title: Chlamydia species-dependent differences in the growth requirement for lysosomes.
abstract: Genome reduction is a hallmark of obligate intracellular pathogens such as Chlamydia, where adaptation to intracellular growth has resulted in the elimination of genes encoding biosynthetic enzymes. Accordingly, chlamydiae rely heavily on the host cell for nutrients yet their specific source is unclear. Interestingly, chlamydiae grow within a pathogen-defined vacuole that is in close apposition to lysosomes. Metabolically-labeled uninfected host cell proteins were provided as an exogenous nutrient source to chlamydiae-infected cells, and uptake and subsequent labeling of chlamydiae suggested lysosomal degradation as a source of amino acids for the pathogen. Indeed, Bafilomycin A1 (BafA1), an inhibitor of the vacuolar H(+)/ATPase that blocks lysosomal acidification and functions, impairs the growth of C. trachomatis and C. pneumoniae, and these effects are especially profound in C. pneumoniae. BafA1 induced the marked accumulation of material within the lysosomal lumen, which was due to the inhibition of proteolytic activities, and this response inhibits chlamydiae rather than changes in lysosomal acidification per se, as cathepsin inhibitors also inhibit the growth of chlamydiae. Finally, the addition of cycloheximide, an inhibitor of eukaryotic protein synthesis, compromises the ability of lysosomal inhibitors to block chlamydial growth, suggesting chlamydiae directly access free amino acids in the host cytosol as a preferred source of these nutrients. Thus, chlamydiae co-opt the functions of lysosomes to acquire essential amino acids.
authors.affiliation: Centre for Molecular Microbiology and Infection, Division of Cell and Molecular Biology, Imperial College, London, United Kingdom.
authors.forename: Scot P
authors.initials: SP
authors.lastname: Ouellette
authors.forename: Frank C
authors.initials: FC
authors.lastname: Dorsey
authors.forename: Simon
authors.initials: S
authors.lastname: Moshiach
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.forename: Rey A
authors.initials: RA
authors.lastname: Carabeo
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002417:Cattle; D002689:Chlamydia / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013045:Species Specificity
chemical_list: D000596:Amino Acids; D018942:Macrolides; D012710:Serum Albumin, Bovine; C040929:bafilomycin A1; D003513:Cycloheximide; D042925:Positive Transcriptional Elongation Factor B