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Streptococcus pneumoniae  (pneumococcus) is an opportunistic bacterial pathogen responsible for causing several human diseases including pneumonia, meningitis, and otitis media. Pneumococcus is also a major cause of human ocular infections and is commonly isolated in cases of bacterial keratitis, an infection of the cornea. The ocular pathology that occurs during pneumococcal keratitis is partly due to the actions of pneumolysin (Ply), a cholesterol-dependent cytolysin produced by pneumococcus. The lytic mechanism of Ply is a three step process beginning with surface binding to cholesterol. Multiple Ply monomers then oligomerize to form a prepore. The prepore then undergoes a conformational change that creates a large pore in the host cell membrane, resulting in cell lysis. We engineered a collection of single amino acid substitution mutants at residues (A370, A406, W433, and L460) that are crucial to the progression of the lytic mechanism and determined the effects that these mutations had on lytic function. Both Ply WT  and the mutant Ply molecules (Ply A370G , Ply A370E , Ply A406G , Ply A406E , Ply W433G , Ply W433E , Ply W433F , Ply L460G , and Ply L460E ) were able to bind to the surface of human corneal epithelial cells (HCECs) with similar efficiency. Additionally, Ply WT  localized to cholesterol-rich microdomains on the HCEC surface, however, only one mutant (Ply A370G ) was able to duplicate this behavior. Four of the 9 mutant Ply molecules (Ply A370E , Ply W433G , Ply W433E , and Ply L460E ) were deficient in oligomer formation. Lastly, all of the mutant Ply molecules, except Ply A370G , exhibited significantly impaired lytic activity on HCECs. The other 8 mutants all experienced a reduction in lytic activity, but 4 of the 8 retained the ability to oligomerize. A thorough understanding of the molecular interactions that occur between Ply and the target cell, could lead to targeted treatments aimed to reduce the pathology observed during pneumococcal keratitis.

The Cholesterol-Dependent Cytolysin Pneumolysin from Streptococcus pneumoniae Binds to Lipid Raft Microdomains in Human Corneal Epithelial Cells