Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin

Abstract

Mast cells are emerging as contributors to innate immunity. Mouse mast cells have a pivotal role in protection against bacterial infection, and human cord blood-derived mast cells reduce bacterial viability in culture. The objectives of this study were to determine whether human lung mast cells (HLMCs) might be protective against pneumococcal lung infection through direct antimicrobial activity. Tissue-derived HLMCs and the human mast cell lines HMC-1 and LAD2 were cocultured with wild-type and mutant pneumococci, and viability and functional assays were performed. Mast cells were also stimulated with purified pneumolysin. HLMCs killed wild-type serotype-2 (D39) pneumococci in coculture but had no effect on an isogenic pneumolysin-deficient (PLN-A) pneumococcus. D39 wild-type, but not PLN-A pneumococci, induced the release of leukotriene C4 from human mast cells in a dose-dependent manner, which was not accompanied by histamine release. Stimulation of mast cells with sublytic concentrations of purified pneumolysin replicated this effect. Furthermore, pneumolysin induced the release of the cathelicidin LL-37 from HLMCs, purified LL-37 reduced pneumococcal viability, and neutralizing Ab to LL-37 attenuated mast cell-dependent pneumococcal killing. In addition, at high concentrations, all pneumococcal strains tested reduced HLMC viability through a combination of pneumolysin and H2O2-dependent mechanisms. HLMCs exhibit direct antimicrobial activity to pneumococci through their activation by pneumolysin. This antimicrobial activity is mediated, in part, by the release of LL-37 from HLMCs. This suggests that mast cells provide an early warning system and potentially limit pneumococcal dissemination early in the course of invasive pulmonary pneumococcal disease.

Impaired Innate Mucosal Immunity in Aged Mice Permits Prolonged Streptococcus pneumoniae Colonization

“…We found no functional defects in neutrophils of elderly mice, but BMDM of elderly mice showed lower killing activity against S. pneumoniae and macrophages produced fewer transcripts of the mouse cathelicidin CRAMP, both at baseline and in response to pneumococcal antigen. CRAMP, a mouse analog of human cathelicidin, plays a significant role in mucosal clearance of bacteria and stimulation of the immune system (21) and was recently shown to be relevant for natural clearance of pneumococci (40). However, it has been shown that macrophages can change phenotype and function when cultured in vitro (13) and that ex vivo adaptations can occur when monocytes from elderly mice are given sufficient quantities of cytokines for macrophage differentiation in vitro (41).…”

The Effect of Bacterial, Viral and Fungal Infection on Mast Cell Reactivity in the Allergic Setting

“…Also, the antimicrobial peptide LL-37 has been identified as a means through which mast cells combat infection. It was recently described that human lung mast cells could kill wild-type pneumococci after activation by pneumolysin, but had no effect on pneumolysindeficient Pneumococcus [30] . This was caused by mast cell release of the cathelicidin LL-37, thus exhibiting a direct antimicrobial activity.…”

Inhibitory effects of C4a on chemoattractant and secretagogue functions of the other anaphylatoxins via Gi protein-adenylyl cyclase inhibition pathway in mast cells

“…C4a inhibits mast cells and macrophages during the start-up phase of complement activation but would not during inflammation following the initial stage of complement activation. Mast cells, which are thought to be effector cells in acquired immunity, are emerging as contributors in the process of innate immunity and as connectors between innate and acquired immunities, as in the case of macrophages [11]. Similar to macrophages, mast cells possess the capacity to act as antigen presenting cells [12,13].…”

“…Mast cells have long been viewed as effector cells in acquired immunity, including type I allergy. It has also been shown that mast cells play prominent roles in innate immunity and in the linkage between innate and acquired immunity [11]. Mast cells are capable of engulfing bacteria, migrating to lymph nodes and presenting antigen information to T cells [12,13].…”