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Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects

Award Number: F30HL151136
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/22/2020
PERIOD OF PERFORMANCE END DATE: 05/18/2024

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Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects - ABSTRACT This proposal will determine the mechanism responsible for Granzyme A (GzmA)-mediated inhibition of Mycobacterium tuberculosis (Mtb) growth, to better understand the host immune response. One fourth of the world’s population is infected with Mtb. Currently, BCG strains are the only vaccines available to protect against tuberculosis (TB). γ9δ2 T cells are found at higher frequencies in lungs, which is the primary site of Mtb infection. Our lab has previously shown that TB specific γ9δ2 T cells secrete GzmA upon stimulation with mycobacterial antigens. Furthermore, our lab has demonstrated that GzmA, when released by TB-specific γδ T cells, inhibits the intracellular replication of the pathogen. GzmA is a serine protease found within cytotoxic granules of NK cells, CD8+ CTL, and γδ T cells. It has tryptase activity cleaving basic residues after Arg or Lys, and was originally thought to be an inducer of apoptosis in the target cell in a perforin-dependent manner similar to Granzyme B. However, more recent literature has shown that GzmA at a physiologic concentration (nM) does not cause apoptosis. Instead, it induces monocytes/macrophages to produce pro-inflammatory cytokines. Our lab has shown that GzmA in a perforin-independent manner induces the infected macrophage to secrete pro-inflammatory cytokines, such as TNF-alpha and IL-1β, and inhibits the intracellular growth of mycobacteria. A transcriptomal analysis was performed, which failed to identify the mechanism of GzmA- mediated inhibition. We hypothesize that given the proteolytic nature of GzmA, a rational approach to investigate this mechanism would be to perform a proteomic analysis. GzmA route of entry and enzyme catalysis will be studied in Aim 1 to better understand the necessary steps for inhibition. In Aim 2, the Endoplasmic Reticulum (ER) stress response and purinergic channel activation will be interrogated: these two pathways were discovered during preliminary proteomic experiments, and will be modulated by knocking out genes or inhibiting key factors in cell lines and/or primary cells. Finally, additional global proteomic screens will be conducted to detect other differentially expressed proteins in Aim 3. Overall, this project will help in the design of novel immunotherapeutic and/or chemotherapeutic solutions for TB protection and will aid the WHO’s current goal to decrease TB deaths of 90% by 2030. A proposed comprehensive training plan includes these exciting studies that will allow me to develop needed skills for my career goal to become a successful independent physician-scientist.


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 = -$2,603 )
2025	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Lung Diseases Research	000	4	3/25/2025	NON-COMPETING CONTINUATION	-$2,603
														Subtotal = -$2,603

Issue Date FY: 2024 ( Subtotal = -$4,750 )
2024	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Lung Diseases Research	000	4	7/10/2024	NON-COMPETING CONTINUATION	-$4,750
														Subtotal = -$4,750

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Lung Diseases Research	000	4	7/21/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Lung Diseases Research	000	3	7/20/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $31,464 )
2021	2021	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Lung Diseases Research	000	2	7/6/2021	NON-COMPETING CONTINUATION	$31,464
														Subtotal = $31,464

Issue Date FY: 2020 ( Subtotal = $30,948 )
2020	2020	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Lung Diseases Research	001	1	7/22/2020	NEW	$0
2020	2020	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Lung Diseases Research	000	1	7/22/2020	NEW	$30,948
														Subtotal = $30,948

Grand Total All Awards = $159,505

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Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects

Award Number: F30HL151136

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/22/2020

PERIOD OF PERFORMANCE END DATE: 05/18/2024

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