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The Bacterial Genetic Basis of Bone Disease and Dissemination in Mycobacterial Infection: Roles of ESX-5 Secreted WXG Effectors

Award Number: R01AI127715
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mycobacterium tuberculosis (Mtb) remains a leading cause of infectious death worldwide. Although tuberculosis generally remains confined to the lung, pathogenic mycobacteria also can disseminate to other tissues, resulting in some of the most dangerous manifestations of the infection. The interplay of bacterial and host factors that contribute to dissemination is incompletely understood. Beginning with an outbreak strain presenting with high rates of extrapulmonary dissemination and an extremely high rate of tuberculous bone disease, we identified a full-length vavriant of the Type VII secretion system substrate EsxM as an important component of the clinical phenotype. EsxM was intact in the outbreak strain and so-called “ancestral lineages” but truncated in modern Mtb strains. The active version of EsxM modulates the motility of infected macrophages leading to dissemination, but has been compromised in “modern-lineage” Mtb strains. The work proposed here will 1) interrogate the mechanisms by which the bacterial secreted effector EsxM modulates the behavior of infected macrophages; 2) identify how EsxM and its closely related paralogs are regulated in the bacteria during infection, including investigating non-redundant roles for the closely-related paralogs; and 3) translate these findings into murine and zebrafish models of dissemination and bone disease. These studies will provide insights into the bacterial genetic regulators of dissemination of infection, a fundamentally important question in our understanding of tuberculosis and other infectious diseases.


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 = $520,238 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	6	11/1/2024	NON-COMPETING CONTINUATION	$520,238
														Subtotal = $520,238

Issue Date FY: 2024 ( Subtotal = $536,328 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	5	9/3/2024	COMPETING CONTINUATION	$53,632
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	12/13/2023	COMPETING CONTINUATION	$482,696
														Subtotal = $536,328

Issue Date FY: 2023 ( Subtotal = -$35 )
2023	2020	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	4	8/29/2023	NON-COMPETING CONTINUATION	-$35
														Subtotal = -$35

Issue Date FY: 2020 ( Subtotal = $435,628 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	4	8/19/2020	NON-COMPETING CONTINUATION	$435,628
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	5/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $435,628

Issue Date FY: 2019 ( Subtotal = $435,628 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	8/7/2019	NON-COMPETING CONTINUATION	$435,628
														Subtotal = $435,628

Issue Date FY: 2018 ( Subtotal = $435,628 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	6/22/2018	NON-COMPETING CONTINUATION	$435,628
														Subtotal = $435,628

Issue Date FY: 2017 ( Subtotal = $432,448 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	8/15/2017	NEW	$432,448
														Subtotal = $432,448

Grand Total All Awards = $2,795,863

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The Bacterial Genetic Basis of Bone Disease and Dissemination in Mycobacterial Infection: Roles of ESX-5 Secreted WXG Effectors

Award Number: R01AI127715

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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