Selective inhibition of Coxiella burnetii replication by the steroid hormone progesterone

Coxiella burnetii is a zoonotic bacterial obligate intracellular parasite and the cause of Query (Q) fever. During natural infection of female animals, C. burnetii shows tropism for the placenta and is associated with late-term abortion, at which time pathogen titer in placental tissue can exceed one billion bacteria per gram tissue. During later stages of pregnancy, placental trophoblasts serve as the major source of progesterone, a steroid hormone known to affect replication of some pathogens. During infection of placental-derived JEG-3 cells, C. burnetii showed sensitivity to progesterone, but not the immediate precursor pregnenolone, or estrogen, another major mammalian steroid hormone. Using host cell-free culture, progesterone was determined to have a direct inhibitory effect on C. burnetii replication. Synergy between the inhibitory effect of progesterone and the efflux pump inhibitors verapamil and 1-(1-naphthylmethyl)-piperazine is consistent with a role for efflux pumps in preventing progesterone-mediated inhibition of C. burnetii activity. Sensitivity of C. burnetii to progesterone, but not structurally related molecules, is consistent with the ability of progesterone to influence pathogen replication in progesterone-producing tissues.