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Mathematical modeling of Mycobacterium tuberculosis dissemination

Award Number: R01AI158963
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/22/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Mathematical modeling of Mycobacterium tuberculosis dissemination - Research Summary Tuberculosis (TB), a disease caused by the bacteria Mycobacterium tuberculosis (Mtb), remains a major infec- tious disease of humans in the world. After the initial local infection of one site in the lung Mtb somehow dissem- inates in the lung and often spreads beyond the lung. In fact, extrapulmonary TB is a hallmark of the disease in young children and immunocompromised adults that is difﬁcult to diagnose and treat. Our understanding of Mtb dissemination, both within the lung and beyond, remains limited, however. In this proposal we assembled a team of scientists with expertise in computational biology (Ganusov, Aitchison, Duffy, Langston) and TB pathogenesis (Urdahl, Sherman, Behar) to provide quantitative understanding of mechanisms of Mtb dissemination the lung and systemically. To this end, we will be using a number of highly innovative techniques such as i) a novel animal model of TB: infection of mice with an ultra low dose (ULD, 1-3 colony forming units, CFU) of Mtb along with a set of 50 barcoded Mtb strains, ii) an Mtb strain H37Rv-pBP10 with the replication clock plasmid, allowing to estimate how quickly bacteria are eliminated in vivo, and iii) mRNA-based gene signatures predicting bacterial numbers in murine lungs and TB disease progression risk in humans. With three complementary speciﬁc aims we will pro- vide detailed, quantitative understanding of fundamental processes of how Mtb disseminates from the deposition in lung alveoli to the whole lung and systemically. In Aim 1 we will determine the pathway of Mtb dissemination within the lung using a novel model of ULD-infected mice that mimics better human infection than many other animal models. In particular, we will discriminate between alternative hypotheses of Mtb spread in the lungs such the “bubble model” (in which Mtb spreads locally between lung lobes) and the “reseeding model” (in which Mtb spreads hematogenously to different parts of the lung after disseminating systemically). In Aim 2 we will determine the contribution of different cell populations, including Mtb-speciﬁc CD4 T cell response, to kinetics of Mtb dissemination systemically in mice infected with conventional doses (CD, 150 CFU) of Mtb. To parameterize best ﬁt models we will use data from experiments with Mtb H37Rv carrying the replication clock plasmid pBP10. Finally, in Aim 3 we will attempt to improve on our recently derived mRNA-based gene signatures predicting CFU in murine lungs using cutting-edge graph theory-based methods of data dimensionality reduction. We will also perform experiments and deﬁne a new signature predicting disseminated TB in mice, and test its accuracy using data from monkeys and humans. Taken together, by combining experimental data from highly innovative experiments involving novel techniques (ultra low dose infections, barcoded strains, replication clock plasmid, microarray-based gene signatures) we will provide a quantitative understanding of how Mtb disseminates in the lung and systemically in the body.


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: 2026 ( Subtotal = $685,991 )
2026	2026	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	5	3/31/2026	NON-COMPETING CONTINUATION	$685,991
														Subtotal = $685,991

Issue Date FY: 2025 ( Subtotal = $678,174 )
2025	2025	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	4	5/1/2025	NON-COMPETING CONTINUATION	$678,174
														Subtotal = $678,174

Issue Date FY: 2024 ( Subtotal = $634,089 )
2024	2024	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	004	3	7/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$494,103
2024	2024	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	3/13/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$575,582
2024	2024	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	002	3	5/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$58,507
2024	2023	UNIVERSITY OF TENNESSEE	201 ANDY HOLT TOWER	KNOXVILLE	TN	37996	KNOX	USA	Allergy and Infectious Diseases Research	003	2	7/25/2024	NON-COMPETING CONTINUATION	-$494,103
2024	2023	UNIVERSITY OF TENNESSEE	201 ANDY HOLT TOWER	KNOXVILLE	TN	37996	KNOX	USA	Allergy and Infectious Diseases Research	000	2	3/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $634,089

Issue Date FY: 2023 ( Subtotal = $570,739 )
2023	2023	UNIVERSITY OF TENNESSEE	201 ANDY HOLT TOWER	KNOXVILLE	TN	37996	KNOX	USA	Allergy and Infectious Diseases Research	000	2	2/28/2023	NON-COMPETING CONTINUATION	$570,739
														Subtotal = $570,739

Issue Date FY: 2022 ( Subtotal = $591,637 )
2022	2022	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Allergy and Infectious Diseases Research	000	1	4/22/2022	NEW	$591,637
														Subtotal = $591,637

Grand Total All Awards = $3,160,630

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Mathematical modeling of Mycobacterium tuberculosis dissemination

Award Number: R01AI158963

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/22/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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