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

Strange, N; Luu, L; Ong, V; Wee, BA; Phillips, MJA; McCaughey, L; Steele, JR; Barlow, CK; Cranfield, CG; Myers, G; Mazraani, R; Rock, C; Timms, P; Huston, WM

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

Strange, N Luu, L

Ong, V Wee, BA Phillips, MJA McCaughey, L

Steele, JR Barlow, CK Cranfield, CG Myers, G

Mazraani, R Rock, C Timms, P Huston, WM

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Publisher:: AMER SOC MICROBIOLOGY
Publication Type:: Journal Article
Citation:: J Bacteriol, 2024, 206, (4), pp. e0037123
Issue Date:: 2024-04-18

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Field	Value	Language
dc.contributor.author	Strange, N
dc.contributor.author	Luu, L https://orcid.org/0000-0003-2516-2121
dc.contributor.author	Ong, V
dc.contributor.author	Wee, BA
dc.contributor.author	Phillips, MJA
dc.contributor.author	McCaughey, L https://orcid.org/0000-0001-5897-0163
dc.contributor.author	Steele, JR
dc.contributor.author	Barlow, CK
dc.contributor.author	Cranfield, CG
dc.contributor.author	Myers, G https://orcid.org/0000-0002-4756-4810
dc.contributor.author	Mazraani, R
dc.contributor.author	Rock, C
dc.contributor.author	Timms, P
dc.contributor.author	Huston, WM
dc.contributor.editor	Galperin, MY
dc.date.accessioned	2024-12-06T04:44:44Z
dc.date.available	2024-12-06T04:44:44Z
dc.date.issued	2024-04-18
dc.identifier.citation	J Bacteriol, 2024, 206, (4), pp. e0037123
dc.identifier.issn	0021-9193
dc.identifier.issn	1098-5530
dc.identifier.uri	http://hdl.handle.net/10453/182401
dc.description.abstract	UNLABELLED: Chlamydia trachomatis 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 Chlamydia 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 (aasC). AasC 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. IMPORTANCE: Chlamydia trachomatis 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 Chlamydia using a novel inhibitor. In the present study, we characterized genetic variants of Chlamydia trachomatis 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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER SOC MICROBIOLOGY
dc.relation	University of Technology Sydney
dc.relation.ispartof	J Bacteriol
dc.relation.isbasedon	10.1128/jb.00371-23
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	06 Biological Sciences, 07 Agricultural and Veterinary Sciences, 11 Medical and Health Sciences
dc.subject.classification	Microbiology
dc.subject.classification	30 Agricultural, veterinary and food sciences
dc.subject.classification	31 Biological sciences
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.mesh	Chlamydia trachomatis
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Cell Line
dc.subject.mesh	Peptide Hydrolases
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Cell Line
dc.subject.mesh	Chlamydia trachomatis
dc.subject.mesh	Peptide Hydrolases
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Chlamydia trachomatis
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Cell Line
dc.subject.mesh	Peptide Hydrolases
dc.subject.mesh	Bacterial Proteins
dc.title	HtrA, fatty acids, and membrane protein interplay in Chlamydia trachomatis to impact stress response and trigger early cellular exit.
dc.type	Journal Article
utslib.citation.volume	206
utslib.location.activity	United States
utslib.for	06 Biological Sciences
utslib.for	07 Agricultural and Veterinary Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Provost
pubs.organisational-group	University of Technology Sydney/Provost/Jumbunna
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Health Technologies (CHT)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Institute of Biomedical Materials and Devices (IBMD)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Institute for Microbiology & Infection (AIMI)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Institute for Microbiology & Infection (AIMI)/Australian Institute for Microbiology & Infection (AIMI) Associate Members
pubs.organisational-group	University of Technology Sydney/UTS Groups/Institute of Biomedical Materials and Devices (IBMD)/Institute of Biomedical Materials and Devices (IBMD) Associate Members
utslib.copyright.status	open_access	*
dc.date.updated	2024-12-06T04:44:38Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	206
utslib.citation.issue	4

Abstract:

UNLABELLED: Chlamydia trachomatis 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 Chlamydia 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 (aasC). AasC 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. IMPORTANCE: Chlamydia trachomatis 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 Chlamydia using a novel inhibitor. In the present study, we characterized genetic variants of Chlamydia trachomatis 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.

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http://hdl.handle.net/10453/182401