1. Combined Human Genome-wide RNAi and Metabolite Analyses Identify IMPDH as a Host-Directed Target against Chlamydia Infection.
- Author
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Rother M, Gonzalez E, Teixeira da Costa AR, Wask L, Gravenstein I, Pardo M, Pietzke M, Gurumurthy RK, Angermann J, Laudeley R, Glage S, Meyer M, Chumduri C, Kempa S, Dinkel K, Unger A, Klebl B, Klos A, and Meyer TF
- Subjects
- Animals, Cell Survival, Chlamydia Infections pathology, Chlamydia trachomatis growth & development, Chlamydia trachomatis pathogenicity, Citric Acid Cycle, Clustered Regularly Interspaced Short Palindromic Repeats genetics, Energy Metabolism, Female, Glucose metabolism, HEK293 Cells, HeLa Cells, Humans, Lung microbiology, Lung pathology, Male, Metabolic Networks and Pathways genetics, Metabolic Networks and Pathways physiology, Mice, Mice, Inbred C57BL, Middle Aged, Models, Animal, NIH 3T3 Cells, Nucleotides metabolism, Chlamydia Infections metabolism, Chlamydia trachomatis metabolism, Genome, Human, Host-Pathogen Interactions genetics, Host-Pathogen Interactions physiology, IMP Dehydrogenase genetics, IMP Dehydrogenase metabolism, RNA Interference
- 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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