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Non-tuberculous mycobacterium and B cells in the stimulation of ectopic germinal centers and immunological control of pulmonary tuberculosis

Award Number: K99AI173401
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Non-tuberculous mycobacterium and B cells in the stimulation of ectopic germinal centers and immunological control of pulmonary tuberculosis - Project Summary Human tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis (Mtb) and represents an enormous challenge to global health because of the inadequacy of currently available drugs and vaccines. The most common clinical manifestation is pulmonary TB, and Bacille Calmette Guerin (BCG) is the only licensed vaccine for protection against TB; however, its efficacy is highly variable. Today at least 52 countries have reported multidrug-resistant (MDR) and extensive drug-resistant (XDR) TB cases which cannot be cured or contained by current TB therapy. Thus, there is an urgent need to develop new therapies/vaccines that effectively prevent or cure TB. It is well established that the generation of an adaptive immune response against Mtb occurs inside germinal centers (GCs) in secondary lymphoid organs (SLOs), such as spleen and lesion draining lymph nodes, where antigen‐presenting cells (APCs) and antigen-specific circulating T and B lymphocytes interact, clonally expand, and are disseminated to sites of infection. We found that mice vaccinated with BCG and exposed to Mycobacterium avium [a non-tuberculous mycobacterium (NTM)] via drinking water provide more robust and longer-term protection than BCG alone as determined by reduced Mtb bacterial burden and inflammatory progression of infection. Interestingly, these mice also developed ectopic germinal centers (eGC) in the lungs and have an increased number of B-cells and higher levels of anti-Mtb cell lysate-specific IgA and IgG antibodies. These findings suggest that NTM and B-cells play a critical role in generating protective immunity against pulmonary Mtb infection, and the formation of eGC in these mice is a crucial factor in this improved immunity. Thus, investigating the mechanism of eGC formation and the role of NTM and B-cells in its stimulation is an important question to understand TB pathogenesis and develop effective vaccines and therapies. In this K99/R00 application, we propose three aims: 1) investigating the key differences between eGC in lungs and conventional GCs in lymph nodes, 2) evaluating the role of NTM and B-cells in eGC stimulation, and 3) characterizing the antigen-specificity and affinity of eGC B-cells against Mtb antigens. The results of this proposal will bring us one step closer to understanding the B-cell and antibody-mediated mechanisms of protection from TB.


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 = $0 )
2026	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	1/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $112,360 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	7/19/2024	NON-COMPETING CONTINUATION	$112,360
														Subtotal = $112,360

Issue Date FY: 2023 ( Subtotal = $112,362 )
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	7/28/2023	NEW	$112,362
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	001	1	8/9/2023	NEW	$0
														Subtotal = $112,362

Grand Total All Awards = $224,722

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Non-tuberculous mycobacterium and B cells in the stimulation of ectopic germinal centers and immunological control of pulmonary tuberculosis

Award Number: K99AI173401

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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