title: Defensins enable macrophages to inhibit the intracellular proliferation of Listeria monocytogenes.
abstract: Listeria monocytogenes is a facultative intracellular pathogen that infects a large diversity of host cells, including macrophages. To avoid the phagosome microbicidal environment, L. monocytogenes secretes a pore-forming toxin (listeriolysin O, LLO) that releases the bacterium into the cytoplasm. We hypothesized that the α-defensins (HNPs) and/or humanized θ-defensin (RC-1) peptides produced by human and non-human primate neutrophils, respectively, cooperate with macrophages to control L. monocytogenes infection. Our results establish that HNP-1 and RC-1 enable macrophages to control L. monocytogenes intracellular growth by inhibiting phagosomal escape, as a consequence, bacteria remain trapped in a LAMP-1-positive phagosome. Importantly, HNP-1 interaction with macrophages and RC-1 interaction with bacteria are required to prevent macrophage infection. In accordance with these results, RC-1 is a more potent anti-listerial peptide than HNP-1 and HNP-1 is acquired by macrophages and trafficked to the phagocytosed bacteria. Finally, HNP-1 and RC-1 antimicrobial activity is complemented by their ability to prevent LLO function through two mechanisms, blocking LLO-dependent perforation of macrophage membranes and the release of LLO from the bacteria. In conclusion, at the site of infection the cooperation between antimicrobial peptides, such as HNP-1, and macrophages likely plays a critical role in the innate immune defence against L. monocytogenes.
authors.affiliation: Departments of Microbiology and Internal Medicine, Center for Microbial Interface Biology, Ohio State University, Columbus, OH, USA.
authors.forename: Eusondia
authors.initials: E
authors.lastname: Arnett
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lehrer
authors.forename: Pratikhya
authors.initials: P
authors.lastname: Pratikhya
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Seveau
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000276:immunology; D001427:Bacterial Toxins / Q000378:metabolism; D002478:Cells, Cultured; D023082:Defensins / Q000276:immunology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006460:Hemolysin Proteins / Q000378:metabolism; D006801:Humans; D008089:Listeria monocytogenes / Q000254:growth & development* / Q000378:metabolism / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology; D023084:alpha-Defensins / Q000276:immunology*
chemical_list: D000890:Anti-Infective Agents; D001427:Bacterial Toxins; D023082:Defensins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D052118:Lysosomal-Associated Membrane Protein 1; D023084:alpha-Defensins; C450142:theta-defensin; C038705:hlyA protein, Listeria monocytogenes