Salmonella copper homeostasis and its adaptations to survive inside macrophages

MENDEZ ANDREA AE; CHECA, SUSANA K; SONCINI, FERNANDO C.

Congreso; Copper 2022 Sorrento; 2022

Copper (Cu) is a bactericidal host innate immune component that primary targets the bacterial cell envelope. In presence of oxygen, most enteric species rely on the periplasmic multicopper oxidase CueO to maintain the envelope Cu-homeostasis. When CueO is inactive, i.e. under anaerobic conditions, the CusCFBA efflux system encoded by the cus locus is necessary to get rid of Cu excess from this compartment. We noticed that this locus was lost from the Salmonella core genome. At the same time, Salmonella acquired cueP, coding for a periplasmic Cu-chaperone. As cus, cueP was shown to be essential for bacterial survival in Cu-rich environments under anaerobic conditions, suggesting that it can functionally substitute CusCFBA. To test this, we reintroduced the E. coli cus locus into the chromosome of the Salmonella wild-type or the ΔcueP strain. While the integrated cus locus does not affect Cu-resistance under aerobic conditions, it increases Cu tolerance in anaerobiosis, irrespective of the presence or absence of cueP. Interestingly in the presence of Cu, CueP expression is higher than that of the Cus system and persisted over time. Finally, we observed that, regardless the presence or absence of cus, a cueP deleted mutant shows a deficiency in replication inside macrophages compared to the wild type strain. Our results demonstrate that CueP and CusCFBA exert redundant functions for metal resistance, but not for intracellular Salmonella survival and therefore for virulence of this pathogen. As a consequence, CueP emerges as a putative target for anti-virulence therapies to control animal and human salmonellosis.