Abstract
Mycobacterium avium complex induces macrophage apoptosis. However, the M. avium components that inhibit or trigger apoptosis and their regulating mechanisms remain unclear. We recently identified the immunodominant MAV2054 protein by fractionating M. avium culture filtrate protein by multistep chromatography; this protein showed strong immuno-reactivity in M. avium complex pulmonary disease and in patients with tuberculosis. Here, we investigated the biological effects of MAV2054 on murine macrophages. Recombinant MAV2054 induced caspase-dependent macrophage apoptosis. Enhanced reactive oxygen species production and JNK activation were essential for MAV2054-mediated apoptosis and MAV2054-induced interleukin-6, tumour necrosis factor, and monocyte chemoattractant protein-1 production. MAV2054 was targeted to the mitochondrial compartment of macrophages treated with MAV2054 and infected with M. avium. Dissipation of the mitochondrial transmembrane potential (ΔΨm) and depletion of cytochrome c also occurred in MAV2054-treated macrophages. Apoptotic response, reactive oxygen species production, and ΔΨm collapse were significantly increased in bone marrow-derived macrophages infected with Mycobacterium smegmatis expressing MAV2054, compared to that in M. smegmatis control. Furthermore, MAV2054 expression suppressed intracellular growth of M. smegmatis and increased the survival rate of M. smegmatis-infected mice. Thus, MAV2054 induces apoptosis via a mitochondrial pathway in macrophages, which may be an innate cellular response to limit intracellular M. avium multiplication.
Highlights
Apoptosis signal-regulating kinase 1 (ASK1), and mitochondrial death signalling[13] or tumour necrosis factor (TNF) and Fas[14]
Apoptosis was significantly greater in cells treated with MAV2054 as compared to untreated control or cells treated with antigen 85 complex (Ag85) (Fig. 1B)
Mycobacterium avium complex (MAC) live within macrophages, and infection of macrophages by MAC can lead to their apoptotic death; the induction of macrophage apoptosis is strain-specific[13,14,15,42]
Summary
Apoptosis signal-regulating kinase 1 (ASK1), and mitochondrial death signalling[13] or tumour necrosis factor (TNF) and Fas[14]. To improve the understanding of the cellular mechanisms of mycobacterial pathogenesis, it is important to identify and characterise the bacterial components involved in modulating macrophage apoptosis. Several apoptosis-inducing factors of M. tuberculosis have been identified: 19-kDa protein[12,17] and lipoarabinomannan[18] via Toll-like receptor 2, PE_PGRS33 with TNF-α-inducing ability19, 38-kDa protein with up-regulation of cell death receptor[20], and heparin-binding hemagglutinin (HBHA) via mitochondrial targeting[9]. The sonic extracts from M. avium cause apoptosis of monocytes and macrophages[21], indicating that MAC contains a component involved in modulating apoptosis. We identified M. avium MAV2052 protein, which induced apoptosis in murine macrophages[22]. We identified MAV2054 protein with strong immuno-reactivity in MAC pulmonary disease as well as in patients with tuberculosis by fractionation of M. avium culture filtrate proteins[26]. M. smegmatis expressing MAV2054 increased macrophage apoptosis in vivo and in vitro, its growth within macrophages was suppressed, and MAV2054 expression attenuated the virulence of M. smegmatis
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