Rhinovirus and Innate Immune Function of Airway Epithelium

Ganjian, Haleh; Rajput, Charu; Elzoheiry, Manal; Sajjan, Umadevi

doi:10.3389/fcimb.2020.00277

Cited by 25 publications

(24 citation statements)

References 164 publications

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“…This focus was based on the observation that wheezing in association with HRV infection is a risk factor for AA. 36,37 The TLR-IRF-IFN pathway (Fig 5 , B, top) plays a role in HRV immunity, 38,39 and deficiencies along this pathway (including TLR7) have been linked to AA risk and/or severity. [40][41][42][43] We found that several HRV-associated TLRs (TLR2/7/8), IRFs (IRF7/9), signaling mediators (MYD88), sensors (IFIH1, DDX58), and downstream effectors (STAT1, STAT2), as well as a gene signature of IFN-stimulated genes (ISG; used as a proxy for type I IFN levels 44 ), had lower expression in the maladaptive versus adaptive and resilient phenotypes (Fig 5 E7 and E8).…”

Section: Maladaptive Phenotype and Aa Risk: Shared Molecular Determinants In Peripheral Bloodmentioning

confidence: 99%

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases

Smith

Harper

Meunier

et al. 2021

Journal of Allergy and Clinical Immunology

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Background: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. Objective: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. Methods: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. Results: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8 1 T cells, whereas airway inflammation associated with both CD8 1 T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8 1 T cells, lower CD4 1 mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. Conclusions: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-ofadverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

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Section: Maladaptive Phenotype and Aa Risk: Shared Molecular Determinants In Peripheral Bloodmentioning

confidence: 99%

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases

Smith

Harper

Meunier

et al. 2021

Journal of Allergy and Clinical Immunology

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“…In asthma, RV-induced exacerbations are a major cause of disease morbidity and mortality, and increasing healthcare costs 30 . Airway epithelial cells, the primary target of respiratory viruses such as RV, can mount both inflammatory and antiviral innate immune responses aimed to efficiently clear the virus 31 . In our previous study, we provided the first evidence that RV infection in human primary airway epithelial cell culture and mouse models induces the expression of IP and this induction enhances the host antiviral mechanism 9 .…”

Section: Discussionmentioning

confidence: 99%

Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection

Dimasuay

Schaunaman

Berg

et al. 2022

Sci Rep

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Immunoproteasomes (IP) serve as an important modulator of immune responses to pathogens and other pathological factors. LMP7/β5i, one of the IP subunits, plays a critical role in autoimmune diseases by downregulating inflammation. Rhinovirus (RV) infection is a major risk factor in the exacerbations of respiratory inflammatory diseases, but whether LMP7 regulates RV-mediated inflammation in the lung particularly in the airway epithelium, the first line of defense against RV infection, remains unclear. In this study, we determined whether airway epithelial LMP7 promotes the resolution of RV-mediated lung inflammation. Inducible airway epithelial-specific LMP7-deficient (conditional knockout, CKO) mice were generated to reveal the in vivo anti-inflammatory and antiviral functions of LMP7. By using LMP7-deficient primary human airway epithelial cells generated by CRISPR-Cas9, we confirmed that airway epithelial LMP7 decreased pro-inflammatory cytokines and viral load during RV infection. Additionally, airway epithelial LMP7 enhanced the expression of a negative immune regulator A20/TNFAIP3 during viral infection that may contribute to the anti-inflammatory function of LMP7. We also discovered that induction of LMP7 by a low dose of polyinosinic:polycytidylic acid (PI:C) reduced RV-mediated inflammation in our CKO mice infected with RV. Our findings suggest that airway epithelial LMP7 has anti-inflammatory and antiviral functions that is critical to the resolution of RV-mediated lung inflammation. Induction of airway epithelial LMP7 may open a novel avenue for therapeutic intervention against RV infection.

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“…After entering endosomes, TLR 3 and TLR 7/8 bind to double-and single-stranded RNA, respectively. Interactions with these TLRs trigger activation of the NF-κB pathway and increase production of interferon (IFN)-β, IFN-γ, IL-6, and IL-8 ( Jacobs et al, 2013 ; Makris and Johnston, 2018 ; Ganjian et al, 2020 ). Geng et al reported that kakkonto treatment decreases the mRNA and protein levels of TLR7 and myeloid differentiation primary response 88 in murine lung tissues infected with H1N1 influenza virus, indicating that kakkonto exerts an inhibitory effect on activation of the NF-κB pathway ( Geng et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Kakkonto Inhibits Cytokine Production Induced by Rhinovirus Infection in Primary Cultures of Human Nasal Epithelial Cells

et al. 2021

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Rhinovirus (RV) is a primary etiologic agent of common cold that can subsequently acutely exacerbate bronchial asthma or chronic obstructive pulmonary disease. Kakkonto (Ge-gen-tang in Chinese), one of the most frequently prescribed traditional Japanese (Kampo) medicines, is used for treating common cold, shoulder stiffness, or inflammatory diseases of the upper body. Previous experimental studies have indicated that kakkonto exerts antiviral and anti-inflammatory effects on the influenza virus and the human respiratory syncytial virus. However, there is a lack of reports investigating the efficacy of kakkonto in RV infection. Hence, the aim of the current study was to investigate the effects of kakkonto on RV infection of human nasal epithelial (HNE) cells. HNE cells obtained via endoscopic sinus surgery were cultured and infected with RV14, with or without kakkonto treatment. The supernatants from the cells were collected, and the RV14 titer and cytokine levels were assessed. Reverse transcription-polymerase chain reaction was performed to determine the amount of viral RNA, while the level of nuclear factor kappa B (NF-κB) subunits in the nucleus was assessed by enzyme-linked immunosorbent assay. Although kakkonto treatment did not reduce RV14 titer or RNA levels, indicating that it did not inhibit RV14 proliferation, it was found to reduce the production of specific pro-inflammatory cytokines, including interleukin (IL)-8, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein-1 (MCP-1). Unlike that observed with the kakkonto extract, none of the crude drugs contained in kakkonto reduced IL-8 level. Furthermore, though kakkonto treatment significantly reduced p50 levels, it did not impact the p65 subunit of NF-κB. These results indicated that kakkonto can inhibit inflammation caused by RV infection and may exert an immunomodulatory effect on HNE cells. This is the first report to elucidate the effects of kakkonto extract on RV infection in primary cultures of HNE cells, providing evidence that kakkonto may act as an effective therapy for RV infection and subsequent airway inflammation.

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Rhinovirus and Innate Immune Function of Airway Epithelium

Cited by 25 publications

References 164 publications

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases

Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection

Kakkonto Inhibits Cytokine Production Induced by Rhinovirus Infection in Primary Cultures of Human Nasal Epithelial Cells

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