A single residue determines acid sensitivity in a bacterial hemolysin.

Intracellular parasites must walk a fine line, invading and exploiting a host cell without killing it too quickly. On page 1029, Glomski et al. show how a single amino acid determines not only the pH optimum of a bacterial hemolysin, but also the virulence of an important pathogen. The data help explain how Listeria monocytogenes distinguishes between the membranes of acidic vesicles, which the bacterium must pierce to enter the cytosol, and the plasma membrane, which must remain intact while the parasite reproduces.

The activity of the L. monocytogenes pore-forming hemolysin listeriolysin O (LLO) is strongly induced by low pH. By amino acid substitution, the authors determined that changing a single residue largely relieves this pH dependence, but bacteria expressing the pH-independent form of the enzyme are 100-fold less virulent in mice. The virulence defect is not in cellular entry. The mutants escape from acidified phagosomes, grow in the cytosol, and spread from cell to cell. But bacteria expressing the mutant LLO permeabilize the host cell membrane prematurely. The authors propose that the acidic pH optimum of LLO is an adaptation to the parasitic lifestyle, allowing Listeria to penetrate acidic vesicles while leaving the plasma membrane intact. ▪