Chlamydia pneumoniae relies on host glutathione for its growth and induces integrated stress response-mediated changes in macrophage glutathione metabolism.

The obligate intracellular bacterium Chlamydia pneumoniae can enter into persistent phenotype, which is refractory to antibiotics and causes prolonged inflammatory state in the host. Molecular mechanisms enabling C. pneumoniae intracellular survival and governing the balance between persistent and productive infection phenotype remain poorly understood. In this study, the role of glutathione (GSH) metabolism in C. pneumoniae growth and progeny production was studied in THP-1 macrophages and A549 epithelial cells. Results indicate that depletion of cellular GSH pools decreased C. pneumoniae replication, but only if the constituent amino acids were also sequestered from the culture. C. pneumoniae infection increased the expression of GSH biosynthetic genes but also upregulated ChaC1, an intracellular enzyme involved in GSH breakage. C. pneumoniae infection was found to increase PERK phosphorylation in THP-1 macrophages and chemical inhibition of PERK prevented the infection-induced upregulation of GSH biosynthesis and GSH degradation genes and suppressed C. pneumoniae replication. C. pneumoniae -induced ChaC1 upregulation was also suppressed by protein kinase R inhibitor or treatment with ISRIB, indicating an involvement of redundant pathways of the host cell stress response. The data suggest that C. pneumoniae requires amino acids derived from the host cell GSH pools to enable active bacterial replication.