OmpR and Prc contribute to switch the Salmonella morphogenetic program in response to phagosome cues

Salmonella enterica serovar Typhimurium infects eukaryotic cells residing within membrane‐bound phagosomes. In this compartment, the pathogen replaces the morphogenetic penicillin‐binding proteins 2 and 3 (PBP2/PBP3) with PBP2SAL/PBP3SAL, two proteins absent in Escherichia coli. The basis for this switch is unknown. Here, we show that PBP3 protein levels drop drastically when S. Typhimurium senses acidity, high osmolarity and nutrient scarcity, cues that activate virulence functions required for intra‐phagosomal survival and proliferation. The protease Prc and the transcriptional regulator OmpR contribute to lower PBP3 levels whereas OmpR stimulates PBP2SAL/PBP3SAL production. Surprisingly, despite being essential for division in E. coli, PBP3 levels also drop in non‐pathogenic and pathogenic E. coli exposed to phagosome cues. Such exposure alters E. coli morphology resulting in very long bent and twisted filaments indicative of failure in the cell division and elongation machineries. None of these aberrant shapes are detected in S. Typhimurium. Expression of PBP3SAL restores cell division in E. coli exposed to phagosome cues although the cells retain elongation defects in the longitudinal axis. By switching the morphogenetic program, OmpR and Prc allow S. Typhimurium to properly divide and elongate inside acidic phagosomes maintaining its cellular dimensions and the rod shape. Salmonella switches morphogenetic peptidoglycan synthases inside eukaryotic cells, a phenomenon triggered by three cues: acid pH, high osmolarity and nutrient scarcity. OmpR responds to acid pH upregulating alternative synthases PBP2SAL and PBP3SAL. Prc fine‐tunes PBP3 levels and prevents escape of PBP2SAL/PBP3SAL production in extracellular bacteria, in which PBP2/PBP3 direct rod shape. Escherichia coli, which lacks PBP2SAL/PBP3SAL, displays gross morphological alterations if exposed to phagosome cues due to decrease in levels of its morphogenetic peptidoglycan synthases.