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New insights into a persistent problem — chlamydial infections
Richard P. Morrison
Department of Microbiology, Montana State University, Bozeman, Montana, USA
Address correspondence to: Richard P. Morrison, Department of Microbiology, Lewis Hall, Room 109, Montana State University, Bozeman, Montana 59717, USA. Phone: (406) 994-7959; Fax: (406) 994-4926; E-mail: morrison@montana.edu.
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Published June 1, 2003 - More info
J Clin Invest. 2003;111(11):1647–1649. https://doi.org/10.1172/JCI18770.
© 2003 The American Society for Clinical Investigation
Chlamydial infections are noted for the broad array of clinically distinct manifestations that they produce, ranging from acute self-limiting ocular and genital infections to chronic inflammatory diseases that result in blindness or infertility. Trachoma, an ocular infection, is caused by Chlamydia trachomatis serovars A–C and is a primary cause of preventable blindness. The majority of C. trachomatis serovars (D–K) cause urogenital infection, which can progress to serious genital tract disease in men and women. A genetic basis for the remarkable tissue tropism of the various chlamydial serovars (i.e., ocular vs. urogenital strains) was first proposed by Fehlner-Gardiner et al., based upon their analysis of the tryptophan synthase gene cluster (trpRBA) of laboratory strains of chlamydiae (1). They found that the tryptophan synthase genotype is closely linked to the tissue tropism of ocular and genital chlamydial strains; urogenital serovars possess a functional tryptophan synthase and are capable of utilizing indole as a substrate for tryptophan synthesis, whereas ocular isolates possess a nonfunctional tryptophan synthase. In this issue of the JCI, Caldwell et al. have extended that earlier work to include the characterization of tryptophan synthase genes from hundreds of clinical isolates, thereby confirming the correlation between chlamydial tryptophan synthase genotype and tissue tropism (2).
Between the extremes of acute self-limiting infection and chronic inflammatory disease lies the notion of persistent and/or chronic states of chlamydial infection. Cell culture systems have been used for a number of years to demonstrate and study chlamydial persistence in vitro (3). However, the experimental documentation of persistent infection in the human host and of the mechanisms of in vivo persistence has been a much greater challenge. A particularly intriguing hypothesis put forth by the authors is that tryptophan synthase genes function as chlamydial virulence factors and may be involved in the maintenance of persistent/chronic chlamydial infection. That hypothesis is particularly relevant when one considers the key role played by IFN-γ in host defense against chlamydial infection. Caldwell et al. propose a mechanism by which genital chlamydial strains may counter the growth inhibitory effects of IFN-γ by utilizing indole produced by vaginal microbial flora as a substrate for tryptophan synthesis, thus allowing for the continued survival of chlamydiae within a growth-inhibiting environment (2).
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The intracellular developmental cycle of Chlamydia
Key to understanding the pathophysiology of chlamydial disease is an appreciation of the chlamydial developmental cycle (Figure 1) (4). Chlamydial infection is initiated by the attachment to a susceptible host cell of the infectious, metabolically inert elementary body (EB), which then enters the cell within a membrane-bound vesicle, termed an inclusion. The EB rapidly differentiates into a reticulate body (RB), which replicates by binary fission within the confines of the inclusion. Following several rounds of replication, the RBs reorganize to form infectious EBs, which are released by cytolysis from the cell to initiate new infections. Deviations from this typical developmental cycle have been experimentally induced by a variety of stimuli, including IFN-γ, antibiotics, and nutrient deprivation (3). Pertinent to the current discussion is the ability of these stimuli, particularly IFN-γ, to alter chlamydial growth and facilitate persistent or chronic infection.
Figure 1Chlamydial infection is initiated by the attachment of the infectious EB to the host cell, followed by entry of the EB into a membrane-bound vesicle, termed an inclusion. The inclusion evades fusion with host lysosomes, and the EB rapidly differentiates into an RB that replicates by binary fission within the inclusion. Following several rounds of replication, the RBs reorganize and form infectious EBs, which are released from the cell. Under certain conditions, such as in an inflammatory environment where IFN-γ is produced, the intracellular growth of ocular and urogenital chlamydial strains may be altered. IFN-γ induces cellular IDO, which results in a marked decrease in available tryptophan. Depletion of tryptophan either results in chlamydiae cell death or causes chlamydiae to adopt a noninfectious, nonreplicating form that retains viability (persistence). The outcome is dependent on the level and duration of tryptophan depletion and the tryptophan synthase genotype of the infecting chlamydial strain. Persistent forms of chlamydiae can redifferentiate into infectious EBs upon removal of IFN-γ and subsequent replenishing of intracellular tryptophan pools. Alternatively, even in an IFN-γ–rich environment, strains of chlamydiae that possess a functional tryptophan synthase (i.e., genital strains) may use indole (perhaps produced by local microbial flora) as a substrate for tryptophan synthesis to counter the growth inhibitory effects of IFN-γ. This model is far from complete, and the biological processes involved are likely much more complex and interrelated than depicted here. However rudimentary, though, the proposed model provides a reasonable representation of our current understanding.
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