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Understanding bacterial localization and protein dynamics as indicators during tuberculosis treatment efficacy

Award Number: R03AI137630
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary In order to complement the current sputum based methods of tuberculosis (TB) diagnosis and treatment monitoring, novel assays are required to detect the presence of live Mycobacterium tuberculosis (Mtb) bacilli in patients. The discovery of Mtb-specific protein encapsulation in exosomes released from Mtb-infected macrophage culture was the impetus for exploration of the phenomenon in the exosome fraction of serum; targeted mass spectrometry was applied to confirm the identification of over a dozen Mtb-antigens in exosomes isolated from sputum-confirmed tuberculosis patients. Exosomes are small vesicles released from nucleated cells and are a rich-source of biomarkers. To complement and extent the utility of serum exosomes as markers of treatment efficacy, this proposal focuses on the analysis of ultrapure exosomes using unbiased mass spectrometry (MS) for the discovery of Mtb proteins and their kinetic response in 25 TB patients over 4 points during anti-mycobacterial treatment. Targeted MS assays (MRM) will be used to confirm the proteomic differences. Statistical modeling will be used to determine a proteomic signature consistent with clearance of Mtb from the sputum and will be performed with a training set (n = 256, baseline/treatment pairs) and a validation set (n = 64, baseline/treatment pairs) of serum exosome samples. Ultimately, an Mtb protein signature in serum exosomes can be used in conjunction with sputum diagnostics or when sputum is not available (in children and during treatment when production/cough resolves) and will reflect the elimination of transmissible bacilli in the sputum. In order to translate discoveries to a monitoring assay relevant to treatment monitoring in the clinic our methods must be simplified to a platform independent of mass spectrometry, however for the purpose of pre- clinical animal research MRM-MS remains a feasible option for novel drug and treatment regimen efficacy trials.


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: 2022 ( Subtotal = -$4,722 )
2022	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	4/4/2022	NON-COMPETING CONTINUATION	-$4,722
														Subtotal = -$4,722

Issue Date FY: 2019 ( Subtotal = $76,000 )
2019	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	7/10/2019	NON-COMPETING CONTINUATION	$76,000
														Subtotal = $76,000

Issue Date FY: 2018 ( Subtotal = $76,000 )
2018	2018	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	8/10/2018	NEW	$76,000
														Subtotal = $76,000

Grand Total All Awards = $147,278

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Understanding bacterial localization and protein dynamics as indicators during tuberculosis treatment efficacy

Award Number: R03AI137630

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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