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TLR2 and the Tubercle Granuloma

Award Number: R01AI084822
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: 03/01/2011
PERIOD OF PERFORMANCE END DATE: 02/29/2016

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TLR2 and the Tubercle Granuloma - In this application we will explore the hypothesis that Toll-like receptor 2 (TLR2) is the master regulator controlling both protective and pathologic features of the tubercle granuloma. The hypothesis builds on novel findings made in our laboratory. Previously we had reported that TLR9 and TLR2 induce pro- and anti-inflammatory cytokines, respectively, in M. tuberculosis (Mtb)-infected dendritic cells (DCs), while TLR2 induces both pro- and anti-inflammatory cytokines in infected macrophages. A reasonable prediction, based on these observations, is that during Mtb infection the innate anti-inflammatory response triggered by TLR2 may control the magnitude of Th1 effector and memory T cell activation. Contrary to expectation, we found that the absence of TLR2 did not affect the magnitude of the Th1 effector response generated following aerosol infection with Mtb or the induction of recall Th1 memory immunity in response to Mtb challenge. However, the consequence of TLR2 absence to host resistance was manifested at the level of the granuloma. The infected lungs of TLR2KO mice exhibited enhanced inflammation associated with reduced infiltration of FoxP3[+] T regulatory cells (Tregs) into the lung, while lungs from infected WT animals had resolved their inflammation and had small, compact granulomas. Tregs have been shown to thwart host antimicrobial responses against persistent pathogens. Surprisingly, despite the absence of Tregs, lungs from chronically-infected TLR2KO mice exhibited enhanced bacterial burden and loss of granuloma integrity in comparison with infected WT mice indicating a hitherto under-appreciated role for TLR2 in controlling antimicrobial responses in vivo in the granuloma. Preliminary gene expression studies point to the role of TLR2-induced matrix metaloproteinases in regulating granuloma maturation. The following specific hypotheses will be tested in the proposal: i) TLR2-induced MMPs regulate granuloma maturation; ii)TLR2 is essential for macrophage control of Mtb replication and containment within the granuloma; iii) TLR2 induces Tregs which operate primarily as inhibitors of lung immune pathology but not as inhibitors of macrophage antimicrobial responses; iv) TLR2-triggers two distinct signaling pathways for the induction of pro- and anti-inflammatory cytokine production within Mtb- infected macrophages, and v) the signaling pathways cross-regulate each other and Mtb can maneuver the pathways to its own benefit. The collective findings from the proposed studies will provide insights into TLR2-triggered signaling pathways in the tubercle granuloma and unique ways in which they can be manipulated therapeutically.


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: 2018 ( Subtotal = $0 )
2018	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	6	2/1/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	6	1/12/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $397,500 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	6	1/30/2015	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2014 ( Subtotal = $397,500 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	003	5	3/19/2014	NON-COMPETING CONTINUATION	$39,750
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	5	2/7/2014	NON-COMPETING CONTINUATION	$357,750
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	3	1/29/2014	NON-COMPETING CONTINUATION	$16,412
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	4	1/29/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$16,412
														Subtotal = $397,500

Issue Date FY: 2013 ( Subtotal = $370,505 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	3	6/4/2013	NON-COMPETING CONTINUATION	$15,600
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	2/7/2013	NON-COMPETING CONTINUATION	$351,000
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	004	3	1/29/2014	NON-COMPETING CONTINUATION	$16,412
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	3	8/15/2013	NON-COMPETING CONTINUATION	-$203,064
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Allergy and Infectious Diseases Research	005	4	1/29/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$16,412
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Allergy and Infectious Diseases Research	003	4	8/16/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$206,969
														Subtotal = $370,505

Issue Date FY: 2012 ( Subtotal = $390,000 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	2/24/2012	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2011 ( Subtotal = $195,000 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	2/18/2011	NEW	$195,000
														Subtotal = $195,000

Grand Total All Awards = $1,750,505

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TLR2 and the Tubercle Granuloma

Award Number: R01AI084822

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: 03/01/2011

PERIOD OF PERFORMANCE END DATE: 02/29/2016

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