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Host-Directed Therapy to Augment anti-M. tuberculosis Responses in the Setting of HIV Co-infection and to Sterilize the Tuberculoma

Award Number: R01AI134245
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Mycobacterium tuberculosis (Mtb) infection can lead to tuberculosis (TB) disease, causing ~9 million new infections and ~1.8 million deaths globally, every year. A quarter of these are deaths due to the TB/AIDS comorbidity, caused by Mtb/HIV co-infection and the resulting reactivation of LTBI. The resurgence of TB in the last two decades can be attributed to the failure of the anti-TB vaccine, Bacille Calmette-Guerin (BCG) in containing adult, pulmonary TB as well, the emergence of drug-resistance and the AIDS pandemic. The failure to control TB stems from the lack of complete understanding of the virulence and pathogenesis programs utilized by this highly specialized and successful pathogen in order to persist in the lungs of its hosts. As part of its virulence cycle, Mtb modulates host immunity. We have developed a robust macaque model Mtb/HIV co-infection, by using natural routes of Mtb infection and by using Simian Immunodeficiency Virus (SIV) as a surrogate for HIV. This model can be leveraged to study the physiology of Mtb in a true in-vivo setting. Using our model, we show that the expression of IDO (INDO, IDO1), a powerful immunosuppressant of activated CD4+ T cells, is dramatically enhanced in the lung granulomata of macaques. Levels of IDO are induced in a bacterial burden specific manner in myeloid cells. Thus, macaques that control inhaled Mtb infection as LTBI, do not express high levels of IDO in lung lesions, but those that progress to ATB do. IDO levels decline when animals with ATB are chemotherapeutically treated. Upon co-infection with SIV, 2/3rds of the macaques with LTBI reactivate disease - only these animals exhibited lung IDO induction. Finally, nonpathogenic infection with avirulent mutants of Mtb failed to elicit the induction of IDO. Amelioration of IDO enzymatic activity by an FDA, approved, safe compound in-vivo resulted in significant reduction in clinical signs of TB, pathology and bacterial burden, and increased survival. This was accompanied by increased lung T cell proliferation and induction of bronchus associated lymphoid tissue (iBALT). These events reshaped the granuloma is two different ways: i) functionally granulomas from treated (IDO blockaded) animals exhibited no signatures of T cell exhaustion but instead higher expression of T cell differentiation, apoptosis, bacterial killing and lung tissue remodeling pathways; ii) morphologically, greater relocation of T cells was observed to the center of the granulomata. The profoundly better killing of Mtb in macrophages by CD4+ T cells could be modeled in-vitro, in a novel macaque macrophage:CD4+ T cell co- culture system. Our results strongly suggest that IDO modulates a complex immune/metabolic signaling network that promotes bacterial survival, immune dysfunction and disease. Thus, inhibition of IDO is a prime target for adjunctive HDT against the multidrug resistant TB epidemic. Based on these data, we postulate that IDO1-signaling is key to modulating immune responses in human-like lung granulomas. We now propose to leverage the macaque model of LTBI to study if IDO-blockade in-vivo can enhance granuloma performance and sterilize Mtb infection. SIV co-infection will be used to test this. Finally, we will treat Mtb/SIV co-infected animals with a gut homing T cell blocking a4b7 antibody in addition to blockading IDO. We postulate that this dual treatment will reduce the viral load thus preventing reactivation, and enhance the sterilizing potential of IDO blockade.


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 = $0 )
2024	2023	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	7	3/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1,130,921 )
2023	2023	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	002	7	4/14/2023	NON-COMPETING CONTINUATION	$1,130,921
2023	2020	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	5	1/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$851,458
2023	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	3	1/18/2023	NON-COMPETING CONTINUATION	-$851,458
														Subtotal = $1,130,921

Issue Date FY: 2022 ( Subtotal = $1,319,347 )
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	002	6	4/15/2022	NON-COMPETING CONTINUATION	$1,260,778
2022	2020	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	5	1/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,077,090
2022	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	4	1/25/2022	NON-COMPETING CONTINUATION	-$1,018,521
														Subtotal = $1,319,347

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	4	6/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $1,018,521 )
2020	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	4	4/29/2020	NON-COMPETING CONTINUATION	$1,018,521
														Subtotal = $1,018,521

Issue Date FY: 2019 ( Subtotal = $1,149,234 )
2019	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	002	3	3/26/2019	NON-COMPETING CONTINUATION	$916,047
2019	2018	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	004	2	5/2/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2019	2018	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	001	2	1/31/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$866,688
2019	2018	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	1	1/31/2019	NEW	-$633,501
2019	2018	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	003	1	5/2/2019	NEW	-$1
														Subtotal = $1,149,234

Issue Date FY: 2018 ( Subtotal = $640,007 )
2018	2018	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	1	5/16/2018	NEW	$640,007
														Subtotal = $640,007

Grand Total All Awards = $5,258,030

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Host-Directed Therapy to Augment anti-M. tuberculosis Responses in the Setting of HIV Co-infection and to Sterilize the Tuberculoma

Award Number: R01AI134245

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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