Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection
Human rhinoviruses (HRV) are the most common cause of viral respiratory tract infections. While normally mild and self-limiting in healthy adults, HRV infections are associated with bronchiolitis in infants, pneumonia in immunocompromised patients, and exacerbations of asthma and COPD. The human cat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00085/full |
| _version_ | 1818960761776504832 |
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| author | Víctor Casanova Filipa Henderson Sousa Priyanka Shakamuri Pavel Svoboda Chloé Buch Mathilde D'Acremont Maria A. Christophorou Jan Pohl Craig Stevens Peter G. Barlow |
| author_facet | Víctor Casanova Filipa Henderson Sousa Priyanka Shakamuri Pavel Svoboda Chloé Buch Mathilde D'Acremont Maria A. Christophorou Jan Pohl Craig Stevens Peter G. Barlow |
| author_sort | Víctor Casanova |
| collection | DOAJ |
| description | Human rhinoviruses (HRV) are the most common cause of viral respiratory tract infections. While normally mild and self-limiting in healthy adults, HRV infections are associated with bronchiolitis in infants, pneumonia in immunocompromised patients, and exacerbations of asthma and COPD. The human cathelicidin LL-37 is a host defense peptide (HDP) with broad immunomodulatory and antimicrobial activities that has direct antiviral effects against HRV. However, LL-37 is known to be susceptible to the enzymatic activity of peptidyl arginine deiminases (PAD), and exposure of the peptide to these enzymes results in the conversion of positively charged arginines to neutral citrullines (citrullination). Here, we demonstrate that citrullination of LL-37 reduced its direct antiviral activity against HRV. Furthermore, while the anti-rhinovirus activity of LL-37 results in dampened epithelial cell inflammatory responses, citrullination of the peptide, and a loss in antiviral activity, ameliorates this effect. This study also demonstrates that HRV infection upregulates PAD2 protein expression, and increases levels of protein citrullination, including histone H3, in human bronchial epithelial cells. Increased PADI gene expression and HDP citrullination during infection may represent a novel viral evasion mechanism, likely applicable to a wide range of pathogens, and should therefore be considered in the design of therapeutic peptide derivatives. |
| first_indexed | 2024-12-20T12:02:41Z |
| format | Article |
| id | doaj.art-97021935b95c4928993fd3c6c76f5b5a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T12:02:41Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-97021935b95c4928993fd3c6c76f5b5a2022-12-21T19:41:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00085471202Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus InfectionVíctor Casanova0Filipa Henderson Sousa1Priyanka Shakamuri2Pavel Svoboda3Chloé Buch4Mathilde D'Acremont5Maria A. Christophorou6Jan Pohl7Craig Stevens8Peter G. Barlow9School of Applied Sciences, Edinburgh Napier University, Edinburgh, United KingdomSchool of Applied Sciences, Edinburgh Napier University, Edinburgh, United KingdomBiotechnology Core Facility Branch, Division of Scientific Resources, US Centers for Disease Control and Prevention, Atlanta, GA, United StatesBiotechnology Core Facility Branch, Division of Scientific Resources, US Centers for Disease Control and Prevention, Atlanta, GA, United StatesSchool of Applied Sciences, Edinburgh Napier University, Edinburgh, United KingdomSchool of Applied Sciences, Edinburgh Napier University, Edinburgh, United KingdomMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United KingdomBiotechnology Core Facility Branch, Division of Scientific Resources, US Centers for Disease Control and Prevention, Atlanta, GA, United StatesSchool of Applied Sciences, Edinburgh Napier University, Edinburgh, United KingdomSchool of Applied Sciences, Edinburgh Napier University, Edinburgh, United KingdomHuman rhinoviruses (HRV) are the most common cause of viral respiratory tract infections. While normally mild and self-limiting in healthy adults, HRV infections are associated with bronchiolitis in infants, pneumonia in immunocompromised patients, and exacerbations of asthma and COPD. The human cathelicidin LL-37 is a host defense peptide (HDP) with broad immunomodulatory and antimicrobial activities that has direct antiviral effects against HRV. However, LL-37 is known to be susceptible to the enzymatic activity of peptidyl arginine deiminases (PAD), and exposure of the peptide to these enzymes results in the conversion of positively charged arginines to neutral citrullines (citrullination). Here, we demonstrate that citrullination of LL-37 reduced its direct antiviral activity against HRV. Furthermore, while the anti-rhinovirus activity of LL-37 results in dampened epithelial cell inflammatory responses, citrullination of the peptide, and a loss in antiviral activity, ameliorates this effect. This study also demonstrates that HRV infection upregulates PAD2 protein expression, and increases levels of protein citrullination, including histone H3, in human bronchial epithelial cells. Increased PADI gene expression and HDP citrullination during infection may represent a novel viral evasion mechanism, likely applicable to a wide range of pathogens, and should therefore be considered in the design of therapeutic peptide derivatives.https://www.frontiersin.org/article/10.3389/fimmu.2020.00085/fullrhinovirusvirusinflammationpeptideLL-37cathelicidin |
| spellingShingle | Víctor Casanova Filipa Henderson Sousa Priyanka Shakamuri Pavel Svoboda Chloé Buch Mathilde D'Acremont Maria A. Christophorou Jan Pohl Craig Stevens Peter G. Barlow Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection Frontiers in Immunology rhinovirus virus inflammation peptide LL-37 cathelicidin |
| title | Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection |
| title_full | Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection |
| title_fullStr | Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection |
| title_full_unstemmed | Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection |
| title_short | Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection |
| title_sort | citrullination alters the antiviral and immunomodulatory activities of the human cathelicidin ll 37 during rhinovirus infection |
| topic | rhinovirus virus inflammation peptide LL-37 cathelicidin |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00085/full |
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