Assessing a Potential Role of Host Pannexin 1 during Chlamydia trachomatis Infection

Mary J Mckuen,Kenneth A Fields,Gerhard Dahl,David M Ojcius

doi:10.1371/journal.pone.0063732

Abstract

Pannexin 1 (Panx1) is a plasma membrane channel glycoprotein that plays a role in innate immune response through association with the inflammasome complex. Probenecid, a classic pharmacological agent for gout, has also been used historically in combination therapy with antibiotics to prevent cellular drug efflux and has been reported to inhibit Panx1. As the inflammasome has been implicated in the progression of Chlamydia infections, and with chlamydial infections at record levels in the US, we therefore investigated whether probenecid would have a direct effect on Chlamydia trachomatis development through inhibition of Panx1. We found chlamydial development to be inhibited in a dose-dependent, yet reversible manner in the presence of probenecid. Drug treatment induced an aberrant chlamydial morphology consistent with persistent bodies. Although Panx1 was shown to localize to the chlamydial inclusion, no difference was seen in chlamydial development during infection of cells derived from wild-type and Panx1 knockout mice. Therefore, probenecid may inhibit C. trachomatis growth by an as yet unresolved mechanism.

Highlights

Chlamydiae are obligate intracellular pathogens that preferentially replicate within mucosal columnar epithelial cells
We found that probenecid treatment directly inhibited chlamydial development in a dose-dependent and reversible manner, yet the mechanism of probenecid inhibition appears to be independent of Pannexin 1 (Panx1)
Inhibition of C. trachomatis Development by Probenecid C. trachomatis growth can be quantitatively examined via enumeration of accumulating infectious forming units (IFUs)

Summary

Introduction

Chlamydiae are obligate intracellular pathogens that preferentially replicate within mucosal columnar epithelial cells. A mainstay treatment for gout, probenecid has been shown to function by inhibition of membrane transporters including those for organic anions (OAT) [13,14], drug efflux [15] and more recently, pannexin 1 (Panx1) [16]. Identical IFU patterns were detected when HeLa cells were pretreated with probenecid prior to infection with C. trachomatis (data not shown).

Results

Conclusion