and also in production of cytokines and chemokines, which recruit inflammatory cells and influence adaptive immunity. These defense mechanisms usually result in rapid virus clearance. However, respiratory viruses elaborate strategies to evade antiviral mechanisms and immune responses. They may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms. In addition, they can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones. Finally, by inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, they favor lung damage and further impair host antiviral mechanisms.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the airway epithelium is a central frontline defender against respiratory viruses through physical barrier, mucociliary clearance, and innate/adaptive immune functions, but that viruses subvert these defenses to cause epithelial damage, dysregulated inflammation, mucus obstruction, and secondary bacterial infection. It synthesizes mechanisms of epithelial protection and viral evasion and discusses therapeutic implications.

Key findings

  • The airway epithelium defends against respiratory viruses via cell-cell junctions, the mucociliary escalator, and immune recognition through TLRs and intracellular sensors such as RIG-I/MDA5; it produces antiviral substances including type I and III interferons, lactoferrin, β-defensins, and nitric oxide, plus cytokines/chemokines that recruit innate and adaptive immune cells.
  • Respiratory viruses evade these defenses by inhibiting IFN synthesis or downstream signaling (e.g., RSV NS2 targets RIG-I; RSV NS1/NS2 inhibit STAT2; influenza NS1 inhibits PKR), disrupting tight junctions and epithelial repair, shifting Th1 responses toward Th2, and inducing mucus hypersecretion and mucostasis.
  • Viral respiratory tract infections are the most common illnesses worldwide; rhinoviruses are the most frequent agents, and vRTIs are linked to exacerbations of asthma, cystic fibrosis, and COPD and to later recurrent wheeze/asthma risk. The paper reports that vRTIs lead to more than 400,000 hospitalizations per year among children in the United States.
  • Viruses promote secondary bacterial infection: during influenza pandemics, bacterial coinfections with *Streptococcus pneumoniae*, *Haemophilus influenzae*, and *Staphylococcus aureus* contributed importantly to mortality, and the majority of deaths during the 1918–1919 flu pandemic were due to bacterial pneumonia. Mechanisms include decreased clearance, increased paracellular permeability, and virus-induced bacterial adherence.

Methods

  • Design: narrative review.
  • Data or sample: published literature on airway epithelial defense and respiratory virus pathogenesis; no primary cohort, experimental sample, or statistical analysis is reported.
  • Main analysis: thematic synthesis of epithelial barrier, mucociliary, innate, and adaptive immune mechanisms, viral evasion strategies, and pathways promoting bacterial infection; includes summary tables of the “wounded soldier” model and studies on bacterial adherence to human respiratory epithelial cells during viral infection.

Limitations

  • The paper does not state limitations.
  • Evident from the text: as a narrative review, it does not describe a systematic search strategy, inclusion criteria, or quantitative synthesis, and it relies on heterogeneous in vitro, animal, and clinical studies.
  • Evident from the text: several mechanisms are explicitly described as unresolved or speculative, including whether NLRP3 directly senses viral RNA, the role of airway epithelial cell-induced inflammation in virus-specific disease severity, and whether high inflammatory mediator levels reflect dysregulated inflammation versus increased viral replication.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1128/cmr.00014-10

Cites

341 of 341 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 257 cited sources checked · 0 supported · 0 flagged

  • Premisecitation
    § INTRODUCTION

    Airway mucin production is induced by many respiratory viruses, including rhinovirus and influenza virus.

    “Airway mucin production is induced by many respiratory viruses, including rhinovirus and influenza virus (278, 336).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Premisecitation
    § INTRODUCTION

    Epithelial cells are attached to their neighbors by cell-cell junctions including tight junctions, adherens junctions, gap junctions, and desmosomes.

    “They are attached to their neighbors by cell-cell junctions, including tight junctions (TJs), adherens junctions (AJs), gap junctions, and desmosomes (234).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Interpretationnone given
    § INTRODUCTION

    Increased production of mucus allows for better trapping and clearance of viruses.

    “The increased production of mucus allows for better trapping and clearance of viruses.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § INTRODUCTION

    Airway epithelial cells rapidly recognize pathogens through pattern recognition receptors such as Toll-like receptors and intracellular viral sensors.

    “Airway epithelial cells rapidly recognize pathogens through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and intracellular viral sensors (3) (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisecitation
    § INTRODUCTION

    TLRs play a crucial role in the initiation of immune responses in the respiratory epithelium.

    “TLRs play a crucial role in the initiation of immune responses in the respiratory epithelium (45, 175).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation
    § INTRODUCTION

    Activation of epithelial cells results in immediate host defense responses including production of antiviral substances and proinflammatory cytokines that recruit and activate other mucosal innate immune cells and initiate mechanisms of adaptive immunity.

    “Activation of epithelial cells results in immediate host defense responses that include production of antiviral substances as well as proinflammatory cytokines which recruit and activate other mucosal innate immune cells and initiate mechanisms of adaptive immunity (108).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § INTRODUCTION

    The airway epithelium is central to the defense of the lung against pathogens through the combined function of ciliated epithelial and secretory cells maintaining efficient mucociliary clearance and through a variety of other host defense mechanisms.

    “Besides its role in maintaining the conduit for air to and from the alveoli, the airway epithelium is central to the defense of the lung against pathogens, through the combined function of ciliated epithelial and secretory cells maintaining efficient mucociliary clearance and through a variety of other host defense mechanisms (45, 65, 144).”
    Quote in the paperSubstantial claim0 of 3 sources checked
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  • May combine two claims.

    Interpretationreasoning
    § Abstract

    The airway epithelium acts as a frontline defense against respiratory viruses through physical barrier, mucociliary apparatus, and immunological functions.

    “The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Primary human airway epithelial cells and cell lines derived from them express 10 TLRs (TLR1 to -10), and TLR expression has been documented for human biopsy tissue.

    “Primary human airway epithelial cells and cell lines derived from them have been shown to express 10 TLRs (TLR1 to -10) (188, 260), and TLR expression has been documented for human biopsy tissue (101).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Interpretationreasoning
    § Abstract

    By inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, respiratory viruses favor lung damage and further impair host antiviral mechanisms.

    “Finally, by inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, they favor lung damage and further impair host antiviral mechanisms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given
    § INTRODUCTION

    While airway defense mechanisms efficiently fight respiratory viruses most of the time, resulting in rapid clearance with minimal clinical consequences, viruses have found ways of avoiding immune responses in the airways, with the potential consequence of severe respiratory disease.

    “While airway defense mechanisms efficiently fight respiratory viruses most of the time, resulting in rapid clearance of the virus with minimal clinical consequences, viruses have found ways of avoiding immune responses in the airways, with the potential consequence of severe respiratory disease.”
    Quote in the paperNot a substantial claim

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    Interpretationnone given
    § Abstract

    Respiratory viruses can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones.

    “In addition, they can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § INTRODUCTION

    Innate immune responses of the epithelium allow for control of viral invasion and replication, and adaptive responses allow for effective viral clearance through cells of the adaptive immune system.

    “Innate immune responses of the epithelium allow for control of viral invasion and replication, and adaptive responses allow for effective viral clearance through cells of the adaptive immune system.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § INTRODUCTION

    Mucin overproduction and excessive mucus formation can lead to airway obstruction and exacerbation of preexisting airway disease, turning a powerful innate cleaning defense system into a detrimental mechanism.

    “However, mucin overproduction and excessive mucus formation can lead to airway obstruction and exacerbation of preexisting airway disease, turning a powerful innate cleaning defense system into a detrimental mechanism (see The Wounded Soldier) (239, 298).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Abstract

    These defense mechanisms usually result in rapid virus clearance.

    “These defense mechanisms usually result in rapid virus clearance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given
    § Abstract

    Respiratory viruses may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms.

    “They may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Type III IFNs possess antiviral properties similar to those of type I IFNs but appear to be expressed especially by epithelial cells and consequently exert host protection primarily at epithelial surfaces.

    “Type III IFNs possess antiviral properties similar to those of type I IFNs but appear to be expressed especially by epithelial cells and consequently exert host protection primarily at epithelial surfaces (8, 9, 335).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Premisecitation
    § INTRODUCTION

    Binding of RNA species to RIG-I and MDA5 leads to interaction of CARDs within an adaptor protein called IPS-1, MAVS, VISA, or Cardif, which mediates recruitment and activation of protein kinases that phosphorylate IRF-3, leading to synthesis of type I and type III IFNs.

    “Binding of RNA species to RIG-I and MDA5 leads to interaction of CARDs within an adaptor protein called IPS-1, MAVS, VISA, or Cardif (222). This outer mitochondrial membrane protein mediates the recruitment and activation of protein kinases that phosphorylate the transcription factor IRF-3, leading to the synthesis of type I and type III IFNs (155).”
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    Premisecitation
    § INTRODUCTION

    RSV induces replication-mediated activation of the IFN-beta promoter via RIG-I signaling.

    “For example, RSV induces replication-mediated activation of the IFN-β promoter via RIG-I signaling (253).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § INTRODUCTION

    The RSV fusion protein interacts with TLR4, which then signals through MyD88 to induce immune responses in airway epithelial cells.

    “It has been shown that the RSV fusion protein interacts with TLR4, which then signals through MyD88 to induce immune responses in airway epithelial cells (28, 92, 103, 152), and a recent study demonstrated RSV interaction with TLR2 and TLR6, promoting a proinflammatory response (190).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § INTRODUCTION

    IFNs, lactoferrin, beta-defensins, and nitric oxide are considered the most important epithelium-derived antiviral host defense molecules.

    “Among them, IFNs, lactoferrin (LF), β-defensins (BDs), and nitric oxide (NO) are considered the most important epithelium-derived antiviral host defense molecules (Fig. 1).”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § INTRODUCTION

    TLRs trigger activation predominantly of MAP kinases and several key transcription factors, including NF-kB, IRF-3, and IRF-7, resulting in induction of numerous proinflammatory cytokines and type I and type III IFNs.

    “TLRs trigger activation predominantly of mitogen-activated protein (MAP) kinases and of several key transcription factors, including NF-κB, interferon regulatory factor 3 (IRF-3), and IRF-7, resulting in the induction of numerous proinflammatory cytokines and type I (α and β) and type III (λ) IFNs (120).”
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    Premisecitation
    § INTRODUCTION

    RIG-I detects negative-sense ssRNA viruses that bear a 5-prime-triphospho-RNA genome, such as influenza virus and RSV, and plays a crucial role in the antiviral response to infection with these viruses.

    “In contrast, RIG-I has been shown to detect negative-sense ssRNA viruses that bear a 5′-triphospho-RNA genome, such as influenza virus and RSV, and appears to play a crucial role in the antiviral response to infection with these viruses (138).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § INTRODUCTION

    NLRP3 expression and production of IL-1beta are induced in primary human airway epithelial cells in response to influenza A virus infection.

    “NLRP3 expression and production of IL-1β are induced in primary human airway epithelial cells in response to influenza A virus infection, but it has yet to be determined whether NLRP3 acts directly as a PRR for viral RNA or if it is activated only indirectly in response to PRR signaling (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisenone given
    § INTRODUCTION

    IFN-alpha and IFN-beta are central to the early antiviral response of virus-infected cells and are expressed by many epithelial cell types.

    “IFN-α and IFN-β were among the first antiviral agents to be characterized and are still seen as central to the early antiviral response of virus-infected cells.”
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    Premisecitation
    § INTRODUCTION

    Lactoferrin prevents entry of virus into the host cell, either by blocking cellular receptors or by direct binding to virus particles.

    “It prevents entry of virus into the host cell, either by blocking cellular receptors or by direct binding to virus particles (290).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § INTRODUCTION

    MDA5 detects small RNA viruses such as rhinoviruses and is critical in regulating IFN-beta, IFN-lambda, and proinflammatory cytokine transcription.

    “MDA5 has been shown to detect small RNA viruses such as rhinoviruses and is critical in regulating IFN-β, IFN-λ, and proinflammatory cytokine transcription (138).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Kato, H., O. Takeuchi, S. Sato, M. Yoneyama, M. Yamamoto, K. Matsui, S. Uematsu, A. Jung, T. Kawai, K. J. Ishii, O. Yamaguchi, K. Otsu, T. Tsujimura, C. S. Koh, C. Reis e Sousa, Y. Matsuura, T. Fujita, and S. Akira. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101-105. [DOI] [PubMed] [Google Scholar]

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    Interpretationreasoning
    § INTRODUCTION

    This defective IFN response may promote susceptibility to infection by impairing the ability of the infected host cell to undergo early apoptosis and by allowing increased virus replication and cytolysis of infected cells.

    “This defective IFN response may promote susceptibility to infection by impairing the ability of the infected host cell to undergo early apoptosis and by allowing increased virus replication and, ultimately, cytolysis of infected cells.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § INTRODUCTION

    Four human beta-defensins (hBD-1 to -4) for airway mucosal defense have been identified in respiratory epithelial cells, but only hBD-2 and hBD-3 act against respiratory viruses.

    “Four hBDs (hBD-1 to -4) for airway mucosal defense have been identified in respiratory epithelial cells, but only hBD-2 and hBD-3 act against respiratory viruses (52, 73, 148, 267, 324).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Premisecitation
    § INTRODUCTION

    Data for humans show that increased exhaled nitric oxide after rhinovirus infection is correlated with reduced airway hyperresponsiveness in asthmatic patients, suggesting a beneficial effect of NO in virus-induced asthma exacerbations.

    “Data for humans show that increased exhaled nitric oxide after rhinovirus infection is correlated with reduced airway hyperresponsiveness in asthmatic patients, suggesting a beneficial effect of NO in virus-induced asthma exacerbations (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § INTRODUCTION

    Activation of NF-kB is common to many respiratory viruses, as demonstrated for rhinovirus, RSV, and influenza virus.

    “Activation of NF-κB is common to many respiratory viruses, as demonstrated for rhinovirus (129, 203), RSV (24), and influenza virus (145).”
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    Premisecitation
    § INTRODUCTION

    Increased virus (parainfluenza virus 3) replication in airway epithelial cells from CF patients is due at least partly to a lack of NOS-2 induction in response to virus, and NO donor or NOS-2 overexpression provides protection from virus infection.

    “The importance of nitric oxide production in antiviral defense of the airway epithelium is demonstrated by studies showing that increased virus (parainfluenza virus 3) replication in airway epithelial cells from CF patients is due at least partly to a lack of NOS-2 induction in response to virus and that NO donor or NOS-2 overexpression provides protection from virus infection (333, 334).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [333] Zheng, S., B. P. De, S. Choudhary, S. A. Comhair, T. Goggans, R. Slee, B. R. Williams, J. Pilewski, S. J. Haque, and S. C. Erzurum. 2003. Impaired innate host defense causes susceptibility to respiratory virus infections in cystic fibrosis. Immunity 18:619-630. [DOI] [PubMed] [Google Scholar]

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    • cites [334] Zheng, S., W. Xu, S. Bose, A. K. Banerjee, S. J. Haque, and S. C. Erzurum. 2004. Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium. Am. J. Physiol. Lung Cell. Mol. Physiol. 287:L374-L381. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § INTRODUCTION

    NOS-2 is induced and NO production increased after infection with respiratory viruses.

    “NOS-2 is induced and NO production increased after infection with respiratory viruses (136, 191, 246, 287).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [136] Kao, Y. J., P. A. Piedra, G. L. Larsen, and G. N. Colasurdo. 2001. Induction and regulation of nitric oxide synthase in airway epithelial cells by respiratory syncytial virus. Am. J. Respir. Crit. Care Med. 163:532-539. [DOI] [PubMed] [Google Scholar]

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    • cites [191] Murphy, A. W., T. A. Platts-Mills, M. Lobo, and F. Hayden. 1998. Respiratory nitric oxide levels in experimental human influenza. Chest 114:452-456. [DOI] [PubMed] [Google Scholar]

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    • cites [246] Sanders, S. P., J. Kim, K. R. Connolly, J. D. Porter, E. S. Siekierski, and D. Proud. 2001. Nitric oxide inhibits rhinovirus-induced granulocyte macrophage colony-stimulating factor production in bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 24:317-325. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Respiratory epithelial cells produce high levels of NO, as evidenced by detection of NO in exhaled breath and of NO reaction products in bronchoalveolar lavage fluid from human lungs.

    “Respiratory epithelial cells produce high levels of NO, as evidenced by detection of NO in exhaled breath and of NO reaction products (e.g., NO2− and NO3−) in bronchoalveolar lavage fluid from human lungs (77).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Gaston, B., J. M. Drazen, J. Loscalzo, and J. S. Stamler. 1994. The biology of nitrogen oxides in the airways. Am. J. Respir. Crit. Care Med. 149:538-551. [DOI] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    Bronchial biopsy specimens from subjects undergoing experimental rhinovirus infection show T-cell infiltration of the airway epithelium.

    “Bronchial biopsy specimens from subjects undergoing experimental rhinovirus infection show T-cell infiltration of the airway epithelium (69).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Fraenkel, D. J., P. G. Bardin, G. Sanderson, F. Lampe, S. L. Johnston, and S. T. Holgate. 1995. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am. J. Respir. Crit. Care Med. 151:879-886. [DOI] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    RSV strains have been documented to induce different patterns and severities of inflammatory responses.

    “RSV strains have also been documented to induce different patterns and severities of inflammatory responses (173, 174, 271).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [173] McNamara, P. S., B. F. Flanagan, C. A. Hart, and R. L. Smyth. 2005. Production of chemokines in the lungs of infants with severe respiratory syncytial virus bronchiolitis. J. Infect. Dis. 191:1225-1232. [DOI] [PubMed] [Google Scholar]

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    • cites [174] McNamara, P. S., B. F. Flanagan, A. M. Selby, C. A. Hart, and R. L. Smyth. 2004. Pro- and anti-inflammatory responses in respiratory syncytial virus bronchiolitis. Eur. Respir. J. 23:106-112. [DOI] [PubMed] [Google Scholar]

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    • cites [271] Smyth, R. L., K. J. Mobbs, U. O'Hea, D. Ashby, and C. A. Hart. 2002. Respiratory syncytial virus bronchiolitis: disease severity, interleukin-8, and virus genotype. Pediatr. Pulmonol. 33:339-346. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § INTRODUCTION

    Airway epithelial cells enhance cDC migration into the epithelium via MIP-3alpha/CCL20 production, and MIP-3alpha/CCL20 induction has been demonstrated in several viral infections such as influenza virus infection.

    “Airway epithelial cells have been shown to enhance cDC migration into the epithelium via MIP-3α/CCL20 production (232), and MIP-3α/CCL20 induction has been demonstrated in several viral infections, such as influenza virus infection (178, 308).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [232] Reibman, J., Y. Hsu, L. C. Chen, B. Bleck, and T. Gordon. 2003. Airway epithelial cells release MIP-3alpha/CCL20 in response to cytokines and ambient particulate matter. Am. J. Respir. Cell Mol. Biol. 28:648-654. [DOI] [PubMed] [Google Scholar]

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    • cites [178] Message, S. D., and S. L. Johnston. 2004. Host defense function of the airway epithelium in health and disease: clinical background. J. Leukoc. Biol. 75:5-17. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [308] Wareing, M. D., A. B. Lyon, B. Lu, C. Gerard, and S. R. Sarawar. 2004. Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. J. Leukoc. Biol. 76:886-895. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Upon extrinsic and intrinsic stimuli such as viral infections, the complex regulatory mechanism between airway epithelial cells and immune cells is lost or shifts and proinflammatory immune responses are initiated.

    “However, upon extrinsic and intrinsic stimuli such as viral infections, this complex regulatory mechanism is lost or shifts and proinflammatory immune responses are initiated (113, 301).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [113] Holt, P. G., D. H. Strickland, M. E. Wikstrom, and F. L. Jahnsen. 2008. Regulation of immunological homeostasis in the respiratory tract. Nat. Rev. Immunol. 8:142-152. [DOI] [PubMed] [Google Scholar]

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    • cites [301] Wang, H., Z. Su, and J. Schwarze. 2009. Healthy but not RSV-infected lung epithelial cells profoundly inhibit T cell activation. Thorax 64:283-290. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisenone given
    § INTRODUCTION

    pDCs are not efficient antigen-presenting cells; their antiviral action is mediated by production of large amounts of IFN-alpha, which delivers a powerful innate response to limit viral replication.

    “In contrast to cDCs, pDCs are not efficient antigen-presenting cells. Rather, their antiviral action is mediated by production of large amounts of IFN-α, which delivers a powerful innate response to limit viral replication.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Upon viral infection, pDCs are recruited rapidly from the bone marrow, and within several days they form the majority of DCs in the lung.

    “Upon viral infection, pDCs are recruited rapidly from the bone marrow, and within several days, they form the majority of DCs in the lung (300).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [300] Wang, H., N. Peters, and J. Schwarze. 2006. Plasmacytoid dendritic cells limit viral replication, pulmonary inflammation, and airway hyperresponsiveness in respiratory syncytial virus infection. J. Immunol. 177:6263-6270. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Studies of mice presensitized by recombinant vaccinia viruses showed that after RSV infection, animals exhibiting mainly Th2 cytokine responses developed enhanced disease with severe symptoms, whereas those with Th1 responses had reduced immunopathology and enhanced viral clearance.

    “For instance, studies of mice presensitized by recombinant vaccinia viruses showed that after RSV infection, animals exhibiting mainly Th2 cytokine responses developed enhanced disease with severe symptoms, whereas those with Th1 responses had reduced immunopathology and enhanced viral clearance (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Alwan, W. H., W. J. Kozlowska, and P. J. Openshaw. 1994. Distinct types of lung disease caused by functional subsets of antiviral T cells. J. Exp. Med. 179:81-89. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    The appearance of antigen-specific effector T cells in the airways is observed around 6 to 7 days after infection with influenza and parainfluenza viruses.

    “The appearance of antigen-specific effector T cells in the airways is observed around 6 to 7 days after infection with influenza and parainfluenza viruses (275).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] Swain, S. L., R. W. Dutton, and D. L. Woodland. 2004. T cell responses to influenza virus infection: effector and memory cells. Viral Immunol. 17:197-209. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Pandemic influenza viruses, including H5N1 avian influenza virus and the H1N1 2009 California influenza virus strain, have been associated with more severe inflammation than seasonal influenza virus strains, and the magnitude of inflammation is believed to be a major contributing factor to disease severity.

    “For instance, pandemic influenza viruses, including H5N1 avian influenza virus and the H1N1 2009 California influenza virus strain, have been associated with more severe inflammation than seasonal influenza virus strains, and it is believed that the magnitude of inflammation is a major contributing factor to disease severity (17, 200, 209, 283, 319).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Bellani, G., L. Guerra, A. Pesenti, and C. Messa. 2010. Imaging of lung inflammation during severe influenza A: H1N1. Intensive Care Med. 36:717-718. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [200] Osterlund, P., J. Pirhonen, N. Ikonen, E. Ronkko, M. Strengell, S. M. Makela, M. Broman, O. J. Hamming, R. Hartmann, T. Ziegler, and I. Julkunen. 2010. Pandemic H1N1 2009 influenza A virus induces weak cytokine responses in human macrophages and dendritic cells and is highly sensitive to the antiviral actions of interferons. J. Virol. 84:1414-1422. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [209] Perrone, L. A., J. K. Plowden, A. Garcia-Sastre, J. M. Katz, and T. M. Tumpey. 2008. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 4:e1000115. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    NK cells play an important role in the innate immune response against respiratory viruses, with their function being elimination of virus-infected cells and modulation of adaptive immunity toward an efficient antiviral response.

    “NK cells also play an important role in the innate immune response against respiratory viruses, with their function being the elimination of a variety of target cells, including virus-infected cells, and the modulation of adaptive immunity toward an efficient antiviral response (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Biron, C. A., K. B. Nguyen, G. C. Pien, L. P. Cousens, and T. P. Salazar-Mather. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17:189-220. [DOI] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    Rhinovirus group C strains are thought to be associated with increased inflammation and morbidity compared with rhinovirus group A or B strains.

    “Similarly, rhinovirus group C strains are thought to be associated with increased inflammation and morbidity compared with rhinovirus group A or B strains (10, 125).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Arden, K. E., C. E. Faux, N. T. O'Neill, P. McErlean, A. Nitsche, S. B. Lambert, M. D. Nissen, T. P. Sloots, and I. M. Mackay. 2010. Molecular characterization and distinguishing features of a novel human rhinovirus (HRV) C, HRVC-QCE, detected in children with fever, cough and wheeze during 2003. J. Clin. Virol. 47:219-223. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [125] Jin, Y., X. H. Yuan, Z. P. Xie, H. C. Gao, J. R. Song, R. F. Zhang, Z. Q. Xu, L. S. Zheng, Y. D. Hou, and Z. J. Duan. 2009. Prevalence and clinical characterization of a newly identified human rhinovirus C species in children with acute respiratory tract infections. J. Clin. Microbiol. 47:2895-2900. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Airway epithelial cells induce migration of Th1 cells into the mucosa via production of RANTES/CCL5 and IP-10/CXCL10 and that of Th2 cells via production of IL-1beta.

    “Airway epithelial cells induce migration of Th1 cells into the mucosa via production of RANTES/CCL5 and IP-10/CXCL10 and that of Th2 cells via production of IL-1β (178).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Message, S. D., and S. L. Johnston. 2004. Host defense function of the airway epithelium in health and disease: clinical background. J. Leukoc. Biol. 75:5-17. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § INTRODUCTION

    Airway epithelial cells not only mediate innate immune responses but also regulate adaptive immune responses through interactions with DCs and T and B lymphocytes.

    “Airway epithelial cells not only mediate innate immune responses but also regulate adaptive immune responses through interactions with DCs and T and B lymphocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Inhibition of neutrophil recruitment to the lung had no effect on virus clearance in a mouse model of influenza virus infection, suggesting only a minor role of neutrophils in this model of respiratory viral infection.

    “Interestingly, however, inhibition of neutrophil recruitment to the lung had no effect on virus clearance in a mouse model of influenza virus infection, suggesting only a minor role of neutrophils in this model of respiratory viral infection (309).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [309] Wareing, M. D., A. L. Shea, C. A. Inglis, P. B. Dias, and S. R. Sarawar. 2007. CXCR2 is required for neutrophil recruitment to the lung during influenza virus infection, but is not essential for viral clearance. Viral Immunol. 20:369-378. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § INTRODUCTION

    In in vitro culture systems, bronchial epithelium generates higher viral loads and more expression of virus-inducible mediators than the comparator epithelial cells cultured in the same manner.

    “Using in vitro culture systems, some differences between susceptibilities to rhinovirus infection have been noted, with bronchial epithelium generating higher viral loads and more expression of virus-inducible mediators than those in bronchial epithelial cells cultured in the same manner (163).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Lopez-Souza, N., S. Favoreto, H. Wong, T. Ward, S. Yagi, D. Schnurr, W. E. Finkbeiner, G. M. Dolganov, J. H. Widdicombe, H. A. Boushey, and P. C. Avila. 2009. In vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human subjects. J. Allergy Clin. Immunol. 123:1384-1390. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    Rhinovirus-induced cytotoxicity was shown in bronchial epithelial cells after rhinovirus infection.

    “Whereas rhinovirus-induced cytotoxicity was shown in bronchial epithelial cells after rhinovirus infection (27)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Bossios, A., S. Psarras, D. Gourgiotis, C. L. Skevaki, A. G. Constantopoulos, P. Saxoni-Papageorgiou, and N. G. Papadopoulos. 2005. Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells. Respir. Res. 6:114. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    Cytotoxicity upon infection with certain viruses may depend on the virus strain, infection conditions, and infected cell type and density.

    “Cytotoxicity upon infection with certain viruses may depend on the virus strain, infection conditions, and infected cell type and density (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Bossios, A., S. Psarras, D. Gourgiotis, C. L. Skevaki, A. G. Constantopoulos, P. Saxoni-Papageorgiou, and N. G. Papadopoulos. 2005. Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells. Respir. Res. 6:114. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • May combine two claims.

    Interpretationnone given
    § INTRODUCTION

    vRTIs can lead to perturbed inflammatory responses and increased mucus production, which is detrimental rather than protective to the host.

    “We further discuss how vRTIs can lead to perturbed inflammatory responses and to increased mucus production, which will be detrimental rather than protective to the host.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § INTRODUCTION

    Considering that the airway epithelium is the main site of viral infection, it is likely to contribute significantly to the type and magnitude of the inflammatory response.

    “However, considering that the airway epithelium is the main site of viral infection, it is likely to contribute significantly to the type and magnitude of the inflammatory response.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The airway epithelium is the main site of viral infection.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    TGF-β increases airway wound repair through MMP-2 upregulation.

    “For instance, TGF-β increases airway wound repair through MMP-2 upregulation (154).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Lechapt-Zalcman, E., V. Pruliere-Escabasse, D. Advenier, S. Galiacy, C. Charriere-Bertrand, A. Coste, A. Harf, M. P. d'Ortho, and E. Escudier. 2006. Transforming growth factor-beta1 increases airway wound repair via MMP-2 upregulation: a new pathway for epithelial wound repair? Am. J. Physiol. Lung Cell. Mol. Physiol. 290:L1277-L1282. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § INTRODUCTION

    Migrating basal airway epithelial cells repopulate damaged areas, proliferate, and differentiate until epithelial integrity has been restored.

    “Migrating basal airway epithelial cells repopulate damaged areas, proliferate, and differentiate until epithelial integrity has been restored (242).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Sacco, O., M. Silvestri, F. Sabatini, R. Sale, A. C. Defilippi, and G. A. Rossi. 2004. Epithelial cells and fibroblasts: structural repair and remodelling in the airways. Paediatr. Respir. Rev. 5(Suppl. A):S35-S40. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    MMPs play a crucial role in the remodeling of the matrix onto which cells migrate, and many pathways are involved in this process.

    “MMPs play a crucial role in the remodeling of the matrix onto which cells migrate, and many pathways are involved in this process (294).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [294] Visse, R., and H. Nagase. 2003. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92:827-839. [DOI] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § INTRODUCTION

    Most viruses have efficient ways to inhibit IFN synthesis, to bind and inactivate secreted IFN molecules, to block IFN-activated signaling, or to disturb the action of IFN-induced antiviral proteins.

    “Most viruses have efficient ways to inhibit IFN synthesis, to bind and inactivate secreted IFN molecules, to block IFN-activated signaling, or to disturb the action of IFN-induced antiviral proteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    NS2 prevents RIG-I signaling by interfering with the RIG-I-MAVS interaction, therefore severely limiting signaling mediated by the critical interaction between the sensor RIG-I and its specific adaptor, MAVS.

    “It is currently believed that NS2 prevents RIG-I signaling by interfering with the RIG-I-MAVS interaction, therefore severely limiting signaling mediated by the critical interaction between the sensor RIG-I and its specific adaptor, MAVS (161).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Ling, Z., K. C. Tran, and M. N. Teng. 2009. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J. Virol. 83:3734-3742. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § INTRODUCTION

    V proteins may be expressed at high levels during the initial stages of infection and therefore limit IRF3 activation by binding IKK-ɛ and preventing IRF-3 activation, and hence IFN induction.

    “V proteins may be expressed at high levels during the initial stages of infection and therefore limit IRF3 activation by binding IKK-ɛ and preventing IRF-3 activation, and hence IFN induction (165).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Lu, L. L., M. Puri, C. M. Horvath, and G. C. Sen. 2008. Select paramyxoviral V proteins inhibit IRF3 activation by acting as alternative substrates for inhibitor of kappaB kinase epsilon (IKKe)/TBK1. J. Biol. Chem. 283:14269-14276. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Rhinoviruses induce the production of proangiogenic molecules, including amphiregulin and VEGF, and therefore may lead to increased angiogenesis.

    “Furthermore, they induce the production of proangiogenic molecules, including amphiregulin (a member of the epidermal growth factor [EGF] family) and vascular endothelial growth factor (VEGF), and therefore may lead to increased angiogenesis (156, 220).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [156] Leigh, R., W. Oyelusi, S. Wiehler, R. Koetzler, R. S. Zaheer, R. Newton, and D. Proud. 2008. Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling. J. Allergy Clin. Immunol. 121:1238-1245. [DOI] [PubMed] [Google Scholar]

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    • cites [220] Psarras, S., E. Volonaki, C. L. Skevaki, M. Xatzipsalti, A. Bossios, H. Pratsinis, S. Tsigkos, D. Gourgiotis, A. G. Constantopoulos, A. Papapetropoulos, P. Saxoni-Papageorgiou, and N. G. Papadopoulos. 2006. Vascular endothelial growth factor-mediated induction of angiogenesis by human rhinoviruses. J. Allergy Clin. Immunol. 117:291-297. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § INTRODUCTION

    The NS1 and NS2 proteins of RSV inhibit STAT-2 activation, thus blocking IFN-α/β function.

    “The NS1 and NS2 proteins of RSV inhibit STAT-2 activation, thus blocking IFN-α/β function (161, 162).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [161] Ling, Z., K. C. Tran, and M. N. Teng. 2009. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J. Virol. 83:3734-3742. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [162] Lo, M. S., R. M. Brazas, and M. J. Holtzman. 2005. Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness. J. Virol. 79:9315-9319. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § INTRODUCTION

    Airway epithelial cells have receptors for and respond to IL-4, IL-13, and IL-25.

    “A role for airway epithelial cells in contributing to the Th2 phenotype is possible, as they have receptors for and respond to IL-4, IL-13, and IL-25 (68, 115).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [68] Fort, M. M., J. Cheung, D. Yen, J. Li, S. M. Zurawski, S. Lo, S. Menon, T. Clifford, B. Hunte, R. Lesley, T. Muchamuel, S. D. Hurst, G. Zurawski, M. W. Leach, D. M. Gorman, and D. M. Rennick. 2001. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985-995. [DOI] [PubMed] [Google Scholar]

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    • cites [115] Hurst, S. D., T. Muchamuel, D. M. Gorman, J. M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T. T. Kung, J. K. Brieland, S. M. Zurawski, R. W. Chapman, G. Zurawski, and R. L. Coffman. 2002. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169:443-453. [DOI] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    In allergic asthmatic subjects, Th1 responses to rhinovirus are downregulated, as indicated by lower levels of IL-12 and IFN-γ, whereas Th2 responses are increased, with higher levels of IL-4, IL-5, and IL-13.

    “In allergic asthmatic subjects, Th1 responses to rhinovirus are downregulated, as indicated by lower levels of IL-12 and IFN-γ, whereas Th2 responses are increased, with higher levels of IL-4, IL-5, and IL-13 (179).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Message, S. D., V. Laza-Stanca, P. Mallia, H. L. Parker, J. Zhu, T. Kebadze, M. Contoli, G. Sanderson, O. M. Kon, A. Papi, P. K. Jeffery, L. A. Stanciu, and S. L. Johnston. 2008. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc. Natl. Acad. Sci. U. S. A. 105:13562-13567. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    RSV and rhinovirus can lead to induction of the pro-Th2 cytokine TSLP, suggesting a direct link between viral infection of the epithelium and an altered immune response toward a Th2 pattern.

    “Furthermore, RSV and rhinovirus can lead to induction of the pro-Th2 cytokine TSLP, suggesting a direct link between viral infection of the epithelium and an altered immune response toward a Th2 pattern (4, 157, 264).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Allakhverdi, Z., M. R. Comeau, H. K. Jessup, B. R. Yoon, A. Brewer, S. Chartier, N. Paquette, S. F. Ziegler, M. Sarfati, and G. Delespesse. 2007. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J. Exp. Med. 204:253-258. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [157] Lemanske, R. F., Jr., D. J. Jackson, R. E. Gangnon, M. D. Evans, Z. Li, P. A. Shult, C. J. Kirk, E. Reisdorf, K. A. Roberg, E. L. Anderson, K. T. Carlson-Dakes, K. J. Adler, S. Gilbertson-White, T. E. Pappas, D. F. Dasilva, C. J. Tisler, and J. E. Gern. 2005. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J. Allergy Clin. Immunol. 116:571-577. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [264] Sigurs, N., R. Bjarnason, F. Sigurbergsson, and B. Kjellman. 2000. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am. J. Respir. Crit. Care Med. 161:1501-1507. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Influenza virus infection results in decreased tracheal mucociliary velocity and clearance of S. pneumoniae.

    “This is illustrated by studies showing that influenza virus infection results in decreased tracheal mucociliary velocity and clearance of S. pneumoniae (172, 213).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [172] McCullers, J. A., A. R. Iverson, R. McKeon, and P. J. Murray. 2008. The platelet activating factor receptor is not required for exacerbation of bacterial pneumonia following influenza. Scand. J. Infect. Dis. 40:11-17. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [213] Pittet, L. A., L. Hall-Stoodley, M. R. Rutkowski, and A. G. Harmsen. 2010. Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae. Am. J. Respir. Cell Mol. Biol. 42:450-460. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Rhinoviruses disrupt airway epithelial barrier functions and promote the paracellular migration of bacteria such as H. influenzae.

    “For instance, rhinoviruses disrupt airway epithelial barrier functions and promote the paracellular migration of bacteria such as H. influenzae (244).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [244] Sajjan, U., Q. Wang, Y. Zhao, D. C. Gruenert, and M. B. Hershenson. 2008. Rhinovirus disrupts the barrier function of polarized airway epithelial cells. Am. J. Respir. Crit. Care Med. 178:1271-1281. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § INTRODUCTION

    Perturbation of the epithelial barrier upon virus infection may increase paracellular permeability and facilitate translocation of bacteria and their soluble products into the submucosa.

    “In addition, perturbation of the epithelial barrier upon virus infection may increase paracellular permeability and facilitate translocation of bacteria and their soluble products into the submucosa.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [244] Sajjan, U., Q. Wang, Y. Zhao, D. C. Gruenert, and M. B. Hershenson. 2008. Rhinovirus disrupts the barrier function of polarized airway epithelial cells. Am. J. Respir. Crit. Care Med. 178:1271-1281. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation
    § INTRODUCTION

    Mechanisms involved in ciliostasis could be mediated by ion alterations during viral attachment and replication, by direct damage to the ciliary system, or by damage through the induction of NO, cyclic AMP, calmodulin, and InP3 production, which alters baseline ciliary beat frequency or modulates hfh4 and mdnh5 gene expression, resulting in absent or dysfunctional ciliary function.

    “Mechanisms involved in ciliostasis are poorly understood but could be mediated by ion alterations during viral attachment and replication, by direct damage to the ciliary system, or by damage through the induction of NO, cyclic AMP, calmodulin, and inositol 1,4,5-triphosphate (InP3) production, which alters baseline ciliary beat frequency (33) or modulates hfh4 and mdnh5 gene expression, resulting”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Chilvers, M. A., and C. O'Callaghan. 2000. Local mucociliary defence mechanisms. Paediatr. Respir. Rev. 1:27-34. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [169] Mall, M. A. 2008. Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: lessons from mouse models. J. Aerosol Med. Pulm. Drug Deliv. 21:13-24. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Rhinovirus increases the expression of ICAM-1, which serves as a receptor both for itself and for H. influenzae.

    “It also increases the expression of ICAM-1, which serves as a receptor both for itself and for H. influenzae (11, 316).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Avadhanula, V., C. A. Rodriguez, J. P. Devincenzo, Y. Wang, R. J. Webby, G. C. Ulett, and E. E. Adderson. 2006. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner. J. Virol. 80:1629-1636. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [316] Whiteman, S. C., A. Bianco, R. A. Knight, and M. A. Spiteri. 2003. Human rhinovirus selectively modulates membranous and soluble forms of its intercellular adhesion molecule-1 (ICAM-1) receptor to promote epithelial cell infectivity. J. Biol. Chem. 278:11954-11961. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    RSV upregulates cellular receptors such as ICAM-1 and CEACAM-1, leading to an increase of bacterial adherence, whereas influenza virus has no effect on the expression of these receptors.

    “For instance, whereas RSV upregulates cellular receptors such as ICAM-1 and CEACAM-1, leading to an increase of bacterial adherence, influenza virus has no effect on the expression of these receptors (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Avadhanula, V., C. A. Rodriguez, J. P. Devincenzo, Y. Wang, R. J. Webby, G. C. Ulett, and E. E. Adderson. 2006. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner. J. Virol. 80:1629-1636. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Increased bacterial adherence facilitates biofilm formation and could represent a critical step in permanent airway colonization by P. aeruginosa in cystic fibrosis patients.

    “Increased bacterial adherence facilitates biofilm formation and could represent a critical step in permanent airway colonization by P. aeruginosa in cystic fibrosis patients (98).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Hassett, D. J., T. R. Korfhagen, R. T. Irvin, M. J. Schurr, K. Sauer, G. W. Lau, M. D. Sutton, H. Yu, and N. Hoiby. 2010. Pseudomonas aeruginosa biofilm infections in cystic fibrosis: insights into pathogenic processes and treatment strategies. Expert Opin. Ther. Targets 14:117-130. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Virus-induced cell death may expose new receptors for bacterial adherence or impair mechanical removal of attached pathogens.

    “In addition, virus-induced cell death may expose new receptors for bacterial adherence or impair mechanical removal of attached pathogens (30, 41, 96).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Bragonzi, A., E. Copreni, S. de Bentzmann, M. Ulrich, and M. Conese. 2004. Airway epithelial cell-pathogen interactions. J. Cyst. Fibros. 3(Suppl. 2):197-201. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [41] de Bentzmann, S., C. Plotkowski, and E. Puchelle. 1996. Receptors in the Pseudomonas aeruginosa adherence to injured and repairing airway epithelium. Am. J. Respir. Crit. Care Med. 154:S155-S162. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [96] Hament, J. M., J. L. Kimpen, A. Fleer, and T. F. Wolfs. 1999. Respiratory viral infection predisposing for bacterial disease: a concise review. FEMS Immunol. Med. Microbiol. 26:189-195. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § INTRODUCTION

    Mechanisms responsible for the increased adherence to respiratory epithelial cells differ between viruses and also between cell types.

    “Mechanisms responsible for the increased adherence to respiratory epithelial cells differ between viruses and also between cell types.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Steroids are well established as suppressors of viral and bacterial inflammation and mucin production and may modulate epithelial damage, injury, and repair.

    “For example, steroids are well established as suppressors of viral (56, 268, 296) and bacterial (100) inflammation and mucin production and may modulate epithelial damage, injury, and repair.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [56] Edwards, M. R., M. W. Johnson, and S. L. Johnston. 2006. Combination therapy: synergistic suppression of virus-induced chemokines in airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 34:616-624. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [268] Skevaki, C. L., I. Christodoulou, I. S. Spyridaki, I. Tiniakou, V. Georgiou, P. Xepapadaki, D. A. Kafetzis, and N. G. Papadopoulos. 2009. Budesonide and formoterol inhibit inflammatory mediator production by bronchial epithelial cells infected with rhinovirus. Clin. Exp. Allergy 39:1700-1710. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [296] Volonaki, E., S. Psarras, P. Xepapadaki, D. Psomali, D. Gourgiotis, and N. G. Papadopoulos. 2006. Synergistic effects of fluticasone propionate and salmeterol on inhibiting rhinovirus-induced epithelial production of remodelling-associated growth factors. Clin. Exp. Allergy 36:1268-1273. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Impairment of TLR4 and TLR5 has been demonstrated after influenza virus infection, leading to reduced neutrophil recruitment and increased P. aeruginosa and S. pneumoniae adherence in airway epithelial cells.

    “Impairment of TLR4 and TLR5 has been demonstrated after influenza virus infection, leading to reduced neutrophil recruitment and increased P. aeruginosa and S. pneumoniae adherence in airway epithelial cells (46).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Didierlaurent, A., J. Goulding, S. Patel, R. Snelgrove, L. Low, M. Bebien, T. Lawrence, L. S. van Rijt, B. N. Lambrecht, J. C. Sirard, and T. Hussell. 2008. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J. Exp. Med. 205:323-329. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § CONCLUSIONS

    vRTIs lead to more than 400,000 hospitalizations per year among children in the United States and are therefore a major burden on the health care system.

    “They lead to more than 400,000 hospitalizations per year among children in the United States and are therefore a major burden on the health care system (105, 180, 194).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [105] Henrickson, K. J., S. Hoover, K. S. Kehl, and W. Hua. 2004. National disease burden of respiratory viruses detected in children by polymerase chain reaction. Pediatr. Infect. Dis. J. 23:S11-S18. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [180] Mizgerd, J. P. 2006. Lung infection—a public health priority. PLoS Med. 3:e76. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [194] Nair, H., D. J. Nokes, B. D. Gessner, M. Dherani, S. A. Madhi, R. J. Singleton, K. L. O'Brien, A. Roca, P. F. Wright, N. Bruce, A. Chandran, E. Theodoratou, A. Sutanto, E. R. Sedyaningsih, M. Ngama, P. K. Munywoki, C. Kartasasmita, E. A. Simoes, I. Rudan, M. W. Weber, and H. Campbell. 2010. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 375:1545-1555. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    A recent study demonstrated effectiveness of the ketomacrolide telithromycin in asthma exacerbations.

    “A recent study demonstrated effectiveness of the ketomacrolide telithromycin in asthma exacerbations (128).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Johnston, S. L., F. Blasi, P. N. Black, R. J. Martin, D. J. Farrell, and R. B. Nieman. 2006. The effect of telithromycin in acute exacerbations of asthma. N. Engl. J. Med. 354:1589-1600. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    A recent study found no protective effect of leukotriene receptor antagonists in a trial of post-RSV bronchiolitis in children.

    “a recent study found no protective effect of the above in a trial of post-RSV bronchiolitis in children (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Bisgaard, H., A. Flores-Nunez, A. Goh, P. Azimi, A. Halkas, M. P. Malice, J. L. Marchal, S. B. Dass, T. F. Reiss, and B. A. Knorr. 2008. Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. Am. J. Respir. Crit. Care Med. 178:854-860. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    In in vitro culture systems, azithromycin was able to augment rhinovirus-induced IFNs and their inducible genes and to decrease virus replication.

    “By use of in vitro culture systems, azithromycin was able to augment rhinovirus-induced IFNs and their inducible genes and to decrease virus replication (81).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Gielen, V., S. L. Johnston, and M. R. Edwards. 2010. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur. Respir. J. 36:646-654. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § CONCLUSIONS

    vRTIs are an important cause of morbidity and, in some cases, mortality.

    “vRTIs are an important cause of morbidity and, in some cases, mortality.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [105] Henrickson, K. J., S. Hoover, K. S. Kehl, and W. Hua. 2004. National disease burden of respiratory viruses detected in children by polymerase chain reaction. Pediatr. Infect. Dis. J. 23:S11-S18. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [180] Mizgerd, J. P. 2006. Lung infection—a public health priority. PLoS Med. 3:e76. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [194] Nair, H., D. J. Nokes, B. D. Gessner, M. Dherani, S. A. Madhi, R. J. Singleton, K. L. O'Brien, A. Roca, P. F. Wright, N. Bruce, A. Chandran, E. Theodoratou, A. Sutanto, E. R. Sedyaningsih, M. Ngama, P. K. Munywoki, C. Kartasasmita, E. A. Simoes, I. Rudan, M. W. Weber, and H. Campbell. 2010. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 375:1545-1555. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § INTRODUCTION

    A recent study demonstrated that children admitted to hospital with asthma-related symptoms were less likely to have used therapies, including leukotriene receptor antagonists.

    “While a recent study demonstrated that children admitted to hospital with asthma-related symptoms were less likely to have used therapies, including leukotriene receptor antagonists (127)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Johnston, N. W., S. L. Johnston, J. M. Duncan, J. M. Greene, T. Kebadze, P. K. Keith, M. Roy, S. Waserman, and M. R. Sears. 2005. The September epidemic of asthma exacerbations in children: a search for etiology. J. Allergy Clin. Immunol. 115:132-138. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § CONCLUSIONS

    Respiratory viruses have evolved strategies to subvert epithelial defense mechanisms and can lead to complications such as loss of epithelial integrity, perturbed inflammatory responses, increased mucus production, and secondary bacterial infections.

    “However, respiratory viruses have evolved strategies to subvert epithelial defense mechanisms and can lead to complications such as loss of epithelial integrity, perturbed inflammatory responses, increased mucus production, and secondary bacterial infections.”
    Quote in the paperNot a substantial claim
77 of 77

  • The paper relies on this without support.

    The airway epithelium is the main site of viral infection.

    “However, considering that the airway epithelium is the main site of viral infection, it is likely to contribute significantly to the type and magnitude of the inflammatory response.”

  • The paper relies on this without support.

    The physiochemical characteristics of the upper (nasal) and lower (bronchial) epithelia are very similar.

    “The general consensus is that the physiochemical characteristics of the upper (nasal) and lower (bronchial) epithelia are very similar”

  • The paper relies on this without support.

    The airway epithelium plays an important role as a protective physical and functional barrier between the external environment and underlying tissues and as a central element in the initiation and regulation of innate and adaptive immune responses in the lung.

    “The airway epithelium plays an important role as a protective physical and functional barrier between the external environment and underlying tissues and as a central element in the initiation and regulation of innate and adaptive immune responses in the lung.”

  • The paper relies on this without support.

    Airway epithelial cells are the principal hosts for respiratory viruses.

    “Airway epithelial cells are the principal hosts for respiratory viruses.”

  • The paper relies on this without support.

    Apoptosis acts as a protective mechanism to limit replication and spread of the virus to other cells, but exaggerated apoptosis can lead to a loss of integrity and protection of the epithelium, with detrimental consequences.

    “Apoptosis acts as a protective mechanism to limit replication and spread of the virus to other cells, but exaggerated apoptosis can lead to a loss of integrity and protection of the epithelium, with detrimental consequences.”

  • The paper relies on this without support.

    Epithelial repair initiates quickly after injury.

    “Epithelial repair initiates quickly after injury.”

  • The paper relies on this without support.

    Mucus contains many components that bind bacteria.

    “Mucus contains many components that bind bacteria.”

  • The paper relies on this without support.

    Most respiratory viral infections are self-limited and associated with minor morbidity.

    “Fortunately, most respiratory viral infections are self-limited and associated with minor morbidity.”

  • The paper relies on this without support.

    A frequent point of interference by viruses is the Jak-STAT signaling pathway, used by IFNs to induce transcription of antiviral genes.

    “A frequent point of interference by viruses is the Jak-STAT signaling pathway, used by IFNs to induce transcription of antiviral genes.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mucus production in the respiratory tract is increased to facilitate viral clearance during infections, but excessive mucus production can lead to airway obstruction by impeding mucociliary clearance.

    “First, mucus production in the respiratory tract is increased to facilitate viral clearance during infections. However, excessive mucus production can lead to airway obstruction by impeding mucociliary clearance (125).”

    From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [125]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Bronchial cells are compared with bronchial cells instead of nasal cells

    Minor

    The text says bronchial epithelium produced higher viral loads than bronchial epithelial cells cultured the same way. The cited reference instead identifies the comparison as bronchial versus nasal cells.

  • Table 2 calls non-human specimens human

    Minor

    Table 2 is headed as a list of studies using human respiratory epithelial cells, but its first entry uses murine tracheal explants; other entries also list animal tissues or cells.

  • HPIV-3 is expanded as metapneumovirus rather than parainfluenza virus

    Minor

    Table 2's footnote expands HPIV-3 as human metapneumovirus type 3, whereas the paper's cited reference uses the name human parainfluenza virus type 3.

  • TLR7 is assigned two different RNA ligands

    Minor

    The first passage says TLR7 recognizes double-stranded RNA, while the later passage says TLR7 recognizes single-stranded RNA.

  • Table 2 misidentifies the bacterium in its 1982 study

    Minor

    The table lists S. pneumoniae for reference 131, but that reference's title identifies type 1a group B streptococci.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Yang, L., Y. Luo, J. Wei, and S. He. 2010. Integrative genomic analyses on IL28RA, the common receptor of interferon-lambda1, -lambda2 and -lambda3. Int. J. Mol. Med. 25 : 807-812.

Cited by

Sorted by citations

Related

Authors
Vareille, M., Kieninger, E., Edwards, M. R., & Regamey, N.
Affiliations
  • Division of Respiratory Medicine, Department of Pediatrics, University Children's Hospital of Bern, Inselpital, 3010 Bern, Switzerland
  • University of Bern (CH)
  • Asthma UK (GB)
ORCID
Venue
Clinical Microbiology Reviews
Publisher
American Society for Microbiology
Published
2011-01
Volume
24
Issue
1
Pages
210-229
ISSN
  • 0893-8512 (ISSN-L)
  • 1098-6618
DOI
10.1128/cmr.00014-10
PMC
PMC3021210
OpenAlex
W2145181045
Semantic Scholar
a942a5a52b73a1f1befb07f36f25743cfed15229
Cited by
655
References
341
Citations by year
2026: 25 · 2025: 39 · 2024: 40 · 2023: 57 · 2022: 44 · 2021: 64 · 2020: 52 · 2019: 36 · 2018: 36 · 2017: 45 · 2016: 44 · 2015: 49 · 2014: 48 · 2013: 47 · 2012: 21
FWCI
3.55
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Clinical Microbiology Reviews (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion)
Funders
National Institute for Health and Care Research (NF-SI-0508-10212)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
airway epithelium, respiratory viruses, innate immunity, interferon, lactoferrin, beta-defensins, nitric oxide, cytokines and chemokines, viral immune evasion, epithelial barrier integrity, mucus hypersecretion, mucostasis, lung injury, viral clearance
MeSH terms
Humans, Immunity, Innate, Respiratory Tract Infections, Viruses, Respiratory Mucosa, Adaptive Immunity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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