Thursday, November 21, 2024 11/21/2024

Brucella induces STING-mediated Guanylate-Binding Protein expression and Unfolded Protein Response: Balancing Bacterial Elimination, Inflammation and Disease

Award Number: R01AI116453
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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1 Summary 2 Brucellosis is one of the world’s most frequent zoonotic diseases with over 500,000 3 new human infections every year. Human brucellosis in Brazil represents an additional 4 economic burden due to health care costs and has a major social impact due to 5 decreased productivity and quality of life and occasionally incapacitation or death. 6 Brucella abortus strain 19 vaccine is the principal vaccine used to prevent transmission 7 of brucellosis from cattle to humans worldwide and in Brazil and it is not a select agent. 8 The mechanisms that mediate protection by strain 19 are poorly understood. Host 9 mechanisms of innate immunity induced by the vaccine that control infection remain 10 obscure. Additionally, the vaccine contains several properties that are inhibitory to host 11 immunity. We have demonstrated that B. abortus, bacterial DNA and LPS leads to 12 inflammasome activation via STING/GBP (guanylate-binding protein) axis that limits 13 Brucella replication. In contrast, B. abortus induces the Unfolded Protein Response 14 (UPR) that favors Brucella survival in the host. Therefore, our long-term goal is to 15 resolve the black box of how Brucella activates innate immune components that 16 results in host resistance versus bacterial subversion of the immune response. 17 Based on these compelling preliminary data, we propose to test the central hypothesis 18 that Brucella abortus strain 19 activates protective innate immune mediators via 19 STING/GBP pathway and triggers the UPR to secure intracellular replication. Our 20 specific aims are: 1) To define which STING-mediated guanylated-binding proteins 21 (GBPs) are important to release bacterial DNA and LPS into host cells to activate 22 inflammasome receptors; 2) To determine whether the Unfolded Protein 23 Response (UPR) induced by Brucella regulates macrophage polarization to 24 facilitate bacterial persistence; 3) To determine whether the transcription factor 25 HIF-1α-dependent metabolic changes in macrophages induced by Brucella affect 26 inflammasome activation and bacterial clearance. We believe that our approach will 27 shed light on the mechanisms of immunity and/or pathogenesis of this important 28 human and animal pathogen. Finally, the investigators on this proposal have a strong 29 track record in brucellosis research and a unique combination of key expertise in 30 microbiology, innate immunity and cell biology.


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 = $144,676 )
2024	2024	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE				BRA	Allergy and Infectious Diseases Research	000	9	4/24/2024	NON-COMPETING CONTINUATION	$144,676
														Subtotal = $144,676

Issue Date FY: 2023 ( Subtotal = $144,760 )
2023	2023	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG			BRA	Allergy and Infectious Diseases Research	000	8	4/12/2023	NON-COMPETING CONTINUATION	$144,760
														Subtotal = $144,760

Issue Date FY: 2022 ( Subtotal = $149,343 )
2022	2022	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG			BRA	Allergy and Infectious Diseases Research	000	7	5/2/2022	NON-COMPETING CONTINUATION	$144,909
2022	2020	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG			BRA	Allergy and Infectious Diseases Research	001	5	9/23/2022	NON-COMPETING CONTINUATION	$4,434
														Subtotal = $149,343

Issue Date FY: 2021 ( Subtotal = $143,340 )
2021	2021	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG			BRA	Allergy and Infectious Diseases Research	001	6	5/5/2021	COMPETING CONTINUATION	$147,774
2021	2021	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG			BRA	Allergy and Infectious Diseases Research	002	6	9/7/2021	COMPETING CONTINUATION	$0
2021	2020	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG			BRA	Allergy and Infectious Diseases Research	000	5	2/22/2021	NON-COMPETING CONTINUATION	-$4,434
														Subtotal = $143,340

Issue Date FY: 2020 ( Subtotal = $140,535 )
2020	2020	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG	31270-901		BRA	Allergy and Infectious Diseases Research	000	5	12/19/2019	NON-COMPETING CONTINUATION	$140,535
														Subtotal = $140,535

Issue Date FY: 2019 ( Subtotal = $140,612 )
2019	2019	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG	31270-901		BRA	Allergy and Infectious Diseases Research	000	4	12/21/2018	NON-COMPETING CONTINUATION	$140,612
														Subtotal = $140,612

Issue Date FY: 2018 ( Subtotal = $142,180 )
2018	2018	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA	AV. ANTONIO CARLOS 6627, UNID ADM II	BELO HORIZONTE	MG	31270-901		BRA	Allergy and Infectious Diseases Research	000	3	12/19/2017	NON-COMPETING CONTINUATION	$142,180
														Subtotal = $142,180

Issue Date FY: 2017 ( Subtotal = $142,186 )
2017	2017	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA - FUNDEP.	AV. ANTONIO CARLOS 6.627, - 4o ANDAR	BELO HORIZONTE	MG	31270-901		BRA	Allergy and Infectious Diseases Research	000	2	2/2/2017	NON-COMPETING CONTINUATION	$142,186
														Subtotal = $142,186

Issue Date FY: 2016 ( Subtotal = $142,186 )
2016	2016	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA- FUNDEP	AV ANTONIO CARLOS 6627	BELO HORIZONTE 31270				BRA	Allergy and Infectious Diseases Research	001	1	5/13/2016	NEW	$0
2016	2016	FUNDACAO DE DESENVOLVIMENTO DA PESQUISA- FUNDEP	AV ANTONIO CARLOS 6627	BELO HORIZONTE				BRA	Allergy and Infectious Diseases Research	000	1	1/19/2016	NEW	$142,186
														Subtotal = $142,186

Grand Total All Awards = $1,289,818

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Brucella induces STING-mediated Guanylate-Binding Protein expression and Unfolded Protein Response: Balancing Bacterial Elimination, Inflammation and Disease

Award Number: R01AI116453

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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