Peptidoglycan Recognition Proteins kill bacteria by inducing suicide through protein-sensing two-component systems

Mammalian Peptidoglycan Recognition Proteins (PGRPs), similar to antimicrobial lectins, bind to bacterial cell wall and kill bacteria through an unknown mechanism. We show that PGRPs enter Gram-positive cell wall at the site of daughter cell separation during cell division. In Bacillus subtilis PGRPs activate the CssR-CssS two-component system that detects and disposes of misfolded proteins exported out of bacterial cells. This activation results in membrane depolarization, cessation of intracellular peptidoglycan, protein, RNA, and DNA synthesis, and production of hydroxyl radicals, which are responsible for bacterial death. PGRPs also bind to the outer membrane in Escherichia coli and activate functionally homologous CpxA-CpxR two-component system, which results in bacterial death. We excluded other potential bactericidal mechanisms (inhibition of extracellular peptidoglycan synthesis, hydrolysis of peptidoglycan, and membrane permeabilization). Thus we reveal a novel mechanism of bacterial killing by innate immunity proteins that bind to cell wall or outer membrane and exploit bacterial stress defense response to kill bacteria.