Dendritic cells endocytose Bacillus anthracis spores: implications for anthrax pathogenesis.
Phagocytosis of inhaled Bacillus anthracis spores and subsequent trafficking to lymph nodes are decisive events in the progression of inhalational anthrax because they initiate germination and dissemination of spores. Found in high frequency throughout the respiratory track, dendritic cells (DCs) routinely take up foreign particles and migrate to lymph nodes. However, the participation of DCs in phagocytosis and dissemination of spores has not been investigated previously. We found that human DCs readily engulfed fully pathogenic Ames and attenuated B. anthracis spores predominately by coiling phagocytosis. Spores provoked a loss of tissue-retaining chemokine receptors (CCR2, CCR5) with a concurrent increase in lymph node homing receptors (CCR7, CD11c) on the membrane of DCs. After spore infection, immature DCs displayed a mature phenotype (CD83(bright), HLA-DR(bright), CD80(bright), CD86(bright), CD40(bright)) and enhanced costimulatory activity. Surprisingly, spores activated the MAPK cascade (ERK, p38) within 30 min and stimulated expression of several inflammatory response genes by 2 h. MAPK signaling was extinguished by 6 h infection, and there was a dramatic reduction of secreted TNF-alpha, IL-6, and IL-8 in the absence of DC death. This corresponded temporally with enzymatic cleavage of proximal MAPK signaling proteins (MEK-1, MEK-3, and MAP kinase kinase-4) and may indicate activity of anthrax lethal toxin. Taken together, these results suggest that B. anthracis may exploit DCs to facilitate infection.
Brittingham
Katherine C
KC
U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
Ruthel
Gordon
G
Panchal
Rekha G
RG
Fuller
Claudette L
CL
Ribot
Wilson J
WJ
Hoover
Timothy A
TA
Young
Howard A
HA
Anderson
Arthur O
AO
Bavari
Sina
S
D000881:Anthrax / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D001408:Bacillus anthracis / Q000276:immunology* / Q000472:pathogenicity* / Q000648:ultrastructure; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology* / Q000648:ultrastructure; D004705:Endocytosis / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D019707:Receptors, Chemokine / Q000096:biosynthesis; D013171:Spores, Bacterial / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D014774:Virulence
D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D019707:Receptors, Chemokine