title: Modulation of the local neutrophil response by a novel hyaluronic acid-binding peptide reduces bacterial burden during staphylococcal wound infection.
abstract: Novel approaches targeting the host's immune response to treat Staphylococcus aureus infections have significant potential to improve clinical outcomes, in particular during infection with antibiotic-resistant strains. The hyaluronic acid-binding peptide (HABP) PEP35 was assessed for its ability to treat S. aureus infections using a clinically relevant murine model of surgical wound infection. PEP35 demonstrated no direct antimicrobial activity against a range of antibiotic-susceptible and antibiotic-resistant clinical isolates of Staphylococcus aureus. However, when this peptide was administered at the onset of infection and up to 4 h postchallenge with a methicillin-susceptible (MSSA) or a methicillin-resistant (MRSA) strain of S. aureus, it significantly reduced the bacterial burden at the wound infection site. PEP35 reduced the tissue bacterial burden by exclusively modulating the local neutrophil response. PEP35 administration resulted in a significant early increase in local CXCL1 and CXCL2 production, which resulted in a more rapid influx of neutrophils to the infection site. Importantly, neutrophil influx was not sustained after treatment with PEP35, and administration of PEP35 alone did not induce a local inflammatory response. The immunomodulatory effects of PEP35 on CXC chemokine production were TLR2 and NF-κB dependent. We propose a novel role for a HABP as an innate immunomodulator in the treatment of MSSA and MRSA surgical wound infection through enhancement of the local CXC chemokine-driven neutrophil response.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Lee
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Greenwich
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Han
authors.forename: Andrew
authors.initials: A
authors.lastname: Cumming
authors.forename: Laura
authors.initials: L
authors.lastname: Saward
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
mesh_terms: D000818:Animals; D002460:Cell Line; D019743:Chemokines, CXC / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D014946:Wound Infection / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D019743:Chemokines, CXC; D018960:Hyaluronan Receptors; D007155:Immunologic Factors; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2