title: CXCL14 displays antimicrobial activity against respiratory tract bacteria and contributes to clearance of Streptococcus pneumoniae pulmonary infection.
abstract: 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.
authors.affiliation: Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland; and.
authors.forename: Chen
authors.initials: C
authors.lastname: Dai
authors.affiliation: Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland; and.
authors.forename: Paola
authors.initials: P
authors.lastname: Basilico
authors.affiliation: Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland; and.
authors.forename: Tiziana Patrizia
authors.initials: TP
authors.lastname: Cremona
authors.affiliation: Department of Medical, Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Collins
authors.affiliation: Department of Medical, Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Moser
authors.affiliation: Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland; and.
authors.forename: Charaf
authors.initials: C
authors.lastname: Benarafa
authors.affiliation: Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland; and marlene.wolf@tki.unibe.ch.
authors.forename: Marlene
authors.identifier: http://orcid.org/0000-0002-7283-4683
authors.initials: M
authors.lastname: Wolf
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019743:Chemokines, CXC / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D004269:DNA, Bacterial; D004195:Disease Models, Animal; D016209:Interleukin-8 / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D053146:Myeloblastin / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000276:immunology* / Q000648:ultrastructure
chemical_list: D000890:Anti-Infective Agents; C517518:CXCL14 protein, mouse; D019743:Chemokines, CXC; D004269:DNA, Bacterial; D016209:Interleukin-8; D010446:Peptide Fragments; D000249:Adenosine Monophosphate; D053146:Myeloblastin