Abstract
ABSTRACTChlamydia is an obligate intracellular bacterium and the most common reportable cause of human infection in the United States. This pathogen proliferates inside a eukaryotic host cell, where it resides within a membrane-bound compartment called the chlamydial inclusion. It has an unusual developmental cycle, marked by conversion between a replicating form, the reticulate body (RB), and an infectious form, the elementary body (EB). We found that the small molecule H89 slowed inclusion growth and decreased overall RB replication by 2-fold but caused a 25-fold reduction in infectious EBs. This disproportionate effect on EB production was mainly due to a defect in RB-to-EB conversion and not to the induction of chlamydial persistence, which is an altered growth state. Although H89 is a known inhibitor of specific protein kinases and vesicular transport to and from the Golgi apparatus, it did not cause these anti-chlamydial effects by blocking protein kinase A or C or by inhibiting protein or lipid transport. Thus, H89 is a novel anti-chlamydial compound that has a unique combination of effects on an intracellular Chlamydia infection.
Highlights
Chlamydia is an obligate intracellular bacterium and the most common reportable cause of human infection in the United States
We show that H89 treatment of C. trachomatis-infected cells slowed inclusion growth and altered the chlamydial developmental cycle by reducing both reticulate body (RB) replication and RB-to-elementary body (EB) conversion
We used 12.5 mM H89 for all experiments described in this study, because it reduced inclusion size by 78% without affecting cell viability or the percentage of host cells with an inclusion, which is a measure of infection efficiency (Fig. 1A to C; see Fig. S1A in the supplemental material)
Summary
Chlamydia is an obligate intracellular bacterium and the most common reportable cause of human infection in the United States. This pathogen proliferates inside a eukaryotic host cell, where it resides within a membrane-bound compartment called the chlamydial inclusion. It has an unusual developmental cycle, marked by conversion between a replicating form, the reticulate body (RB), and an infectious form, the elementary body (EB). The elementary body (EB) is the infectious form that binds and enters a eukaryotic host cell, where it remains within a membrane-bound vacuole called the chlamydial inclusion. Host proteins have been detected in the vicinity of the inclusion [7, 12, 13], but only a few reports document their insertion into the inclusion membrane [14]
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