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Combined human genome-wide RNAi and metabolite analyses identify IMPDH as a host-directed target against Chlamydia infection

Item Type:Article
Title:Combined human genome-wide RNAi and metabolite analyses identify IMPDH as a host-directed target against Chlamydia infection
Creators Name:Rother, M. and Gonzalez, E. and Teixeira da Costa, A.R. and Wask, L. and Gravenstein, I. and Pardo, M. and Pietzke, M. and Gurumurthy, R.K. and Angermann, J. and Laudeley, R. and Glage, S. and Meyer, M. and Chumduri, C. and Kempa, S. and Dinkel, K. and Unger, A. and Klebl, B. and Klos, A. and Meyer, T.F.
Abstract:Chlamydia trachomatis (Ctr) accounts for >130 million human infections annually. Since chronic Ctr infections are extremely difficult to treat, there is an urgent need for more effective therapeutics. As an obligate intracellular bacterium, Ctr strictly depends on the functional contribution of the host cell. Here, we combined a human genome-wide RNA interference screen with metabolic profiling to obtain detailed understanding of changes in the infected cell and identify druggable pathways essential for Ctr growth. We demonstrate that Ctr shifts the host metabolism toward aerobic glycolysis, consistent with increased biomass requirement. We identify key regulator complexes of glucose and nucleotide metabolism that govern Ctr infection processes. Pharmacological targeting of inosine-5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, efficiently inhibits Ctr growth both in vitro and in vivo. These results highlight the potency of genome-scale functional screening for the discovery of drug targets against bacterial infections.
Keywords:RNAi Screen, Chlamydia trachomatis, metabolomics Screen, Nucleotide, Warburg Effect, IMPDH, MMF, Animals, Mice
Source:Cell Host & Microbe
ISSN:1931-3128
Publisher:Elsevier (The Netherlands)
Volume:23
Number:5
Page Range:661-671
Date:9 May 2018
Official Publication:https://doi.org/10.1016/j.chom.2018.04.002
PubMed:View item in PubMed

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