HtrA, fatty acids, and membrane protein interplay in Chlamydia trachomatis to impact stress response and trigger early cellular exit

• Published in: Journal of bacteriology 2024-04, Vol.206 (4), p.e0037123
• Main Authors: Strange, Natalie, Luu, Laurence, Ong, Vanissa, Wee, Bryan A, Phillips, Matthew J A, McCaughey, Laura, Steele, Joel R, Barlow, Christopher K, Cranfield, Charles G, Myers, Garry, Mazraani, Rami, Rock, Charles, Timms, Peter, Huston, Wilhelmina M
• Format: Article
• Language: English
• Subjects: Acyl carrier protein; Bacterial Proteins - genetics; Cell Line; Chlamydia; Chlamydia trachomatis; Chlamydia trachomatis - genetics; Composition; Elementary bodies; Fatty acid composition; Fatty acids; Fatty Acids - metabolism; Gene expression; Host-pathogen interactions; Intracellular; Lipid bilayers; Lipids; Major outer membrane protein; Membrane proteins; Membrane Proteins - metabolism; Membranes; Microbial Pathogenesis; Pathogens; Peptide Hydrolases - metabolism; Proteases; Proteins; Research Article; Reticulate bodies; Sexually transmitted diseases; STD; Stress response; Transcriptomes
• ISSN: 0021-9193; 1098-5530; 1098-5530
• DOI: 10.1128/jb.00371-23

is an intracellular bacterial pathogen that undergoes a biphasic developmental cycle, consisting of intracellular reticulate bodies and extracellular infectious elementary bodies. A conserved bacterial protease, HtrA, was shown previously to be essential for during the reticulate body phase, using a novel inhibitor (JO146). In this study, isolates selected for the survival of JO146 treatment were found to have polymorphisms in the acyl-acyl carrier protein synthetase gene ( ) encodes the enzyme responsible for activating fatty acids from the host cell or synthesis to be incorporated into lipid bilayers. The isolates had distinct lipidomes with varied fatty acid compositions. A reduction in the lipid compositions that HtrA prefers to bind to was detected, yet HtrA and MOMP (a key outer membrane protein) were present at higher levels in the variants. Reduced progeny production and an earlier cellular exit were observed. Transcriptome analysis identified that multiple genes were downregulated in the variants especially stress and DNA processing factors. Here, we have shown that the fatty acid composition of chlamydial lipids, HtrA, and membrane proteins interplay and, when disrupted, impact chlamydial stress response that could trigger early cellular exit. is an important obligate intracellular pathogen that has a unique biphasic developmental cycle. HtrA is an essential stress or virulence protease in many bacteria, with many different functions. Previously, we demonstrated that HtrA is critical for using a novel inhibitor. In the present study, we characterized genetic variants of with reduced susceptibility to the HtrA inhibitor. The variants were changed in membrane fatty acid composition, outer membrane proteins, and transcription of stress genes. Earlier and more synchronous cellular exit was observed. Combined, this links stress response to fatty acids, membrane proteins, and HtrA interplay with the outcome of disrupted timing of chlamydial cellular exit.