Inhibition ofChlamydia pneumoniaeReplication in HEp‐2 Cells by Interferon‐g: Role of Tryptophan Catabolism

Abstract

Interferon-g (IFN-g) induces tryptophan catabolism in HEp-2 cells, possibly via stimulation of host cell indoleamine-2,3-dioxygenase activity, in a dose-dependent (12.5 -1600 U/mL) fashion after 24 h, resulting in a 99% conversion to its metabolites at 1600 U/mL. Replication of Chlamydia pneumoniae isolates A-03 and BAL-16 was inhibited in HEp-2 cells following treatment with 50 and 100 U/mL IFN-g, respectively; however, addition of excess L-tryptophan (200 mg/mL) to monolayers infected with C. pneumoniae resulted in unrestricted growth of both isolates up to 1600 U/mL IFNg. C. pneumoniae could be recovered from IFN-g -treated monolayers, indicating the potential for this bacterium to undergo an altered life cycle, in vitro, analogous to that described in detail for Chlamydia trachomatis. The ability of C. pneumoniae to persist in host tissue despite an immunologic response would be an important attribute in order to cause or exacerbate chronic infections.

Polymorphonuclear Neutrophils Improve Replication ofChlamydia pneumoniaeIn Vivo upon MyD88-Dependent Attraction

“…In this case, cell to cell contact was required, and it was suggested that mannose 6-phosphate receptor expressed on monocytes is implicated in this process. Other possible mechanisms include the regulation of intracellular tryptophan levels in epithelial cells by PMN because C. pneumoniae lacks tryptophan biosynthesis genes (29) and thus is completely dependent on hostderived tryptophan (30). Increasing the supply of this amino acid via TGF-␤-mediated down-regulation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase or the tryptophanyl-tRNA synthetase could represent potential mechanisms (31).…”

Chlamydial SET domain protein functions as a histone methyltransferase

“…Persistence of chlamydial infection has been thought to be important for chronic diseases and has been characterized using model animals and activation stimuli such as cytokines and antibiotics (Beatty et al, 1993;Belland et al, 2003;Malinverni et al, 1995;Mehta et al, 1998). However, molecular-level relationships between chronic disease progression and persistent infection are not yet clear.…”

Chlamydophila pneumoniae in human immortal Jurkat cells and primary lymphocytes uncontrolled by interferon-γ

“…The effect of IFN- effect on chlamydial elimination in human epithelial cells is responsible for IDO induction [9][10][11][12][13][14]; therefore, we next assessed whether gene expression of IDO could be induced by IFN- in Jurkat cells. As shown in Fig.…”

“…Interferon (IFN)- inhibits the replication of pathogenic chlamydiae in human cells by inducing the production of the enzyme indoleamine 2,3-dioxygenase (IDO), resulting in depletion of tryptophan in infected cells, which is an essential amino acid for intracellular growth of pathogenic chlamydiae [9][10][11]. Therefore, induction of IDO is the most important antichlamydial factor in humans, induced by IFN-, and moreover, human-adapted chlamydiae have specifically coevolved with their host to circumvent the effect of IFN- [9][10][11].…”

“…Therefore, induction of IDO is the most important antichlamydial factor in humans, induced by IFN-, and moreover, human-adapted chlamydiae have specifically coevolved with their host to circumvent the effect of IFN- [9][10][11]. In fact, IFN- induces C. pneumoniae persistent infection, characterized by an absence of culturability [12][13][14], altered bacterial RNA and protein levels [6], and morphologically altered chlamydial bodies [12][13][14], with an uncompleted developmental cycle and inhibition of elementary body maturation, followed by 5 bacterial elimination [12][13][14].…”