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Immunoregulation of cellular immunity and tissue homeostasis during Chagas' disease

Award Number: R01AI169482
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: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Immunoregulation of cellular immunity and tissue homeostasis during Chagas' disease - PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America but cases are increasing in non-endemic countries, becoming a global concern. It affects 6 million people and imposes a major economic burden due to early mortality and physical disabilities. Disease progression, from symptomless to severe, is linked to parasite heterogeneity and a variable host immune response. Development of robust CD8+ T cell immunity is a key element of host resistance and T. cruzi persistence and chronic Chagas disease has been associated to suboptimal CD8+ T cell responses. Despite this, the knowledge about pathways that promote robust protective CD8+ T cell immunity to T. cruzi remains incomplete and for instance, the metabolic hurdles faced by effector CD8+ T cells for expansion and differentiation have been barely explored. Also, the progression of T. cruzi infection is thought to be significantly modulated by regulatory immune responses that limit parasite-specific immunity as well as infection-associated immunopathology by mechanisms poorly understood. In this context, defining how effector and regulatory pathways intertwined to allow the generation of optimal cellular immunity against T. cruzi preserving of tissue homeostasis is crucial to understand Chagas disease pathogenesis. In this direction, our published data showed that Treg cells became activated during T. cruzi infection and acquired phenotypic attributes that markedly changed along the infection. Thus, Treg cells acquired features linked to the regulation of type 1 responses and limited CD8+ T cell immunity during the infection acute phase, likely delaying parasite control and favoring chronicity. In contrast, preliminary data demonstrate that Treg cells with tissue repair ties, which were disfavored during the acute phase, accumulated during the chronic phase in nonlymphoid tissues considered targets of T. cruzi and reduced tissue damage. Altogether, our findings highlight numerous changes in the phenotypic and functional profile as well as main location of specialized Treg cells in the transition from acute to chronic phase, suggesting that Treg cell roles switch from deleterious to protective in the course of this infection. A comprehensive characterization of phenotype, function and transcriptional program of Treg cells in different tissues, together with the manipulation of this regulatory subset by different strategies will allow us to define the mechanisms underlying Treg cell mediated regulation of effector immunity and immunopathology in acute and chronic experimental T. cruzi infection. These approaches will guide our evaluation of effector and regulatory pathways and their association to the clinical severity in samples of patients with chronic Chagas disease in order to translate our finding to human health. Altogether, our studies will provide meaningful data about different interacting pathways and, possibly, new mediators that participate in the regulation of effector cellular immunity to T. cruzi and the development of chronic pathology. This information will identify potential new targets for the rational design of therapies for Chagas´ disease and, likely, other chronic infections.


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 = $133,400 )
2026	2026	CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS	HAYA DE LA TORRE Y MEDINA ALLENDE, CIUDAD UNIVERSITARIA	CORDOBA				ARG	Allergy and Infectious Diseases Research	000	5	4/17/2026	NON-COMPETING CONTINUATION	$133,400
														Subtotal = $133,400

Issue Date FY: 2025 ( Subtotal = $133,800 )
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	4	4/9/2025	NON-COMPETING CONTINUATION	$133,800
														Subtotal = $133,800

Issue Date FY: 2024 ( Subtotal = $133,400 )
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	3	4/15/2024	NON-COMPETING CONTINUATION	$133,400
														Subtotal = $133,400

Issue Date FY: 2023 ( Subtotal = $133,800 )
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	2	3/29/2023	NON-COMPETING CONTINUATION	$133,800
														Subtotal = $133,800

Issue Date FY: 2022 ( Subtotal = $133,400 )
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	1	4/1/2022	NEW	$133,400
														Subtotal = $133,400

Grand Total All Awards = $667,800

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Immunoregulation of cellular immunity and tissue homeostasis during Chagas' disease

Award Number: R01AI169482

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: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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