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The role of aberrant gene expression in chlamydial persistence and reactivation

Award Number: R21AI163870
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/13/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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The role of aberrant gene expression in chlamydial persistence and reactivation - Project Summary/Abstract: The bacteria in the Chlamydiales order are intracellular parasites of eukaryotic cells. They are reliant on a de- velopmental cycle consisting of three cell forms termed the reticulate body (RB), the intermediate body (IB) and the elementary body (EB). The EB is infectious but does not replicate. The RB replicates in the host cell but is non-infectious, while the IB is an intermediate form that transitions to the EB form. Completion of this develop- mental cycle is central to chlamydial pathogenesis. Within this order, the genus Chlamydia contains the causative agents of a number of important pathogens of humans. C. psittaci causes zoonotic infections result- ing in pneumonia, while C. pneumoniae is a human pathogen that causes respiratory disease and is linked to atherosclerosis. Biovars of C. trachomatis are the causative agents of trachoma, the leading cause of pre- ventable blindness worldwide, as well as the sexually transmitted disease Chlamydia. Irrespective of the result- ing disease, all chlamydial species share the same obligate intracellular life cycle and developmental cycle. The chlamydial developmental cycle reacts to environmental stresses by exiting the developmental cycle and forming “aberrant” cell forms and delaying the production of infectious EBs. These cell forms can then reenter the productive developmental cycle when the environmental stress is lifted. It is hypothesized that this re- sponse to stress conditions contributes to the clinical observation that chlamydial infections are often chronic or reoccur in a significant number of diagnosed cases. We have developed a live-cell reporter system to follow cell-type switching in real time at the single inclusion level and determined that Chlamydia’s response to stress conditions such as peptidoglycan inhibitors or nutrient stress differs between treatments and over time. Treat- ment with peptidoglycan inhibitors results in a block in RB to IB development creating aberrant polyploid RBs. These aberrant cells express the RB reporter for ~ 10 hours prior to expressing the IB reporter but never ex- press EB reporters or gain infectivity. Nutrient stress such as tryptophan and iron starvation are also reported to cause Chlamydia to exit the productive developmental cycle and form “aberrant” RBs. Our live cell data suggests that these cells do not exhibit the same phenotype as those treated with peptidoglycan inhibitors. Therefore Aim 1 will Determine the phenotype and gene expression profile of aberrant RBs that reacti- vate to produce infectious EBs. IB to EB development is a slow process taking ~10 hours until maximal EB reporter gene expression. We therefore hypothesize that the IB may respond to nutrient stress by halting de- velopment until the nutrient stress is resolved. The IB then could reenter the developmental state producing infectious progeny. Therefore Aim 2 will Determine the contribution of the IB to EB transition in persis- tence.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$978 )
2025	2022	REGENTS OF THE UNIVERSITY OF IDAHO	875 PERIMETER DR	MOSCOW	ID	83844	LATAH	USA	Allergy and Infectious Diseases Research	000	2	7/7/2025	NON-COMPETING CONTINUATION	-$978
														Subtotal = -$978

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	REGENTS OF THE UNIVERSITY OF IDAHO	875 PERIMETER DR	MOSCOW	ID	83844	LATAH	USA	Allergy and Infectious Diseases Research	000	2	5/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $181,821 )
2022	2022	REGENTS OF THE UNIVERSITY OF IDAHO	875 PERIMETER DRIVE MS 3020	MOSCOW	ID	83844	LATAH	USA	Allergy and Infectious Diseases Research	000	2	6/16/2022	NON-COMPETING CONTINUATION	$181,821
														Subtotal = $181,821

Issue Date FY: 2021 ( Subtotal = $217,488 )
2021	2021	REGENTS OF THE UNIVERSITY OF IDAHO	875 PERIMETER DRIVE MS 3020	MOSCOW	ID	83844	LATAH	USA	Allergy and Infectious Diseases Research	000	1	7/12/2021	NEW	$217,488
														Subtotal = $217,488

Grand Total All Awards = $398,331

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The role of aberrant gene expression in chlamydial persistence and reactivation

Award Number: R21AI163870

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/13/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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