The malS-5'UTR weakens the ability of Salmonella enterica serovar Typhi to survive in macrophages by increasing intracellular ATP levels.

Bacterial non-coding RNAs (ncRNAs), as important regulatory factors, are involved in many cellular processes, including virulence and protection against environmental stress. The 5' untranslated region (UTR) of malS (named malS-5'UTR), a regulatory ncRNA, increases the invasive capacity and influences histidine biosynthesis in Salmonella enterica serovar Typhi (S. Typhi). In this study, we found that overexpression of the malS-5'UTR decreased S. Typhi survival within macrophages. A microarray analysis of a strain overexpressing the malS-5'UTR revealed a significant increase in the mRNA levels of the atp operon. The intracellular ATP levels were elevated in the malS-5'UTR overexpression strain. Quantitative real-time polymerase chain reaction results showed that the malS-5'UTR downregulated the mRNA levels of phoP, phoQ, and mgtC. MgtC, its expression is regulated by PhoP/PhoQ two-component regulatory system, inhibits the F1F0 ATP synthase, thereby preventing the accumulation of ATP to non-physiological levels and the acidification of the cytoplasm within macrophages. Thus, we propose that the malS-5'UTR weakens the ability of S. Typhi to survive in macrophages, probably because of the accumulation of ATP within macrophages, by regulating the mRNA levels of mgtC and the atp operon in a phoP-dependent manner.