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Infect. Immun. doi:10.1128/IAI.00668-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Severe tryptophan-starvation blocks onset of conventional persistence and reduces reactivation of Chlamydia trachomatis

Howard Hughes Medical Institute, Department of Laboratory Medicine and Department of Immunobiology, Yale University School of Medicine, New Haven, USA

^* To whom correspondence should be addressed. Email: Ralf.Leonhardt{at}yale.edu.

	Abstract

The intracellular survival of the bacterial pathogen Chlamydia trachomatis depends on protein synthesis by the microbe soon after internalization. Pharmacologic inhibition of bacterial translation inhibits early trafficking of the parasitophorous vacuole (inclusion) to the microtubule-organizing center (MTOC) and promotes its fusion with lysosomes, which is normally blocked by Chlamydia. Depletion of cellular tryptophan pools by interferon--inducible indoleamine-2,3-dioxygenase (IDO) is believed to be the major innate immune mechanism controlling Chlamydia trachomatis infection in human cells, an action to which the bacteria can respond by converting into a non-replicating, but highly reactivatable persistent state. However, whether severe IDO-mediated tryptophan starvation can be sufficient to fully arrest the chlamydial life-cycle thereby counteracting the onset of persistence is unknown. Here we demonstrate that at low exogenous tryptophan concentrations a substantial fraction of Chlamydia trachomatis fails to traffic to the MTOC or to switch into the conventional persistent state in interferon--induced human cells. The organisms stay scattered in the cell periphery, do not retain infectivity and display only low transcriptional activity. Importantly, the rate at which these aberrant Chlamydia become reactivated upon replenishing cellular tryptophan pools is substantially slower. Thus, severe tryptophan depletion in cells with high IDO activity affects chlamydial development more rigorously than previously described.