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Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection



Filipa Henderson Sousa

Priyanka Shakamuri

Pavel Svoboda


Mathilde D'Acremont

Maria A. Christophorou

Jan Pohl


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.


Casanova, V., Sousa, F. H., Shakamuri, P., Svoboda, P., Buch, C., D'Acremont, M., …Barlow, P. G. (2020). Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection. Frontiers in Immunology, 11, Article 85.

Journal Article Type Article
Acceptance Date Jan 13, 2020
Online Publication Date Feb 4, 2020
Publication Date Feb 4, 2020
Deposit Date Feb 4, 2020
Publicly Available Date Feb 4, 2020
Journal Frontiers in Immunology
Electronic ISSN 1664-3224
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 11
Article Number 85
Keywords rhinovirus, virus, inflammation, peptide, LL-37, cathelicidin, citrullination
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