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Infection and Immunity, November 2007, p. 5105-5117, Vol. 75, No. 11
0019-9567/07/$08.00+0     doi:10.1128/IAI.00668-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Severe Tryptophan Starvation Blocks Onset of Conventional Persistence and Reduces Reactivation of Chlamydia trachomatis{triangledown}

Ralf M. Leonhardt,1,3* Seung-Joon Lee,2,{dagger} Paula B. Kavathas,2,3 and Peter Cresswell1,3

Howard Hughes Medical Institute,1 Department of Laboratory Medicine,2 Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut3

Received 14 May 2007/ Returned for modification 21 June 2007/ Accepted 13 August 2007

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 gamma interferon-inducible indoleamine-2,3-dioxygenase (IDO) is believed to be the major innate immune mechanism controlling C. trachomatis infection in human cells, an action to which the bacteria can respond by converting into a nonreplicating but highly reactivatable persistent state. However, whether severe IDO-mediated tryptophan starvation can be sufficient to fully arrest the chlamydial life cycle and thereby counteract the onset of persistence is unknown. Here we demonstrate that at low exogenous tryptophan concentrations a substantial fraction of C. trachomatis bacteria fail to traffic to the MTOC or to switch into the conventional persistent state in gamma 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 bacteria become reactivated upon replenishment of cellular tryptophan pools is substantially lower. Thus, severe tryptophan depletion in cells with high IDO activity affects chlamydial development more rigorously than previously described.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, TAC S669/670, New Haven, CT 06519-1612. Phone: (203) 785-5042. Fax: (203) 785-4461. E-mail: Ralf.Leonhardt{at}yale.edu

{triangledown} Published ahead of print on 27 August 2007.

Editor: F. C. Fang

{dagger} Present address: Department of Internal Medicine, Kangwon National University College of Medicine, Chunchon, Kangwon-Do, South Korea.

Infection and Immunity, November 2007, p. 5105-5117, Vol. 75, No. 11
0019-9567/07/$08.00+0     doi:10.1128/IAI.00668-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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