AUTHORS
Melina B. Cian, Nicole P. Giordano, Revathi Masilamani1, Keaton E. Minor, Zachary D. Dalebroux
ABSTRACT
Salmonella enterica serovarTyphimurium (S. Typhimurium) rely upon the 29 inner-membrane protein, PbgA, to enhance outer-membrane (OM) integrity and 30 promote virulence in mice. The PbgA transmembrane domain (residues 1-190) is 31 essential for viability, while the periplasmic domain (191-586) is dispensable. Residues 32 within the basic region (191-245) bind acidic phosphates on polar phospholipids, like for33 cardiolipins, and are necessary for salmonellae OM integrity. S. Typhimurium increase 34 their OM cardiolipin concentrations during activation of the PhoPQ regulators. The 35 mechanism involves PbgA’s periplasmic globular region (245-586), but the biological 36 role of increasing cardiolipins on the surface is not understood. Non-synonymous37 polymorphisms in three essential lipopolysaccharide (LPS) synthesis regulators,38 lapB/yciM, ftsH, and lpxC variably suppressed pbgAΔ191-586-mutant defects in OM 39 integrity, rifampin resistance, survival in macrophages, and systemic colonization for 40 mice. Compared to the OMs of the wild-type salmonellae, the OMs of thepbgA mutants 41 measured increased levels of lipidA-core molecules, cardiolipins, and 42 phosphatidylethanolamines, and decreased levels of specific phospholipids with 43 cyclopropanated fatty acids. Complementation and substitution mutations in LapB and44 LpxC generally restored the phospholipid and LPS assembly defects for the pbgA 45 mutants. During bacteremia, mice infected with pbgA mutants survived and cleared the 46 bacteria, while animals infected with wild -type salmonellae succumbed within one week. 47 Remarkably, wild-type mice survived asymptomatically withpbgA-lpxC salmonellae in 48 their livers and spleens for months, but Tlr4-deficient animals succumbed to these 49 infections within roughly one week. In summary, S. Typhimurium use PbgA to influence LPS assembly during stress in order to survive, adapt, and proliferate within the host 51 environment.
Click here to read the article, published in the American Society for Microbiology.
