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Antibody-secreting Cells in the Outcome of Trypanosoma cruzi Infection

Award Number: R01AI116432
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: 05/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Antibody-secreting Cells in the Outcome of Trypanosoma cruzi Infection - PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the parasite Trypanosoma cruzi, affects 6 million people and has a major economic impact due to early mortality and physical disabilities. It is endemic in Latin America but has become a global public health concern following the migration of infected people. Disease progression that varies from symptomless to severe, has been linked to both parasite heterogeneity and host-related immunity. Parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Understanding components of host immunity will be crucial to the comprehension of pathogenesis and will allow design of novel therapeutics. The acute phase of Chagas disease results in polyclonal B cell activation that may be related to the important early extrafollicular plasmablast (EF-PB) response that precedes germinal center (GC) reactions. In this direction, the source of polyreactive antibodies (Abs) was not clearly identified. We initially considered that this polyclonal B cell response would restrict anti-parasite responses. However, we observed that EF-PB produce parasite-specific Abs of different isotypes and that signals via BCR, in some way, condition PB generation which requires the participation of T follicular helper (Tfh) cells. Also, the EF-PB are the main source of IL-17 in T. cruzi infected mice and a fraction of them produce IL-6 and other cytokines and express molecules related to antigen presentation. Of note, IL-17 produced by B cells/PB was shown to be key to sustain CD8+T cell activity and survival. Finally, we determined that PB from T. cruzi infected mice express high levels of the ectoenzyme CD39, higher than T cells, which combined with CD73 hydrolyze exogenous ATP to adenosine which plays immunomodulatory functions. The absence of PB in early T. cruzi infection significantly increases the parasitemia, but on the other side, favors the earlier appearance of GC and increases the frequency of TNF+IFN+ T cells suggesting a controversial role of PB. Our findings are particularly timely given reports describing poor clinical outcomes in Covid19 associated with high PB responses. Altogether, the results support our hypothesis that early EF-PB from T. cruzi infected mice have parasite control capacity and can condition disease outcome. We are focused at further characterizing these EF-PB cell population/s to determine their heterogeneity as well as its contribution to protection or pathogenicity. Using different strategies such as single-cell RNAseq, analysis of somatic hypermutation, identification of antigen-specificity and affinity we will perform detailed characterizations of EF-PB in T. cruzi infected mice. By using genetically modified mice, co- culture experiments and mixed bone marrow chimeras we will be able to delineate the role of EF-PB and CD39 in conditioning humoral as well as cellular responses in experimental Chagas disease. The identification of the EF-PB characteristics and roles will be of great significance for the development of new strategies aiming at the therapeutic targeting of B cells in the clinic. For instance, this innovative approach could provide information required to develop an effective vaccine against T. cruzi.


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: 2025 ( Subtotal = $132,888 )
2025	2025	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA				ARG	Allergy and Infectious Diseases Research	000	9	5/1/2025	NON-COMPETING CONTINUATION	$132,888
														Subtotal = $132,888

Issue Date FY: 2024 ( Subtotal = $133,920 )
2024	2024	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA				ARG	Allergy and Infectious Diseases Research	000	8	4/22/2024	NON-COMPETING CONTINUATION	$133,920
														Subtotal = $133,920

Issue Date FY: 2023 ( Subtotal = $133,320 )
2023	2023	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA	CORDOBA			ARG	Allergy and Infectious Diseases Research	000	7	4/12/2023	NON-COMPETING CONTINUATION	$133,320
2023	2019	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA	CORDOBA			ARG	Allergy and Infectious Diseases Research	001	5	6/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $133,320

Issue Date FY: 2022 ( Subtotal = $133,000 )
2022	2022	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA	CORDOBA			ARG	Allergy and Infectious Diseases Research	000	6	4/26/2022	COMPETING CONTINUATION	$133,000
														Subtotal = $133,000

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA	CORDOBA			ARG	Allergy and Infectious Diseases Research	000	5	4/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $133,080 )
2019	2019	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA	CORDOBA	X5000		ARG	Allergy and Infectious Diseases Research	000	5	5/1/2019	NON-COMPETING CONTINUATION	$133,080
														Subtotal = $133,080

Issue Date FY: 2018 ( Subtotal = $133,960 )
2018	2018	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA	CORDOBA	X5000		ARG	Allergy and Infectious Diseases Research	000	4	4/12/2018	NON-COMPETING CONTINUATION	$133,960
														Subtotal = $133,960

Issue Date FY: 2017 ( Subtotal = $133,080 )
2017	2017	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA	CORDOBA	X5000		ARG	Allergy and Infectious Diseases Research	000	3	4/11/2017	NON-COMPETING CONTINUATION	$133,080
														Subtotal = $133,080

Issue Date FY: 2016 ( Subtotal = $133,080 )
2016	2016	CENTRO DE INVESTIGACIONES EN BIOQUIMICA CLINICIA E INMU	HAYA DELA TORRE Y MEDINA	BUENOS AIRES				ARG	Allergy and Infectious Diseases Research	000	2	4/15/2016	NON-COMPETING CONTINUATION	$133,080
														Subtotal = $133,080

Issue Date FY: 2015 ( Subtotal = $133,800 )
2015	2015	CENTRO DE INVESTIGACIONES EN BIOQUIMICA CLINICIA E INMU	HAYA DELA TORRE Y MEDINA	BUENOS AIRES				ARG	Allergy and Infectious Diseases Research	000	1	4/24/2015	NEW	$133,800
														Subtotal = $133,800

Grand Total All Awards = $1,200,128

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Antibody-secreting Cells in the Outcome of Trypanosoma cruzi Infection

Award Number: R01AI116432

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: 05/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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