Dendritic Cells Endocytose Bacillus Anthracis Spores: Implications for Anthrax Pathogenesis

摘要

Phagocytosis of inhaled Bacillus anthracis spores and subsequent trafficking to lymph nodes are decisive events in the progression of inhaled anthrax because they initiate germination and dissemination of spores. Found in high frequency throughout the respiratory tract, DCs routinely take up foreign particles and migrate to the lymph nodes. However, the participation of DCs in phagocytosis and dissemination of spores was not investigated previously. We found that human DCs readily engulfed fully pathogenic and attenuated B. anthracis spores. 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 co-stimulatory activity. Surprisingly, spores activated the mitogen-activated protein kinase (MAPK) cascade (ERK, p38) and stimulated expression of several inflammatory response genes. MAPK signaling was extinguished by 6 h after infection and resulted in dramatically reduced secretion of TNF-a, IL-6, and IL-8, without inducing DC death. This corresponded temporally with enzymatic cleavage of proximal MAPK signaling proteins (MEK-1, -3, and MKK-4) and may indicate activity of anthrax lethal toxin. Taken together, these results suggest that B. anthracis may exploit DCs to facilitate infection.