Factors that modulate the deleterious effect of ammonia generation by chlamydial tryptophan synthase

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Genital Chlamydia trachomatis! (CT) infections are a major public health concern that can adversely affect reproductive health and neonate survival. Interferon gamma (IFNg) is proposed to protect against CT infection by inducing the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1). The ensuing depletion of tryptophan starves CT of this essential amino-acid leading to bacterial eradication. By expressing the chlamydial enzyme tryptophan synthase (TS), genital serovars of CT can escape the effects of IFNg if the microbial metabolite indole is present in the infection microenvironment. TS can salvage indole within the chlamydial inclusion to generate tryptophan. TS expression is tightly regulated by the tryptophan operon repressor (TrpR), which permits transcription of the operon only when tryptophan is absent. We recently discovered that indole derivatives produced by the gut microbiome, termed TrpR de-repressors, rapidly induce the expression of chlamydial TS. Further, when TS is expressed in the absence of indole, the enzyme rapidly deaminates serine to generate ammonia (NH3), a known bactericidal compound. While evaluating the effect of TrpR de-repressors on different chlamydial serovars, we discovered that although de-repression was equally efficient between them, the production of NH3 varied dramatically. Using a combination of approaches, here we propose to: 1) Identify methods by which CT can assimilate NH3 produced by TS; and 2) Determine whether sequence differences in TS between serovars determines their catalytic properties vis-à-vis ammonia generation. The outcome of our findings will permit the design of novel pharmacological approaches against chlamydial infection by augmenting the effect of protective host responses.