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Exploration of the genetic interaction between secreted virulence determinants from pathogenic mycobacteria

Award Number: R21AI142127
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The ESX-1 (ESAT-6 system-1) secretion system is essential for mycobacterial pathogenesis. Yet, the specific role of the ESX-1 secreted proteins (substrates) in protein secretion and virulence remains unclear. Because the inactivation of individual ESX-1 substrate genes reportedly results in the same phenotype, genetic approaches have provided little information regarding the functional roles of ESX-1 substrates. Without understanding the contribution of ESX-1 substrates, the field faces a major hurdle in understanding the mechanisms underlying ESX-1-mediated secretion and virulence. The applicant's long-term goal is to understand the molecular mechanisms underlying mycobacterial protein secretion. The objective of this proposal is to uncover the functional relationships between ESX-1 substrates. The rationale underlying the proposal is that the successful completion of the proposed research will provide basic insight into the relationship between ESX-1 substrates, providing a new framework for understanding ESX-1 secretion. The applicant's lab has uncovered that the deletion of individual ESX-1 substrate genes results in discrete phenotypes that have been previously missed. The central hypothesis of the proposal is that by leveraging the unique secretory phenotypes associated with the deletion of individual and pairs of genes encoding substrates, fundamental but elusive aspects of ESX-1 protein secretion can be defined. The central hypothesis will be tested by these specific aims: 1). Define the requirement of each substrate in ESX-1 secretion. 2) Define the functional relationship between ESX-1 substrates. Under Aim 1, the applicant proposes a quantitative proteomics approach to measure the changes in ESX-1-mediated protein secretion due to the loss of individual ESX-1 substrates. Under Aim 2, the applicant proposes to define genetic relationships between ESX-1 substrates by measuring how pairwise deletion of ESX- 1 substrate genes impacts mycobacterial secretion and virulence. Understanding how individual substrates promote ESX-1 secretion and virulence is significant because it will open new avenues for investigation into how each ESX-1 substrate promotes secretion and virulence, which could inform the treatment and prevention of mycobacterial infections. The proposed research is innovative because it challenges the status quo by providing a means to define discrete phenotypes of and functional relationships between ESX-1 substrates. Collectively, the completion of both aims will advance the field vertically by defining fundamental but elusive features of the mechanistic biology underlying ESX-1 protein secretion.


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 = -$170 )
2024	2020	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	2	1/8/2024	NON-COMPETING CONTINUATION	-$170
														Subtotal = -$170

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	2	12/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $193,125 )
2020	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	2	1/24/2020	NON-COMPETING CONTINUATION	$193,125
														Subtotal = $193,125

Issue Date FY: 2019 ( Subtotal = $231,750 )
2019	2019	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	1	1/29/2019	NEW	$231,750
														Subtotal = $231,750

Grand Total All Awards = $424,705

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Exploration of the genetic interaction between secreted virulence determinants from pathogenic mycobacteria

Award Number: R21AI142127

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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