title: Cathelicidin LL-37 in severe Streptococcus pyogenes soft tissue infections in humans.
abstract: Severe soft tissue infections, such as necrotizing fasciitis and severe cellulitis, caused by group A streptococci (GAS) are rapidly progressing life-threatening infections characterized by massive bacterial loads in the tissue even late after the onset of infection. Antimicrobial peptides are important components of the innate host defense, and cathelicidins have been shown to protect against murine necrotic skin infections caused by GAS. However, it has been demonstrated that the streptococcal cysteine protease SpeB proteolytically inactivates the human cathelicidin LL-37 in vitro. Here we have investigated the expression of LL-37 and its interaction with GAS and SpeB during acute severe soft tissue infections by analyses of patient tissue biopsy specimens. The results showed large amounts of LL-37, both the proform (hCAP18) and the mature peptide, in the tissue. Confocal microscopy identified neutrophils as the main source of the peptide. A distinct colocalization between the bacteria and LL-37 could be noted, and bacterial loads showed positive correlation to the LL-37 levels. Areas with high LL-37 levels coincided with areas with large amounts of SpeB. Confocal microscopy confirmed strong colocalization of GAS, SpeB, and LL-37 at the bacterial surface. Taken together, the findings of this study provide in vivo support of the hypothesis that SpeB-mediated inactivation of LL-37 at the streptococcal surface represents a bacterial resistance mechanism at the infected tissue site in patients with severe GAS tissue infections.
authors.affiliation: Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Johansson
authors.forename: Pontus
authors.initials: P
authors.lastname: Thulin
authors.forename: Parham
authors.initials: P
authors.lastname: Sendi
authors.forename: Erika
authors.initials: E
authors.lastname: Hertzén
authors.forename: Adam
authors.initials: A
authors.lastname: Linder
authors.forename: Per
authors.initials: P
authors.lastname: Akesson
authors.forename: Donald E
authors.initials: DE
authors.lastname: Low
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.forename: Anna
authors.initials: A
authors.lastname: Norrby-Teglund
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000032:analysis; D001706:Biopsy; D005098:Exotoxins / Q000032:analysis; D006801:Humans; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000737:chemistry; D018461:Soft Tissue Infections / Q000276:immunology* / Q000382:microbiology*; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000737:chemistry / Q000276:immunology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D005098:Exotoxins; C027951:erythrogenic toxin; D054804:Cathelicidins