Copper homeostasis in Mycobacterium tuberculosis

Abstract

Copper (Cu) is a trace element essential for the growth and development of almost all organisms, including bacteria. However, Cu overload in most systems is toxic. Studies show Cu accumulates in macrophage phagosomes infected with bacteria, suggesting Cu provides an innate immune mechanism to combat invading pathogens. To counteract the host-supplied Cu, increasing evidence suggests that bacteria have evolved Cu resistance mechanisms to facilitate their pathogenesis. In particular, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has evolved multiple pathways to respond to Cu. Here, we summarize what is currently known about Cu homeostasis in Mtb and discuss potential sources of Cu encountered by this and other pathogens in a mammalian host.

Bacillus subtilis MntR coordinates the transcriptional regulation of manganese uptake and efflux systems

“…Whilst there is wide recognition of the importance of competition for Mn(II) and other metals between hosts and pathogens (Kehl-Fie and Skaar, 2010;Eijkelkamp et al, 2015;Juttukonda and Skaar, 2015;Morey et al, 2015), the ability to resist Mn(II) intoxication is also likely to influence the course of infection. The ability of bacteria to resist metal intoxication (by copper, zinc and, recently appreciated, iron) is important for pathogenesis, as evident from the virulence defects of strains deficient in metal efflux (German et al, 2013;Shi and Darwin, 2015;Besold et al, 2016;Pi et al, 2016), and recent results have begun to extend this notion to Mn(II) (Rosch et al, 2009;Turner et al, 2015). The conditions under which pathogens experience Mn(II) and Fe(II) intoxication in the host are not yet well understood.…”

Rv0474 is a copper‐responsive transcriptional regulator that negatively regulates expression of RNA polymerase β subunit in Mycobacterium tuberculosis

“…Even inside the granuloma copper is utilized by the immune system to contain MTB infection [11]. Other mechanisms include production of reactive nitrogen and oxygen species, displacement of metal co-factors from enzymes, et cetera [14]. Under aerobic conditions, copper reacts with hydrogen peroxide (H 2 O 2 ) to create hydroxyl radical (•OH) and hydroxyl anion (OHÀ).…”

“…Deficiency of mctB gene was found to cause growth retardation of MTB in the lungs and lymph nodes of infected mice and guinea pigs [11]. Copper homeostasis inside the macrophages has been extensively reviewed by Darwin et al [13,14]. Copper homeostasis inside the macrophages has been extensively reviewed by Darwin et al [13,14].…”

Mycobacterium tuberculosis copper-regulated protein SocB is an intrinsically disordered protein that folds upon interaction with a synthetic phospholipid bilayer

“…Mtb has evolved defense mechanisms to survive in host macrophages, including a proteasome, which counteracts reactive nitrogen intermediates . The Mtb proteasome is also associated with normal copper homeostasis that must be maintained for robust virulence in mice . Although it is unknown how the proteasome directly affects copper homeostasis in Mtb , it appears that an unusual copper responsive regulon is repressed in Mtb strains defective for proteasomal degradation .…”

“…2 The Mtb proteasome is also associated with normal copper homeostasis that must be maintained for robust virulence in mice. 3 Although it is unknown how the proteasome directly affects copper homeostasis in Mtb, it appears that an unusual copper responsive regulon is repressed in Mtb strains defective for proteasomal degradation. 4 Under copper depleted conditions, the transcriptional repressor RicR binds to the operator of five different promoters to prevent their expression.…”