Mycobacterial Lysocardiolipin Is Exported from Phagosomes upon Cleavage of Cardiolipin by a Macrophage-Derived Lysosomal Phospholipase A2

Abstract

Pathogenic mycobacteria are able to survive and proliferate in phagosomes within host macrophages (Mφ). This capability has been attributed in part to their cell wall, which consists of various unique lipids. Some of these are important in the host-pathogen interaction, such as resistance against microbicidal effector mechanisms and modulation of host cell functions, and/or are presented as Ags to T cells. Here we show that two lipids are released from the mycobacterial cell wall within the phagosome of infected Mφ and transported out of this compartment into intracellular vesicles. One of these lipids was identified as lysocardiolipin. Lysocardiolipin was generated through cleavage of mycobacterial cardiolipin by a Ca2+-independent phospholipase A2 present in Mφ lysosomes. This result indicates that lysosomal host cell enzymes can interact with released mycobacterial lipids to generate new products with a different intracellular distribution. This represents a novel pathway for the modification of bacterial lipid Ags.

Lipidomics of host–pathogen interactions

“…Lysobisphosphatidic acid and phosphoinositides regulate release of VSV nucleocapsid into cytoplasm [13] SigD/SopB is a type III bacterial derived phosphoinositide phosphatase [29,112] Molecular species of phosphatidylcholine and phosphatidylethanolamine are altered in host plasmamembrane after Plasmodium infection [116] GP Ethanolamine phospholipids required for Sindbis virus production [111] Intracellular mycobacteria release a heterogeneous mixture of lipids [27,113] Growth arrest of Plasmodium [117] and Toxoplasma [85] by disruption of phosphatidylcholine synthesis Semliki Forest virus mRNA capping enzyme requires association with anionic membrane phospholipids for activity [14] Phosphatidylinositol mannosides stimulate fusion of early endosomes with mycobacterial phagosomes [30] Glycosylated phosphatidylinositol causes phagosome maturation arrest [114] SapM, a mycobacterial derived phosphatase hydrolyses PI3P contributing to inhibition of phagolysosome maturation [115] Sphingosine 1-kinase is recruited to nascent phagosomes [118] Inhibition of sphingolipid biosynthesis in T. gondii blocks replication [119] SP Sphingomyelin metabolism important for P. falciparum development [120] Inhibition of cholesterol biosynthesis inhibits Hepatitis C virus RNA replication [15] Inhibition of cholesterol acquisition by the host lowers T. gondii replication [40] ST Cholesterol esterification essential for optimal T. gondii proliferation [121,122] Isopreonoid synthesis inhibitors with anti-malarial [123] and anti-T. gondii activity [124] PR Block of protein farnesylation as antiapicomplexan therapies [125] 5…”

Identification of Rhodococcus equi lipids recognized by host cytotoxic T lymphocytes

“…Processing and presentation of a microbial phospholipid resembling a host lipid are understandable in this light. Although mycobacterial CL has not previously been shown to be presented by CD1 or recognized by T lymphocytes, it can be cleaved by lysosomal enzymes present in mammalian macrophages (Fischer et al, 2001). …”

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

“…TDM toxicity is due to an increase of the tissue specific nicotinamide adenine dinuclease activity decreasing the levels of NAD in several tissues by blocking the electron flow along the (Artman et al, 1964;Barry et al, 1998;Brennan, 2003). During infection and when inside of the phagosome, M.tb is shown to produce large quantities of TDM (Fischer et al, 2001). From many studies d o n e o n T D M , i t i s r e m a r k a b l e t h a t TDM induces lung granulomas and has immunostimulating properties (Bekierkunst, 1968) that are probably at the origin of its antitumoral activity (Bekierkunst et al, 1971a) (Table 1).…”

“…These are phosphatidylglycerol, diphosphatidylglycerol (DPG) and phosphatidylethanolamine. Although the role of these M.tb cell wall phospholipids during infection is uncertain, M.tb cardiolipin (a DPG molecule) is shown to be processed into lysocardiolipin by the lysosomal phospholipase A 2 during M.tb infection (Fischer et al, 2001). Antibodies against M.tb cardiolipin are also found in sera from TB patients (Santiago et al, 1989), and their production is shown to be strictly related to IL-4 and T cells (Fischer et al, 2002).…”

“…Are the properties of the M.tb cell wall altered during infection? Some studies indicate that this may happen in the case for TDM, which is overproduced during M.tb infection Fischer et al, 2001). Why do clinical isolates of M.tb present different cell wall rearrangements than the widely studied M.tb laboratory strains Erdman, H 37 R v , and H 37 R a ?…”