Abstract
Mycobacterium avium subsp. hominissuis is associated with infection of immunocompromised individuals as well as patients with chronic lung disease. M. avium infects macrophages and actively interfere with the host killing machinery such as apoptosis and autophagy. Bacteria alter the normal endosomal trafficking, prevent the maturation of phagosomes and modify many signaling pathways inside of the macrophage by secreting effector molecules into the cytoplasm. To investigate whether M. avium needs to attach to the internal surface of the vacuole membrane before releasing efferent molecules, vacuole membrane proteins were purified and binding to the surface molecules present in intracellular bacteria was evaluated. The voltage-dependent anion channels (VDAC) were identified as components of M. avium vacuoles in macrophages. M. avium mmpL4 proteins were found to bind to VDAC-1 protein. The inactivation of VDAC-1 function either by pharmacological means or siRNA lead to significant decrease of M. avium survival. Although, we could not establish a role of VDAC channels in the transport of known secreted M. avium proteins, we demonstrated that the porin channels are associated with the export of bacterial cell wall lipids outside of vacuole. Suppression of the host phagosomal transport systems and the pathogen transporter may serve as therapeutic targets for infectious diseases.
Highlights
Mycobacterium avium subsp. hominissuis is associated with infection of immunocompromised individuals as well as patients with chronic lung disease
We could not establish a role of voltage-dependent anion channels (VDAC) channels in the transport of known secreted M. avium proteins, we demonstrated that the porin channels are associated with the export of bacterial cell wall lipids outside of vacuole
To investigate the possibility that VDAC oligomerization in M. avium phagosome membrane took place and was involved in the translocation of larger molecules into the cytoplasm, we examined the bacterial survival in macrophages that were pretreated with the 4,4′-Diisothiocyano-2,2′-disulfonic acid stilbene (DIDS), a blocker of VDAC oligomerization, 4 hours prior M. avium infection
Summary
Mycobacterium avium subsp. hominissuis is associated with infection of immunocompromised individuals as well as patients with chronic lung disease. The pathogen is contained within a cytoplasmic vacuole, and intracellular survival is dependent on a number of bacterial virulence determinants used to remodel the vacuolar compartment and to resist the host antimicrobial mechanisms[3,4,5,6]. M. avium actively survives and resists the most effective cellular killing mechanisms by molecules of reactive oxygen intermediates (ROIs) and nitric oxide (NO)[10,11,12] Another characteristic of M. avium is the ability to use apoptosis as a trigger to escape from phagocytes and infect surrounding cells[13, 14]. The interaction between virulent mycobacteria and host antimicrobial mechanisms is assumed to be an active process controlled only by a viable bacilli, since none of above effects occur following phagocytosis of dead mycobacterium or after inhibition of bacterial protein synthesis[15, 16]. The best-characterized ESX-1 locus of RD1 is involved in the secretion of ESAT-6 and CFP-10 of Mycobacterium tuberculosis and Mycobacterium marinum[20, 21] influencing the host cell signaling and cytokine secretion[22] and apparently required for the escape of M. tuberculosis from the phagolysosome into the cytosol[23]
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