Effect of the Purinergic Receptor P2X7 on Chlamydia Infection in Cervical Epithelial Cells and Vaginally Infected Mice

Abstract

Ligation of the purinergic receptor, P2X7R, with its agonist ATP has been previously shown to inhibit intracellular infection by chlamydiae and mycobacteria in macrophages. The effect of P2X7R on chlamydial infection had never been investigated in the preferred target cells of chlamydiae, cervical epithelial cells, nor in vaginally infected mice. In this study, we show that treatment of epithelial cells with P2X7R agonists inhibits partially Chlamydia infection in epithelial cells. Chelation of ATP with magnesium or pretreatment with a P2X7R antagonist blocks the inhibitory effects of ATP. Similarly to previous results obtained with macrophages, ATP-mediated inhibition of infection in epithelial cells requires activation of host-cell phospholipase D. Vaginal infection was also more efficient in P2X7R-deficient mice, which also displayed a higher level of acute inflammation in the endocervix, oviduct, and mesosalpingeal tissues than in infected wild-type mice. However, secretion of IL-1β, which requires P2X7R ligation during infection by other pathogens, was decreased mildly and only at short times of infection. Taken together, these results suggest that P2X7R affects Chlamydia infection by directly inhibiting infection in epithelial cells, rather than through the ability of P2X7R to modulate IL-1β secretion.

The P2X7 receptor and intracellular pathogens: a continuing struggle

“…Likewise, P2X 7 -dependent PLD activation and fusion between vacuoles and lysosomes is involved in inhibition of Chlamydia trachomatis growth in macrophages [17]. These results have been extended by recent studies, which show that P2X 7 activation also inhibits chlamydial infection in a cervical epithelial cell line and in vaginally infected mice [18]. Activation of PLD may be a general mechanism of elimination of parasites that normally reside within intracellular vacuoles that avoid fusion with lysosomes [19] (Fig.…”

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

“…P2X7R activation has been shown to promote the killing of both mycobacteria [50,57,58] and Chlamydia [59,60] in two ways: enhanced maturation of the microbe-containing phagosomes and enhanced killing of the microbe-infected host cells. The first mechanism involves a P2X7R-mediated activation of phospholipase D that facilitates maturation and fusion of the mycobacteria/ chlamydia-containing phagosomes with lysosomes [50].…”

Cell signaling via the P2X7 nucleotide receptor: linkage to ROS production, gene transcription, and receptor trafficking

“…For example, mice deficient in P2X 7 exhibit decreased monoclonal anticollagen-induced arthritis in comparison to wild-type counterparts, and rats treated with oxidized ATP experience less adjuvant-induced pain than control animals [11,12]. In support of the hypothesis that P2X 7 plays a role in host defense against pathogens, P2X 7 -deficient mice were reported to exhibit increased vaginal Chlamydia infection in comparison to wild-type mice [27]. These in vivo results illustrate the involvement of P2X 7 in exacerbating arthritic pain and attenuating pathogen infection, supporting the idea that targeting P2X 7 may be useful in treating certain inflammatory diseases.…”

“…Given that animal and human genetic studies support the concept that P2X 7 is a major immune modulator and may be an effective therapeutic target [11][12][13][14][27][28][29], in this report, we will discuss several key events associated with P2X 7 signaling and trafficking, with an emphasis on their role in mediating/regulating the immune responses of monocytic cells. Specifically, we will provide evidence that P2X 7 stimulation in macrophages promotes ROS production via the extracellular-regulated kinases-1 and 2 (ERK1/2) and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, and that ligand binding to P2X 7 results in activation of the transcription factor cyclic-AMP response element-binding protein (CREB) and the expression of key components of the transcription factor activating protein-1 (AP-1) complex.…”