Mycobacterial P1-Type ATPases Mediate Resistance to Zinc Poisoning in Human Macrophages

Abstract

SummaryMycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene modulation, we observed a burst of free zinc inside macrophages, and intraphagosomal zinc accumulation within a few hours postinfection. Zinc exposure led to rapid CtpC induction, and ctpC deficiency caused zinc retention within the mycobacterial cytoplasm, leading to impaired intracellular growth of the bacilli. Thus, the use of P1-type ATPases represents a M. tuberculosis strategy to neutralize the toxic effects of zinc in macrophages. We propose that heavy metal toxicity and its counteraction might represent yet another chapter in the host-microbe arms race.

Enterococcus faecalis zinc-responsive proteins mediate bacterial defence against zinc overload, lysozyme and oxidative stress

“…Macrophages use at least three defence mechanisms to fight engulfed bacteria, i.e. oxidative burst, zinc overload and lysozyme production (Botella et al, 2011;Gordon et al, 1974). As ZntA Ef is proven here to be involved in defending E. faecalis against all three host attacks, we propose that this efflux system is one of the main constituents that enables E. faecalis to endure life inside the host.…”

“…Macrophages are likely to adapt zinc levels in order to inhibit pathogen growth. A recent study reported that Mycobacterium tuberculosis and E. coli use Ptype ATPases in a strategy to avoid the toxic effects of zinc inside macrophages, in which a burst of free zinc occurs within a few hours following bacterial infection (Botella et al, 2011). The roles of ZntA Ef and EF0759 in E. faecalis survival inside macrophages, and in the resistance of the bacterium to oxidative stress and lysozyme, were thus investigated.…”

“…Such a connection between zinc resistance and higher tolerance to oxidative stress and lysozyme has, to the best of our knowledge, never been described previously. A zinc burst, described to occur inside macrophages (Botella et al, 2011), could indirectly affect the mechanisms of oxidative stress response, as it is known that zinc is able to compete with manganese (Kloosterman et al, 2008;McDevitt et al, 2011), a crucial metal in oxidative stress response, in protein binding. McDevitt et al (2011) found that extracellular zinc inhibits manganese acquisition in Streptococcus pneumoniae by competing for binding to the solute-binding protein PsaA.…”

Un rôle nouveau des métaux de transition dans l’immunité antimicrobienne

“…Une implication directe de la lectine dans l'internalisation de particules virales menant à l'infection n'a jamais été rapportée. La mutation de ce motif ne modifie pas, par exemple, l'entrée infectieuse du virus de la dengue [9]. En revanche, bien que le mutant di-leucine puisse capturer VUUK, nous avons montré qu'il n'est pas en mesure d'assurer l'endocytose du virus conduisant à l'infection des cellules.…”

“…[8]. Plus récemment encore, nous avons montré au laboratoire qu'une autre de ces ATPases de type P chez M. tuberculosis, la protéine CtpC, est impliquée dans la résistance des bactéries à des concentrations potentiellement toxiques de zinc, et qu'un mutant inactivé dans le gène ctpC se multiplie mal dans les macrophages, sa virulence est donc atténuée [9]. Nous avons également observé, par microscopie confocale et électronique, que du zinc est libéré dans les macrophages au cours de l'infection par M. tuberculosis, une fraction de ce zinc libre s'accumulant dans le phagosome mycobactérien (Figure 2A).…”