New activation pathways induced in mast cells by pneumolysine - a cholesterol-dependent cytolysin

Abstract

Pneumolysin (PLY) is a cholesterol-dependent cytolysin (CDC) produced by Streptococcus pneumoniae. In host cells, higher PLY concentrations typically cause cell death, whereas lower, sublytic levels trigger membrane repair and immune responses. These effects are often induced by Ca2+ influx through plasma membrane pores or via pore-independent mechanisms, involving receptor binding. Mast cells respond to PLY through degranulation and the release of cytokines, chemokines, antimicrobial peptides, and lipid mediators. Certain sequence types of S. pneumoniae produce a non-hemolytic PLY variant (PLY-NH), which lacks the ability to form pores. This variant can modulate host responses; however, the mechanism is likely entirely pore-independent and involves reorganisation of the membrane architecture and receptor binding. The response of mast cells to PLY-NH had previously not been characterised. This study demonstrates that mast cells degranulate in response to PLY-NH, with this response being amplified in IgE- sensitised cells. Cholesterol binding and an intact membrane architecture are required to induce degranulation. Additionally, our analysis identified IgE as a novel binding partner of PLY-NH in mast cells, accounting for the increased degranulation of sensitised cells. Collectively, we propose a...

Pneumolyzin (PLY) je cholesterol-dependentní cytolyzin (CDC) produkovany bakterií Streptococcus pneumoniae. V hostitelskych bunkach vyssí koncentrace PLY obvykle vedou k bunecne smrti, zatímco nizsí, sublyticke koncentrace aktivují opravy poskozenych membran a vyvolavají imunitní odpovedi. Tyto efekty jsou casto zprostredkovany influxem vapníku pres pory v plazmaticke membrane, ale take mechanismy nezavislymi na porech, ktere zahrnují vazbu na receptory. Žírne bunky v odpovedi na PLY degranulují a spoustejí produkci cytokinu, chemokinu, antimikrobialních peptidu a lipidovych mediatoru. Nektere sekvencní typy S. pneumoniae produkují nehemolytickou variantu pneumolyzinu (PLY-NH), ktera postrada schopnost vytvaret pory. Tato varianta dokaze ovlivnovat odpovedi hostitele, pricemz mechanismus je zrejme zcela nezavisly na porech a zahrnuje reorganizaci membranove architektury a vazbu na receptory. Odpoveď zírnych bunek na PLY-NH doposud nebyla charakterizovana. Tato studie ukazala, ze zírne bunky degranulují po stimulaci PLY-NH, pricemz tato odpoveď je zesílena v IgE-senzitizovanych bunkach. Vazba na cholesterol a zaroven nenarusena architektura membrany jsou nezbytne k vyvolaní degranulace. Dale nase analyza identifikovala IgE jako novy vazebny partner pneumolyzinu, ktery prispíva ke zvysene degranulaci...