Review
The role of IFN-γ in the outcome of chlamydial infection

https://doi.org/10.1016/S0952-7915(02)00361-8Get rights and content

Abstract

Chlamydia are intracellular bacteria which infect many vertebrates, including humans. They cause a myriad of severe diseases, ranging from asymptomatic infection to pneumonia, blindness or infertility. IFN-γ plays an important role in defense against acute infection and in the establishment of persistence. Chlamydia have evolved mechanisms to escape IFN-γ functions. IFN-γ-mediated effector mechanisms may involve effects on the metabolism of tryptophan or iron, on the inducible NO synthase (iNOS), on the secretion of chemokines and adhesion molecules or on the regulation of T-cell activities. IFN-γ is secreted by the innate and the adaptive arms of the immune system. Within the former, Chlamydia-infected macrophages express IFN-γ that in turn mediates resistance to infection. IFN-α/β are pivotal for both IFN-γ- and iNOS-mediated resistance to chlamydial infection in macrophages.

Introduction

Chlamydial agents are obligate intracytoplasmic parasites of mammalian cells and can damage infected cells in tissues. Chlamydia infect different cell types such as epithelial cells, macrophages, smooth-muscle cells and endothelial cells. Chlamydia share a common developmental microbiology (depicted in Fig. 1) and share a similar genome organization, suggesting a common immunobiology 1., 2.. However, different species of Chlamydia cause different infections ranging from asymptomatic infection to late-stage disease in humans and animals. C. trachomatis, the causative agent of conjunctivitis and trachoma, is the world's leading cause of infectious blindness. C. pneumoniae is responsible for approximately 10% of pneumonia in industrialized countries, and a link between previous C. pneumoniae infections and increased risk of developing atherosclerosis is under investigation [3].

Chlamydial infections often recur or remain persistent, indicating absence of sterilizing immunity. Long-term consequences of recurrent or persistent chlamydial infections can be severe, such as scarring of fallopian tubes in women with salpingitis and scarring of follicular conjunctiva of trachoma patients.

Persistence is defined as a long-term association between Chlamydia and the host, in which the organism remains viable, but in a culture-negative state. In vitro, persistent infection seems to involve incomplete chlamydial growth with a nonreplicative (or slowly replicating), noninfectious but metabolically active stage of development.

Persistent infection has been demonstrated during stressful conditions, such as nutrient depletion, or presence of low levels of interferon γ (IFN-γ). Stress-induced atypical inclusions are generally smaller in diameter and contain reticulate-like aberrant bodies, larger in diameter than typical reticulate bodies (RBs). Resumption of growth and the release of infectious elementary bodies (EBs) are observed upon removal of stress and after the reorganization of the aberrant form into a replicative organism (Fig. 1).

Aberrant chlamydial inclusions express a special bacterial gene and protein profile, including lower levels of lipopolysaccharide (LPS), outer membrane proteins and genes involved in cytokinesis, the presence of transcripts of genes involved in DNA replication and the presence of the stress protein HSP-60 [4]. HSP-60 causes the direct production of inflammatory cytokines, and the oxidation of low density lipoprotein — a process involved in atherogenesis — and induces anti-HSP-60 immune reactivities that correlates with the pathological consequence of chlamydial infections 5., 6..

Chlamydial persistence has been documented in animal models of infection [7]. Indirect evidence suggests that C. trachomatis can persist during human ocular, genital, and joint diseases. The suggestion of persistence of C. pneumoniae in man is supported by the association of infection with chronic conditions such as adult-onset asthma, and atherosclerosis.

This review focuses on the role of IFN-γ in the defense against acute infection and in the establishment of persistence. We describe the protective effector mechanisms that IFN-γ induces, the regulation of IFN-γ synthesis and the innate and adaptive immune cell populations that release IFN-γ during the infection. The escape routes that the bacteria have evolved to withstand the selective pressure posed by this cytokine are also addressed.

Section snippets

The role of IFN-γ in the outcome of chlamydial infection

The importance of IFN-γ in vivo has been demonstrated by the enhanced bacterial levels in IFN-γ−/− or IFN-γ receptor (IFN-γR)−/− mice, or mice treated with anti-IFN-γ antibodies, compared with controls 8., 9., 10., 11., 12. (Table 1). However, variations in susceptibility to IFN-γ have been reported in Chlamydia: whereas IFN-γ−/− mice developed more-severe primary genital-tract infections after infection with human C. trachomatis strains, minimal effects of IFN-γ deficiency were noted on the

IFN-γ-mediated effector mechanisms in the control of Chlamydia

The indoleamine 2,3-dioxygenase (IDO) pathway, which converts L-tryptophan to N-formylkynurenine (thereby limiting tryptophan availability), is implicated in IFN-γ-mediated inhibition of chlamydial replication and in persistence in human cells [22]. Differences in susceptibility of various chlamydial strains to IFN-γ have been explained by their varying ability to acquire or synthesize their own tryptophan. C. pneumoniae and C. trachomatis trachoma serovars, whose growth is inhibited by IFN-γ,

IFN-γ and innate immune responses against Chlamydia

IFN-γ secreted as a result of innate immune responses can control chlamydial infections, as shown by the increased susceptibility of SCID mice treated with neutralizing anti-IFN-γ antibodies [15], and of RAG-1−/−IFN-γR−/− mice compared with RAG-1−/− mice [20•].

NK cells participate in the resistance against a number of bacterial and protozoal infections through their ability to secrete IFN-γ. However, their involvement in the control of chlamydial infection is not clear: NK cells participate in

IFN-γ and adaptive responses against Chlamydia

Both CD8+ and CD4+ T cells produce IFN-γ in response to infection and are probably complementary in warranting protective levels of this cytokine (reviewed in [49]). Adaptive immune protection against C. trachomatis in mice can be demonstrated by transfer of Chlamydia-specific CD4+ or CD8+ T cells. Both subsets are also recruited to sites of infection in nonhuman primate models. IFN-γ release by T cells has been associated with the protective ability of DNA vaccines against C. trachomatis.

Chlamydial escape

Since apoptosis of the infected cell (induced by the pathogen itself or by cytokines, NK cells or T cells) is a common component of the antimicrobial response, it is not surprising that several viruses and bacteria have evolved inhibitory mechanisms against apoptosis. Chlamydia possess a strong antiapoptotic activity to evade the killing mechanisms of CD8+ T cells 64., 65., 66., 67., 68. but also, probably depending on the stage of development, Chlamydia has been indicated to induce apoptosis

Update

Coincubation of dendritic cells, endothelial cells, human vascular smooth muscle cells or peripheral-blood mononuclear cells with Chlamydia or chlamydial components has recently been shown to induce TollR-mediated activation 92., 93., 94., 95.. Whether TollR recognition plays a role in the outcome of chlamydial infection in vivo remains to be explored.

Acknowledgements

This work has been supported by the Swedish Medical Research Council, The Swedish Cancer Foundation, Amgen and the Karolinska Institute.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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