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Published 18 March 2002. doi:10.1083/jcb.200201081
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© The Rockefeller University Press, 0021-9525/2002/3/1029 $5.00
The Journal of Cell Biology, Volume 156, Number 6, March 18, 2002 1029-1038

Article

 The Listeria monocytogenes hemolysin has an acidic pH optimum to compartmentalize activity and prevent damage to infected host cells

Ian J. Glomski1, Margaret M. Gedde1, Albert W. Tsang3, Joel A. Swanson3 and Daniel A. Portnoy1,2

1 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
2 The School of Public Health, University of California, Berkeley, CA 94720
3 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109

Address correspondence to Daniel A. Portnoy, Department of Molecular and Cell Biology, 401 Barker Hall, University of California, Berkeley, CA 94703-3202. Tel.: (510) 643-3925. Fax: (510) 643-6791. E-mail: portnoy{at}uclink4.berkeley.edu

Listeria monocytogenes is a facultative intracellular bacterial pathogen that escapes from a phagosome and grows in the host cell cytosol. The pore-forming cholesterol-dependent cytolysin, listeriolysin O (LLO), mediates bacterial escape from vesicles and is ~10-fold more active at an acidic than neutral pH. By swapping dissimilar residues from a pH-insensitive orthologue, perfringolysin O (PFO), we identified leucine 461 as unique to pathogenic Listeria and responsible for the acidic pH optimum of LLO. Conversion of leucine 461 to the threonine present in PFO increased the hemolytic activity of LLO almost 10-fold at a neutral pH. L. monocytogenes synthesizing LLO L461T, expressed from its endogenous site on the bacterial chromosome, resulted in a 100-fold virulence defect in the mouse listeriosis model. These bacteria escaped from acidic phagosomes and initially grew normally in cells and spread cell to cell, but prematurely permeabilized the host membrane and killed the cell. These data show that the acidic pH optimum of LLO results from an adaptive mutation that acts to limit cytolytic activity to acidic vesicles and prevent damage in the host cytosol, a strategy also used by host cells to compartmentalize lysosomal hydrolases.

Key Words: cytolysins; phagosome; virulence; molecular evolution; macrophages


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