The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium

Bonser, Luke R.; Eckalbar, Walter L.; Rodriguez, Lauren; Shen, Jiangshan Jane; Koh, Kyung Duk; Zlock, Lorna; Christenson, Stephanie A.; Woodruff, Prescott G.; Finkbeiner, Walter E.; Erle, David J.

doi:10.1101/2021.02.25.432762

Cited by 5 publications

(8 citation statements)

References 52 publications

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“…SARS-CoV-2-specific CD4 + effector cells generally do not express Th2 traits ( 39 ), which could play a protective role as shown by the lower susceptibility and less severe outcomes of COVID-19 in asthmatic and atopic patients ( 40 , 41 ). Accordingly, IL-13 was shown to reduce viral burden, possibly by downregulating the expression of angiotensin-converting enzyme 2 (ACE2) in airway epithelial cells ( 42 , 43 ). In addition, M2 macrophage polarization induced by IL-4 and IL-13 fostered tissue repair and resolution of inflammation in ARDS ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Nguyen¹,

Schioppa²,

Tiberio³

et al. 2022

Front. Immunol.

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Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to β-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7. Consistent with this, Tanimilast did not reduce the capability of SCV2-RNA-stimulated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. Both Tanimilast and β-methasone blocked the increase of MHC-I molecules in SCV2-RNA-activated DCs and restrained the proliferation and activation of cytotoxic CD8+ T cells. Our results indicate that Tanimilast can modulate the SCV2-RNA-induced pro-inflammatory and Th1-polarizing potential of DCs, crucial regulators of both the inflammatory and immune response. Given also the remarkable safety demonstrated by Tanimilast, up to now, in clinical studies, we propose this inhaled PDE4 inhibitor as a promising immunomodulatory drug in the scenario of COVID-19.

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Section: Discussionmentioning

confidence: 99%

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Nguyen¹,

Schioppa²,

Tiberio³

et al. 2022

Front. Immunol.

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“…It all suggests that IL-13 released from T helper 2 (Th2) and type 2 innate lymphoid cells (ILC2) cells at the mucosal sites during type 2 inflammation in allergic asthma on top of other known morphological and transcriptional changes might potently induce ACE2 deglycosylation and redistribution which might alter SARS-CoV-2 infection efficiency. Recent publications show that IL-13 can inhibit SARS-CoV-2 infection, as well as can reduce intracellular viral load and cell-to-cell transmission in airway epithelial cells 14, 38 . IL-13 induced mucus hyperproduction can inhibit SARS-CoV-2 infection by forming a physical barrier, but even after mucus removal, viral loads remained to be lower upon IL-13, suggesting further mechanisms to be involved 14 .…”

Section: Resultsmentioning

confidence: 99%

Regulation of mRNA transcripts, protein isoforms, glycosylation and spatial localization of ACE2 and other SARS-CoV-2-associated molecules in human airway epithelium upon viral infection and type 2 inflammation

Stocker

Radzikowska

Tan

et al. 2022

Preprint

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SARS-CoV-2 infection continues to pose a significant life threat, especially in patients with comorbidities. It remains unknown, if asthma or allergen- and virus-induced airway inflammation are risk factors or can constitute some forms of protection against COVID-19. ACE2 and other SARS-CoV-2-related host proteins are limiting factors of an infection, expression of which is regulated in a more complex way than previously anticipated. Hence, we studied the expression of ACE2 mRNA and protein isoforms, together with its glycosylation and spatial localization in house dust mite (HDM)-, interleukin-13 (IL-13)- and human rhinovirus (RV)-induced inflammation in the primary human bronchial airway epithelium of healthy subjects and patients with asthma. IL-13 decreased the expression of long ACE2 mRNA and glycosylation of full-length ACE2 protein via alteration of the N-linked glycosylation process, limiting its availability on the apical side of ciliated cells. RV infection increased short ACE2 mRNA, but it did not influence its protein expression. HDM exposure did not affect ACE2 mRNA or protein. IL-13 and RV significantly regulated mRNA, but not protein expression of TMPRSS2 and NRP1. Regulation of ACE2 and other host proteins was similar in healthy and asthmatic epithelium, underlining the lack of intrinsic differences, but rather the dependence on the inflammatory milieu in the airways.

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“…Jackson et al evaluated expression of ACE2 in the airways of in adults and children with asthma and found that ACE2 expression was lower in the airway of patients with allergic sensitization and asthma compared with patients with nonallergic asthma [29]. Reduced ACE2 expression combined with expression of immunomodulators could contribute to lower COVID-19 susceptibility for patients with nonallergic asthma, and this hypothesis is supported by a growing body of preclinical and clinical evidence [29,[32][33][34][35][36][37]. This study had a number of strengths, including a large sample size of patients from across the United States.…”

Section: Discussionmentioning

confidence: 99%

Patients with allergic asthma have lower risk of severe COVID-19 outcomes than patients with nonallergic asthma

Murphy

Busse

Holweg³

et al. 2022

BMC Pulm Med

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Background Although asthma does not appear to be a risk factor for severe coronavirus disease 2019 (COVID-19), outcomes could vary for patients with different asthma subtypes. The objective of this analysis was to compare COVID-19 outcomes in real-world cohorts in the United States among patients with asthma, with or without evidence of allergy. Methods In a retrospective analysis of the COVID-19 Optum electronic health record dataset (February 20, 2020–January 28, 2021), patients diagnosed with COVID-19 with a history of moderate-to-severe asthma were divided into 2 cohorts: those with evidence of allergic asthma and those without (nonallergic asthma). After 1:1 propensity score matching, in which covariates were balanced and potential bias was removed, COVID-19 outcomes were compared between cohorts. Results From a COVID-19 population of 591,198 patients, 1595 patients with allergic asthma and 8204 patients with nonallergic asthma were identified. After propensity score matching (n = 1578 per cohort), risk of death from any cause after COVID-19 diagnosis was significantly lower for patients with allergic vs nonallergic asthma (hazard ratio, 0.48; 95% CI 0.28–0.83; P = 0.0087), and a smaller proportion of patients with allergic vs nonallergic asthma was hospitalized within − 7 to + 30 days of COVID-19 diagnosis (13.8% [n = 217] vs 18.3% [n = 289]; P = 0.0005). Among hospitalized patients, there were no significant differences between patients with allergic or nonallergic asthma in need for intensive care unit admission, respiratory support, or COVID-19 treatment. Conclusions Asthma subtype may influence outcomes after COVID-19; patients with allergic asthma are at lower risk for hospitalization/death than those with nonallergic asthma.

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The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium

Cited by 5 publications

References 52 publications

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Regulation of mRNA transcripts, protein isoforms, glycosylation and spatial localization of ACE2 and other SARS-CoV-2-associated molecules in human airway epithelium upon viral infection and type 2 inflammation

Patients with allergic asthma have lower risk of severe COVID-19 outcomes than patients with nonallergic asthma

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