Mycobacterium avium MAV2052 protein induces apoptosis in murine macrophage cells through Toll-like receptor 4

Abstract

Mycobacterium avium and its sonic extracts induce apoptosis in macrophages. However, little is known about the M. avium components regulating macrophage apoptosis. In this study, using multidimensional fractionation, we identified MAV2052 protein, which induced macrophage apoptosis in M. avium culture filtrates. The recombinant MAV2052 induced macrophage apoptosis in a caspase-dependent manner. The loss of mitochondrial transmembrane potential (ΔΨm), mitochondrial translocation of Bax, and release of cytochrome c from mitochondria were observed in macrophages treated with MAV2052. Further, reactive oxygen species (ROS) production was required for the apoptosis induced by MAV2052. In addition, ROS and mitogen-activated protein kinases were involved in MAV2052-mediated TNF-α and IL-6 production. ROS-mediated activation of apoptosis signal-regulating kinase 1 (ASK1)-JNK pathway was a major signaling pathway for MAV2052-induced apoptosis. Moreover, MAV2052 bound to Toll-like receptor (TLR) 4 molecule and MAV2052-induced ROS production, ΔΨm loss, and apoptosis were all significantly reduced in TLR4(-/-) macrophages. Altogether, our results suggest that MAV2052 induces apoptotic cell death through TLR4 dependent ROS production and JNK pathway in murine macrophages.

Mutation on lysX from Mycobacterium avium hominissuis impacts the host–pathogen interaction and virulence phenotype

“…This phenotype is coherent with our proteomics data which hitherto revealed that the LysX deficiency in MAH arouses a metabolic alteration which represents an intracellular metabolic status found in MTB, thereby equipping the bacteria for intracellular niches of the host organism [28]. In particular, the gene class of ESX export systems which play a pivotal role in mycobacterial virulence [60] (EccA3, MAV_4606, MAV_0940) and those involved in anti-apoptotic pathways (CysK [61], KatG [62], NuoG [63]) were also differentially regulated in the lysXmut strain.…”

Mycobacterium avium MAV2054 protein induces macrophage apoptosis by targeting mitochondria and reduces intracellular bacterial growth

“…Other reports also showed that ROS are involved in M. avium - and its sonic extracts-induced macrophage apoptosis1321. We also demonstrated that ROS production is required for macrophage apoptosis induced by M. avium MAV205222.…”

“…The sonic extracts from M. avium cause apoptosis of monocytes and macrophages21, indicating that MAC also contains a component involved in modulating apoptosis. Recently, we identified M. avium MAV2052 protein, which induced apoptosis in murine macrophages22. However, the MAC components involved in inhibiting or triggering apoptosis are not well-understood.…”

Nontuberculous Mycobacteria Persistence in a Cell Model Mimicking Alveolar Macrophages

“…We found homologous genes in all NTM strains, with exception of MAV_4563 (coding for a protein with unknown function), which is absent in the M. smegmatis , and the gene coding for a divalent metal cation transporter (MAV_2120), which was exclusively present in M. avium strains. This “ M. avium -specific” pattern was also found for the gene coding the cysteine synthase A (CysK; MAV_2052), which was recently described as potential mediator of apoptotic cell death through TLR4 dependent ROS production and JNK pathway in murine macrophages [29]. MAV_2054, which is likely involved in inducing macrophage apoptosis by targeting mitochondria, was present in both M. avium strains as well as in M. smegmatis [30].…”

“…In order to screen the genomes of the five NTM strains for the presence/absence of known virulence factors, a custom sequence database was created based on a comprehensive list of genes recently gathered by Fedrizzi and colleagues [23], as well as, additional virulence factors retrieved from literature [24,25,26,27,28,29,30,31,32] or from the Virulence Factor Database (VFDB) [33]. A detailed description of the list of searched virulence-associated genes, namely the “locus_tags” in the reference genomes from which individual CDS sequences were extracted, is presented in Table S2.…”