Copper homeostasis and bacterial virulence: Salmonella?s way

SONCINI, F. C.

Córdoba

Congreso; XI Congreso Argentino de Microbiología General; 2015

SAMIGE

Copper is a critical component of proteins involved in a variety of cellular processes including cell growth, differentiation, and survival in organisms from bacteria to plants to mammals. However, it is also toxic even at low levels. The essentiality and at the same time toxicity of copper makes its active handling a vital skill for most organisms. As other organisms, bacteria have evolved specific copper homeostasis systems for maintaining a suitable intracellular concentration of this essential metal and at the same time, avoiding its toxic effects. Recent evidence indicates that copper actively contributes to the host innate immune response against bacterial infections and that along evolution pathogens have acquired specific mechanisms to deal with this intoxicant. Most enterobacterial species harbor the CusR/CusS two-component system to control envelope copper levels. CusR/CusS responds to a raise of periplasmic copper level by inducing the expression of a CBA-type efflux system that eliminates the excess of the metal ion from the periplasm. On the other hand, the bacterial cytoplasm is not predicted to require copper, and cells evolved different strategies to avoid the presence of this toxic ion in this compartment. Gram-negative species rely on a cytoplasmic transcription factor, CueR. Therefore, the independent detection of copper in each compartment provides a physiological advantage; allowing the maintenance of the appropriate quota in the envelope, and its avoidance within the cytoplasm. Salmonella lacks the cus locus, and instead, depends on CueP, a periplasmic cuproprotein encoded by a CueR-controlled gene. Different lines of evidence suggest that CueP is a major component of the Salmonella envelope copper-homeostasis, including its role in copper resistance in anaerobic conditions. This is also reinforced by our initial observation that cueP is mostly present in species in which the cus locus is either absent or incomplete. If CueP is required to maintain the periplasmic copper homeostasis and more important, to overcome its toxic effects when in excess, it can be hypothesized that its expression or activation requires the detection of periplasmic copper excess instead of been controlled by cytoplasmic metal ion levels. We observed that cueP induction requires the concerted activation of both CueR, by copper, and the CpxR/CpxA two-component system, by envelope stress. This co-regulation restricts expression of CueP only to cells encountering copper excess that causes envelope stress. As the number of specific envelope sensing signal-transduction systems present in a typical bacterial genome is limited, coordinated interactions between an envelopestress detector and a signal-dependent cytoplasmic sensor contribute to expand the number and types of signals that can specifically fine-tune the damage responses in the periplasmic compartment.