CXCL14 Displays Antimicrobial Activity against Respiratory Tract Bacteria and Contributes to Clearance of Streptococcus pneumoniae Pulmonary Infection

Dai, Chen; Basilico, Paola; Cremona, Tiziana Patrizia; Collins, Paul; Moser, Bernhard; Benarafa, Charaf; Wolf, Marlene (2015). CXCL14 Displays Antimicrobial Activity against Respiratory Tract Bacteria and Contributes to Clearance of Streptococcus pneumoniae Pulmonary Infection. Journal of immunology, 194(12), pp. 5980-5989. American Association of Immunologists 10.4049/jimmunol.1402634

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CXCL14 is a chemokine with an atypical, yet highly conserved, primary structure characterized by a short N terminus and high sequence identity between human and mouse. Although it induces chemotaxis of monocytic cells at high concentrations, its physiological role in leukocyte trafficking remains elusive. In contrast, several studies have demonstrated that CXCL14 is a broad-spectrum antimicrobial peptide that is expressed abundantly and constitutively in epithelial tissues. In this study, we further explored the antimicrobial properties of CXCL14 against respiratory pathogens in vitro and in vivo. We found that CXCL14 potently killed Pseudomonas aeruginosa, Streptococcus mitis, and Streptococcus pneumoniae in a dose-dependent manner in part through membrane depolarization and rupture. By performing structure-activity studies, we found that the activity against Gram-negative bacteria was largely associated with the N-terminal peptide CXCL141-13. Interestingly, the central part of the molecule representing the β-sheet also maintained ∼62% killing activity and was sufficient to induce chemotaxis of THP-1 cells. The C-terminal α-helix of CXCL14 had neither antimicrobial nor chemotactic effect. To investigate a physiological function for CXCL14 in innate immunity in vivo, we infected CXCL14-deficient mice with lung pathogens and we found that CXCL14 contributed to enhanced clearance of Streptococcus pneumoniae, but not Pseudomonas aeruginosa. Our comprehensive studies reflect the complex bactericidal mechanisms of CXCL14, and we propose that different structural features are relevant for the killing of Gram-negative and Gram-positive bacteria. Taken together, our studies show that evolutionary-conserved features of CXCL14 are important for constitutive antimicrobial defenses against pneumonia.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Dai, Chen; Basilico, Paola; Cremona, Tiziana Patrizia; Benarafa, Charaf and Wolf, Marlene

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-1767

Publisher:

American Association of Immunologists

Funders:

[24] Gottfried und Julia Bangerter- Rhyner Stiftung
[UNSPECIFIED] China Scholarship Council
[4] Swiss National Science Foundation
[UNSPECIFIED] Flight Attendant Medical Research Institute

Language:

English

Submitter:

Marlene Wolf Tobler

Date Deposited:

09 Jul 2015 07:57

Last Modified:

26 Jun 2016 02:05

Publisher DOI:

10.4049/jimmunol.1402634

PubMed ID:

25964486

BORIS DOI:

10.7892/boris.70163

URI:

https://boris.unibe.ch/id/eprint/70163

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