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Glutathione depletion in the CNS and its effects on Mtb infection

Award Number: R15HL143545
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Glutathione depletion in the CNS and its effects on Mtb infection - Project Summary: Tuberculous Meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB) and is associated with significant morbidity and mortality in humans worldwide. Individuals with TBM show a marked deficiency in the levels of glutathione (GSH), the principal non-protein thiol responsible for cellular homeostasis and maintaining the intracellular redox balance. Since the current anti-TB regimen is formulated for pulmonary TB, they are not optimal for treating TBM. Thus, adjunctive immunotherapy is a promising approach to improving the clinical outcome of refractory mycobacterial infections in these cases. We have reported that GSH has direct antimycobacterial activity in vitro and at physiological concentrations. In combination with cytokines such as IL-2 and IL-12, GSH enhances the functional activity of natural killer (NK) cells to inhibit the growth of Mycobacterium tuberculosis (Mtb) inside human monocytes. Similarly, GSH activates the functions of T lymphocytes to control Mtb infection inside human monocytes. In our previous R15 award, we demonstrated that GSH deficiency in the lungs resulted in increased Mtb burden in the lungs and spleen. Furthermore, GSH restoration resulted in favorable immune responses in the lungs leading to improved control of Mtb infection. Importantly, we reported that GSH has additive effects in improving the ability of rifampicin (RIF) to control Mtb infection. Put together, our findings 1) unfold a novel and potentially important innate defense mechanism adopted by human macrophages to control Mtb infection and 2) indicate that GSH controls Mtb infection by functioning as an antimycobacterial agent as well as by enhancing the effector functions of immune cells. However, the underlying mechanisms by which GSH deficiency alters the immune responses leading to increased susceptibility to TBM remains unknown, and the potential use of GSH as a possible therapeutic agent for TBM remains untapped. The translational aspect of the studies proposed in this grant application may lay the foundation for the development of adjunctive pharmacotherapy to improve TBM treatment. Our long-term goals are to acquire a detailed understanding of the pathogenesis of TBM in various settings such as in pediatric subjects and in those with HIV infection and develop novel therapies to combat TBM.


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 = $429,000 )
2024	2024	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Lung Diseases Research	001	2	3/26/2024	COMPETING CONTINUATION	$429,000
2024	2019	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Lung Diseases Research	000	1	12/19/2023	NEW	$0
														Subtotal = $429,000

Issue Date FY: 2019 ( Subtotal = $423,000 )
2019	2019	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Lung Diseases Research	000	1	2/27/2019	NEW	$386,934
2019	2019	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Lung Diseases Research	001	1	4/6/2019	NEW	$36,066
														Subtotal = $423,000

Grand Total All Awards = $852,000

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Glutathione depletion in the CNS and its effects on Mtb infection

Award Number: R15HL143545

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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