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Mechanism of RB-to-EB Conversion in Chlamydia

Award Number: R01AI151212
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: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Mechanism of RB-to-EB Conversion in Chlamydia - Project Summary/Abstract Chlamydia genital infections are the most commonly reported infection in the U.S. All Chlamydia species cause an unusual intracellular infection in which there is conversion between a dividing form of the bacterium (reticulate body or RB) and the infectious form (elementary body or EB). RB-to-EB conversion is critical for producing infectious progeny that can spread the infection to a new host cell, but the mechanisms that regulate it are unknown. There has been a longstanding assumption in the Chlamydia field that conversion is regulated by an extrinsic factor. However, we have obtained data to support a new regulatory mechanism in which RB size is used as an intrinsic factor to control conversion. Based on temporal measurements of chlamydial size and number obtained with three-dimensional electron microscopy (3D EM), we hypothesize that RBs undergo size reduction through successive rounds of replication and can only convert into an EB below a size threshold. In Aim 1, we will test this size control mechanism by determining whether RB size is altered when the timing of RB-to-EB conversion onset is changed. In Aim 2, we will investigate if the size of the first RB plays a role in starting the timer of RB size reduction that eventually culminates in RB-to-EB conversion. In Aim 3, we will study how RB size could be used to regulate conversion. We propose a titration mechanism in which EUO, a repressor of late chlamydial genes, is titrated away in smaller RBs to promote conversion. In Aim 4, we will study alternative mechanisms that utilize extrinsic signals to control conversion. Using mathematical modeling and 3D EM analysis, we will test a contact-dependent mechanism, which is based on contact of the RB with the inclusion membrane as the external signal, and a chlamydial communication mechanism in which the external signal is produced by other chlamydiae. These studies will provide important information about the mechanism of RB-to-EB conversion that can be applied in new therapeutic strategies to block the developmental cycle and the production of infectious progeny.


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: 2024 ( Subtotal = $688,445 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Allergy and Infectious Diseases Research	001	5	5/20/2024	NON-COMPETING CONTINUATION	$68,844
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Allergy and Infectious Diseases Research	000	5	1/11/2024	NON-COMPETING CONTINUATION	$619,601
														Subtotal = $688,445

Issue Date FY: 2023 ( Subtotal = $711,791 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Allergy and Infectious Diseases Research	000	4	2/2/2023	NON-COMPETING CONTINUATION	$711,791
														Subtotal = $711,791

Issue Date FY: 2022 ( Subtotal = $728,276 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	000	3	1/18/2022	NON-COMPETING CONTINUATION	$728,276
														Subtotal = $728,276

Issue Date FY: 2021 ( Subtotal = $678,164 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	001	2	8/30/2021	NON-COMPETING CONTINUATION	$52,248
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	2/1/2021	NON-COMPETING CONTINUATION	$625,916
														Subtotal = $678,164

Issue Date FY: 2020 ( Subtotal = $653,583 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	1/31/2020	NEW	$615,794
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	001	1	5/18/2020	NEW	$37,789
														Subtotal = $653,583

Grand Total All Awards = $3,460,259

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Mechanism of RB-to-EB Conversion in Chlamydia

Award Number: R01AI151212

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: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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