Bacillus anthracis peptidoglycan stimulates an inflammatory response in monocytes through the p38 mitogen-activated protein kinase pathway.
We hypothesized that the peptidoglycan component of B. anthracis may play a critical role in morbidity and mortality associated with inhalation anthrax. To explore this issue, we purified the peptidoglycan component of the bacterial cell wall and studied the response of human peripheral blood cells. The purified B. anthracis peptidoglycan was free of non-covalently bound protein but contained a complex set of amino acids probably arising from the stem peptide. The peptidoglycan contained a polysaccharide that was removed by mild acid treatment, and the biological activity remained with the peptidoglycan and not the polysaccharide. The biological activity of the peptidoglycan was sensitive to lysozyme but not other hydrolytic enzymes, showing that the activity resides in the peptidoglycan component and not bacterial DNA, RNA or protein. B. anthracis peptidoglycan stimulated monocytes to produce primarily TNFalpha; neutrophils and lymphocytes did not respond. Peptidoglycan stimulated monocyte p38 mitogen-activated protein kinase and p38 activity was required for TNFalpha production by the cells. We conclude that peptidoglycan in B. anthracis is biologically active, that it stimulates a proinflammatory response in monocytes, and uses the p38 kinase signal transduction pathway to do so. Given the high bacterial burden in pulmonary anthrax, these findings suggest that the inflammatory events associated with peptidoglycan may play an important role in anthrax pathogenesis.
Langer
Marybeth
M
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Malykhin
Alexander
A
Maeda
Kenichiro
K
Chakrabarty
Kaushik
K
Williamson
Kelly S
KS
Feasley
Christa L
CL
West
Christopher M
CM
Metcalf
Jordan P
JP
Coggeshall
K Mark
KM
D001408:Bacillus anthracis / Q000276:immunology / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000201:enzymology / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004269:DNA, Bacterial; D018836:Inflammation Mediators; D010457:Peptidoglycan; D012329:RNA, Bacterial; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases