Anthrax edema toxin induces maturation of dendritic cells and enhances chemotaxis towards macrophage inflammatory protein 3beta.
Bacillus anthracis secretes two bipartite toxins, edema toxin (ET) and lethal toxin (LT), which impair immune responses and contribute directly to the pathology associated with the disease anthrax. Edema factor, the catalytic subunit of ET, is an adenylate cyclase that impairs host defenses by raising cellular cyclic AMP (cAMP) levels. Synthetic cAMP analogues and compounds that raise intracellular cAMP levels lead to phenotypic and functional changes in dendritic cells (DCs). Here, we demonstrate that ET induces a maturation state in human monocyte-derived DCs (MDDCs) similar to that induced by lipopolysaccharide (LPS). ET treatment results in downregulation of DC-SIGN, a marker of immature DCs, and upregulation of DC maturation markers CD83 and CD86. Maturation of DCs by ET is accompanied by an increased ability to migrate toward the lymph node-homing chemokine macrophage inflammatory protein 3beta, like LPS-matured DCs. Interestingly, cotreating with LT differentially affects the ET-induced maturation of MDDCs while not inhibiting ET-induced migration. These findings reveal a mechanism by which ET impairs normal innate immune function and may explain the reported adjuvant effect of ET.
Maldonado-Arocho
Francisco J
FJ
Department of Microbiology, Immunology, & Molecular Genetics, University of California at Los Angeles, 609 Charles E. Young Dr. East, Los Angeles, CA 90095, USA.
Bradley
Kenneth A
KA
D000942:Antigens, Bacterial / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D001427:Bacterial Toxins / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D054415:Chemokine CCL19 / Q000276:immunology*; D002633:Chemotaxis; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000942:Antigens, Bacterial; D015703:Antigens, CD; D051940:B7-2 Antigen; D001427:Bacterial Toxins; D015815:Cell Adhesion Molecules; D054415:Chemokine CCL19; D007136:Immunoglobulins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C497964:CD86 protein, human; C030325:anthrax toxin