Journal
JOURNAL OF CELL BIOLOGY
Volume 156, Issue 6, Pages 1029-1038Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200201081
Keywords
cytolysins; phagosome; virulence; molecular evolution; macrophages
Categories
Funding
- NIAID NIH HHS [R01 AI027655, AI35950, R37 AI029619, R21 AI035950, R01 AI035950-09, AI27655, R01 AI035950] Funding Source: Medline
Ask authors/readers for more resources
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 bacteria] escape from vesicles and is similar to10-fold more active at an acidic than neutral pH. By swapping dissimilar residues from a pH-insensitive orthologue, perfringolysin 0 (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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available