CtpB Facilitates Mycobacterium tuberculosis Growth in Copper-Limited Niches

Abstract

Copper is required for aerobic respiration by Mycobacterium tuberculosis and its human host, but this essential element is toxic in abundance. Copper nutritional immunity refers to host processes that modulate levels of free copper to alternately starve and intoxicate invading microbes. Bacteria engulfed by macrophages are initially contained within copper-limited phagosomes, which fuse with ATP7A vesicles that pump in toxic levels of copper. In this report, we examine how CtpB, a P-type ATPase in M. tuberculosis, aids in response to nutritional immunity. In vitro, the induced expression of ctpB in copper-replete medium inhibited mycobacterial growth, while deletion of the gene impaired growth only in copper-starved medium and within copper-limited host cells, suggesting a role for CtpB in copper acquisition or export to the copper-dependent respiration supercomplex. Unexpectedly, the absence of ctpB resulted in hypervirulence in the DBA/2 mouse infection model. As ctpB null strains exhibit diminished growth only in copper-starved conditions, reduced copper transport may have enabled the mutant to acquire a “Goldilocks” amount of the metal during transit through copper-intoxicating environments within this model system. This work reveals CtpB as a component of the M. tuberculosis toolkit to counter host nutritional immunity and underscores the importance of elucidating copper-uptake mechanisms in pathogenic mycobacteria.

The interplay between copper metabolism and microbes: in perspective of host copper-dependent ATPases ATP7A/B

“…However, when there is a rapid increase in copper levels, it has been observed that ctpB-knockout M. tuberculosis-infected mice exhibit increased resistance to copper, which enhances the efflux of copper. (Shey-Njila et al, 2022).…”

Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages

“…The balance of micronutrients is important for M.tb survival. The bacterial ATPase CtpB was found to be important for the regulation of copper levels and the optimal growth of M.tb both in vitro and in the mouse model [ 136 ]. The ability of M.tb to mutate and overcome the loss of the ESX-3 type VII secretion system, involved in iron acquisition, and thus restore virulence, has also been described in the mouse model [ 137 ].…”