Anthrax edema toxin cooperates with lethal toxin to impair cytokine secretion during infection of dendritic cells.
Bacillus anthracis secretes two critical virulence factors, lethal toxin (LT) and edema toxin (ET). In this study, we show that murine bone marrow-derived dendritic cells (DC) infected with B. anthracis strains secreting ET exhibit a very different cytokine secretion pattern than DC infected with B. anthracis strains secreting LT, both toxins, or a nontoxinogenic strain. ET produced during infection selectively inhibits the production of IL-12p70 and TNF-alpha, whereas LT targets IL-10 and TNF-alpha production. To confirm the direct role of the toxins, we show that purified ET and LT similarly disrupt cytokine secretion by DC infected with a nontoxinogenic strain. These effects can be reversed by specific inhibitors of each toxin. Furthermore, ET inhibits in vivo IL-12p70 and IFN-gamma secretion induced by LPS. These results suggest that ET produced during infection impairs DC functions and cooperates with LT to suppress the innate immune response. This may represent a new strategy developed by B. anthracis to escape the host immune response.
Tournier
Jean-Nicolas
JN
Département de Biologie des Agents Transmissibles, Centre de Recherches du Service de Santé des Armées, La Tronche Cedex, France. jntournier@crssa.net
Quesnel-Hellmann
Anne
A
Mathieu
Jacques
J
Montecucco
Cesare
C
Tang
Wei-Jen
WJ
Mock
Michèle
M
Vidal
Dominique R
DR
Goossens
Pierre L
PL
D000262:Adenylyl Cyclases / Q000633:toxicity*; D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D021122:Protein Subunits / Q000096:biosynthesis; D013171:Spores, Bacterial / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; C030325:anthrax toxin; D016753:Interleukin-10; D018664:Interleukin-12; D000262:Adenylyl Cyclases