title: Mammalian peptidoglycan recognition proteins kill bacteria by activating two-component systems and modulate microbiome and inflammation.
abstract: Peptidoglycan recognition proteins (PGRPs) are conserved from insects to mammals and function in antibacterial immunity. We have revealed a novel mechanism of bacterial killing by innate immune system, in which mammalian PGRPs bind to bacterial cell wall or outer membrane and exploit bacterial stress defense response to kill bacteria. 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, production of hydroxyl radicals, and cessation of intracellular peptidoglycan, protein, RNA, and DNA synthesis, 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 also results in bacterial death. We excluded other potential bactericidal mechanisms, such as inhibition of extracellular peptidoglycan synthesis, hydrolysis of peptidoglycan, and membrane permeabilization. In vivo, mammalian PGRPs are expressed in polymorphonuclear leukocytes, skin, salivary glands, oral cavity, intestinal tract, eyes, and liver. They control acquisition and maintenance of beneficial normal gut microflora, which protects the host from enhanced inflammation, tissue damage, and colitis.
authors.affiliation: School of Medicine, Indiana University, Gary, Indiana 46408, USA. rdziar@iun.edu
authors.forename: Roman
authors.initials: R
authors.lastname: Dziarski
authors.forename: Des Raj
authors.initials: DR
authors.lastname: Kashyap
authors.forename: Dipika
authors.initials: D
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001412:Bacillus subtilis / Q000187:drug effects* / Q000378:metabolism; D001424:Bacterial Infections / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D001426:Bacterial Proteins / Q000819:agonists* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D054892:Metagenome / Q000187:drug effects / Q000276:immunology*; D010457:Peptidoglycan / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D010457:Peptidoglycan; C118897:peptidoglycan recognition protein