Abstract
BackgroundPhospholipases C (PLCs) are virulence factors found in several bacteria. In Mycobacterium tuberculosis (Mtb) they exhibit cytotoxic effects on macrophages, but the mechanisms involved in PLC-induced cell death are not fully understood. It has been reported that induction of cell necrosis by virulent Mtb is coordinated by subversion of PGE2, an essential factor in cell membrane protection.ResultsUsing two Mtb clinical isolates carrying genetic variations in PLC genes, we show that the isolate 97-1505, which bears plcA and plcB genes, is more resistant to alveolar macrophage microbicidal activity than the isolate 97-1200, which has all PLC genes deleted. The isolate 97-1505 also induced higher rates of alveolar macrophage necrosis, and likewise inhibited COX-2 expression and PGE2 production. To address the direct effect of mycobacterial PLC on cell necrosis and PGE2 inhibition, both isolates were treated with PLC inhibitors prior to macrophage infection. Interestingly, inhibition of PLCs affected the ability of the isolate 97-1505 to induce necrosis, leading to cell death rates similar to those induced by the isolate 97-1200. Finally, PGE2 production by Mtb 97-1505-infected macrophages was restored to levels similar to those produced by 97-1200-infected cells.ConclusionsMycobacterium tuberculosis bearing PLCs genes induces alveolar macrophage necrosis, which is associated to subversion of PGE2 production.
Highlights
Phospholipases C (PLCs) are virulence factors found in several bacteria
Mycobacterium tuberculosis bearing PLCs genes induces alveolar macrophage necrosis, which is associated to subversion of prostaglandin E2 (PGE2) production
Considering that mycobacterial PLCs have cytotoxic effects on macrophages [7], we studied the viability of rat alveolar macrophages infected in vitro with the isolates 97-1200 or 97-1505 to investigate if cell death is associated to mycobacterial PLCs
Summary
Phospholipases C (PLCs) are virulence factors found in several bacteria. In Mycobacterium tuberculosis (Mtb) they exhibit cytotoxic effects on macrophages, but the mechanisms involved in PLC-induced cell death are not fully understood. Among the most known virulence factors, phospholipases C (PLCs) stand out in several intracellular bacteria, including Clostridium perfringens, Corynebacterium pseudotuberculosis, Pseudomonas aeruginosa, Staphylococcus aureus, and Listeria monocytogen [1,2,3,4,5]. 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]. 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 tuberculosis PLCs are encoded by four different genes [8]. Polymorphisms frequently affect PLC genes in Mtb, as observed in different clinical isolates [10]
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