Mast Cell Cathelicidin Antimicrobial Peptide Prevents Invasive Group A Streptococcus Infection of the Skin

Abstract

Mast cells (MC) express cathelicidin antimicrobial peptides that act as broad-spectrum antibiotics and influence the immune defense of multiple epithelial surfaces. We hypothesized that MC help protect against skin infection through the expression of cathelicidin. The susceptibility of MC-deficient mice (Kit Wsh−/−) to invasive group A streptococcus (GAS) was compared with control mice. Following s.c. injection of GAS, MC-deficient mice had 30% larger skin lesions, 80% more lesional bacteria, and 30% more spleens positive for bacteria. In contrast to results obtained when GAS was injected into skin, no significant differences were noted between MC-deficient mice and control mice after GAS was applied topically, indicating that MC activity is most important after barrier penetration. To determine whether these differences were due to MC expression of cathelicidin, MC-deficient mice were reconstituted with MC derived from either wild-type or cathelicidin-deficient (Camp−/−) mice and challenged with GAS. Forty-eight hours after bacterial injection, mice that did not receive MC had an average lesion size of 200 mm2, mice reconstituted with wild-type MC showed lesions comparable to control mice (25 mm2), while mice reconstituted with Camp−/− MC showed an average lesion size of 120 mm2. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) analysis of cathelicidin peptide purified from mast cells defined this as a unique 28-aa peptide. Combined, these results show that MC confer defense against Gram-positive bacterial infection in the skin, a function mediated in part by the expression of a unique cathelicidin peptide.

CD46 Transgenic Mouse Model of Necrotizing Fasciitis Caused by Streptococcus pyogenes Infection

“…In previously published mouse models of skin and soft tissue infection with GAS, the bacteria were inoculated s.c. into the backs (8,32,36), haunches (6), or flanks (1,5,7,38). Compared to such models, the s.c. inoculation into both hind footpads in the present study was a simple procedure, and the obtained data showed a narrow dispersion of reproducibility.…”

Infection of Mast Cells with Live Streptococci Causes a Toll-Like Receptor 2- and Cell-Cell Contact-Dependent Cytokine and Chemokine Response

“…Previous reports have shown that MCs also can respond to other types of live streptococci. For example, MCs have been shown to inhibit the growth of Streptococcus pyogenes by forming extracellular traps (65), and it has also been demonstrated that MCs contribute to the defense toward invasive group A streptococci by secreting cathelicidin (10). Moreover, Streptococcus pneumoniae was previously shown to activate RBL-2H3 cells, a cell line with MC-like characteristics (4).…”

“…On the other hand, there are reports showing that MCs contribute to antibacterial defense without any signs of phagocytic activity (17). It has also been demonstrated that MCs can kill bacteria by formation of extracellular traps (65) and that MCs may express antimicrobial peptides (10).…”

The Cathelicidin LL-37 Activates Human Mast Cells and Is Degraded by Mast Cell Tryptase: Counter-Regulation by CXCL4

“…Regarding our findings that LL-37 similarly induces its own degradation by initiating MC degranulation, evidence is growing that MC-mediated cleavage may play a dual role during the course of inflammation, i.e., as an instigating as well as a limiting process. According to a very recent publication by Di Nardo et al (48), murine MC produce and proteolytically process the precursor CAP-18. However, the major CAP-18-derived cleavage product IGE24, generated upon activation with IL-4, retained microbicidal activity in contrast to the peptides generated by human MC from LL-37.…”