Characterization of the Receptor-Ligand Pathways Important for Entry and Survival ofFrancisella tularensisin Human Macrophages

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Abstract
Inhalational pneumonic tularemia, caused byFrancisella tularensis, is lethal in humans.F. tularensisis phagocytosed by macrophages followed by escape from phagosomes into the cytoplasm. Little is known of the phagocytic mechanisms forFrancisella, particularly as they relate to the lung and alveolar macrophages. Here we examined receptors on primary human monocytes and macrophages which mediate the phagocytosis and intracellular survival ofF. novicida. F. novicidaassociation with monocyte-derived macrophages (MDM) was greater than with monocytes. Bacteria were readily ingested, as shown by electron microscopy. Bacterial association was significantly increased in fresh serum and only partially decreased in heat-inactivated serum. A role for both complement receptor 3 (CR3) and Fcγ receptors in uptake was supported by studies using a CR3-expressing cell line and by down-modulation of Fcγ receptors on MDM, respectively. Consistent with Fcγ receptor involvement, antibody in nonimmune human serum was detected on the surface ofFrancisella. In the absence of serum opsonins, competitive inhibition of mannose receptor (MR) activity on MDM with mannan decreased the association ofF. novicidaand opsonization ofF. novicidawith lung collectin surfactant protein A (SP-A) increased bacterial association and intracellular survival. This study demonstrates that human macrophages phagocytose moreFrancisellathan monocytes with contributions from CR3, Fcγ receptors, the MR, and SP-A present in lung alveoli.

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