The most virulent PLC characterised to date is the α toxin (CPA) from Clostridium perfringens exhibiting lethal, haemolytic, dermonecrotic, vascular permeabilising, and platelet-aggregating properties [2]. Thus, due to their role in the virulence mechanisms of many bacterial pathogens, the relevance of PLCs during mycobacterial infection has been the subject of investigation [6, 7]. Mycobacterium selleckchem tuberculosis PLCs are encoded by A-1210477 solubility dmso four different genes [8]. Three of these genes, plc-A, plc-B, and plc-C, are closely located, constituting an operon, whereas plc-D is located in a different region [8, 9]. Moreover, polymorphisms frequently

affect PLC genes in Mtb, as observed in different clinical isolates [10]. The importance of PLC in mycobacterium virulence

was brought out by the demonstration that triple ΔplcABC and quadruple ΔplcABCD Mtb mutants attenuated tuberculosis infection in mice [6]. In addition, it has been previously shown that all Mtb PLCs present cytotoxic effects on macrophages in vitro. Recombinant PLC proteins expressed in M. smegmatis induced necrosis by hydrolysing membrane constitutive phospholipids into diacylglycerol (DAG) [7]. C. perfringens-PLC also induces cell necrosis through releases of DAG from host membrane by a mechanism dependent on activation of PKC, MEK/ERK, and NFkB pathways, leading to high concentrations of reactive oxygen species selleck chemical (ROS) and oxidative stress [11]. An increasing number of studies have highlighted the

relationship between lipid mediators and cell death. Also, subversion of host eicosanoid biosynthetic pathways has been used as an evasion mechanism by a virulent mycobacterium [12]. It has been recently shown that infection with the attenuated Mtb strain H37Ra resulted Thalidomide in abundant production of the COX-2 product prostaglandin E2 (PGE2), and consequently in activation of membrane repair mechanism. On the other hand, the virulent strain H37Rv induces the production of lipoxin A4 (LXA4), which is an inhibitor of COX-2 expression and favours necrosis in infected cells [13–15]. Thus, the lipid mediators PGE2 and LXA4 appear to exert opposing effects on Mtb-induced cell death in macrophages. Another central lipid mediator in Mtb infection is leukotriene B4 (LTB4). We have previously shown that inhibition of leukotriene synthesis increased susceptibility to mycobacterial infection and pointed out alveolar macrophages as the main target for immunostimulatory actions of LTB4[16, 17]. Given that mycobacterial PLCs have been associated with cell death, in this study we investigated whether this effect is related to the modulation of lipid mediator production induced by PLCs. Using two Mtb clinical isolates bearing genetic variations that affect PLC genes, we investigated how PLCs affect the outcome of Mtb-driven alveolar macrophage death and its relationship with lipid mediator production.