Scientific Publications by FDA Staff

Infect Immun 2010 Jun;78(6):2418-28

Inflammatory cytokine response to Bacillus anthracis peptidoglycan requires phagocytosis and lysosomal trafficking.

Iyer JK, Khurana T, Langer M, West CM, Ballard JD, Metcalf JP, Merkel TJ, Coggeshall KM

During advanced stages of inhalational anthrax, Bacillus anthracis accumulates to high numbers in the bloodstream of the infected host. This bacteremia leads to sepsis during late stage anthrax; however, the mechanisms through which B. anthracis-derived factors contribute to the pathology of infected hosts are poorly defined. Peptidoglycan, a major component of the cell wall of Gram-positive bacteria, can provoke symptoms of sepsis in animal models. We have previously shown that peptidoglycan of B. anthracis has the ability to induce the production of pro-inflammatory cytokines from cells in human blood. Here, we show that biologically-active peptidoglycan is shed from an active culture of encapsulated B. anthracis Ames strain in blood. Peptidoglycan is able to bind to surfaces of responding cells, and internalization of peptidoglycan is required for the production of inflammatory cytokines. We also show the peptidoglycan traffics to lysosomes, and lysosomal function is required for cytokine production. We conclude that peptidoglycan of B. anthracis is initially bound by an unknown extracellular receptor, is phagocytosed and traffics to lysosomes where it is degraded to a product recognized by an intracellular receptor. Binding of the peptidoglycan product to the intracellular receptor causes the production of a pro-inflammatory response. These findings provide new insight into the mechanism by which B. anthracis triggers sepsis during a critical stage of anthrax disease.