Simple Sequence Repeats Mediate Phase Variation of the Mucoid Phenotype in Hypervirulent Klebsiella pneumoniae

Hypervirulent Klebsiella pneumoniae (HV Kp ) express a thick mucoid capsular polysaccharide which is essential for virulence and survival in the bloodstream but inhibits epithelial adhesion and invasion. The molecular mechanisms regulating capsule expression to rapidly adapt to these distinct niches are unknown. Here, we show that high frequency mutations in a poly-G repeat in the regulator of mucoid phenotype gene, rmpA , mediates reversible ON/OFF phase variation of the mucoid phenotype. We find that these mutations generate subpopulations of bacteria with reduced capsule expression and mucoidy. In vitro and in vivo infection models reveal that phase variation to the OFF state facilitates epithelial cell infection while ON switching enhances resistance to the bactericidal activity of human serum and systemic spread to the liver and spleen in a murine infection model. Genomic analysis reveals that the phase variation mechanism is a conserved feature of all HV Kp and that additional novel DNA repeats in rmpD and rmpC drive different combinations of capsule mucoidy and hyperexpression phenotypes. These findings establish a mechanistic basis for how HV Kp occupy such a diverse array of niches during infection, with important implications for the design and implementation of Kp -specific vaccines and therapies.