PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection
Summary: Poly(ADP-ribose) polymerase 1 (PARP1) inhibition improved the ventricular function in Chagas disease (CD). Here, we uncovered that Parp1 depletion enhances cardiac health by regulating CD8+T cell response against Trypanosoma cruzi (Tc) infection. For this, Parp1−/− and wild-type (WT) mice w...
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Elsevier
2025-07-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225011873 |
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| author | Imran H. Chowdhury Nandadeva Lokugamage Nisha J. Garg |
| author_facet | Imran H. Chowdhury Nandadeva Lokugamage Nisha J. Garg |
| author_sort | Imran H. Chowdhury |
| collection | DOAJ |
| description | Summary: Poly(ADP-ribose) polymerase 1 (PARP1) inhibition improved the ventricular function in Chagas disease (CD). Here, we uncovered that Parp1 depletion enhances cardiac health by regulating CD8+T cell response against Trypanosoma cruzi (Tc) infection. For this, Parp1−/− and wild-type (WT) mice were challenged with Tc and euthanized at acute and chronic phases of parasite replication and CD development, respectively. Parp1−/− mice controlled the chronic parasite persistence and associated inflammatory pathology more effectively than WT mice. Parp1−/− enhanced the maturation and stability of metabolically reprogrammed CD8+ effector and memory T cells with increased cytotoxic effects against the parasite. Mechanistically, PARP1 depletion enhanced the NFATc1 translocation to Pdcd1 promoter in CD8+T cells, altered the PD1:PDL1 stoichiometric ratio between CD8+T and antigen-presenting cells, and promoted CD8+T cell longevity and function during chronic Tc infection. We conclude that molecular and chemical inhibitors of PARP1 would offer a potential therapy to arrest CD pathogenesis. |
| format | Article |
| id | doaj-art-d19a7f3ca3084f3eba176a2c25892f49 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-d19a7f3ca3084f3eba176a2c25892f492025-08-20T03:15:22ZengElsevieriScience2589-00422025-07-0128711292610.1016/j.isci.2025.112926PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infectionImran H. Chowdhury0Nandadeva Lokugamage1Nisha J. Garg2Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USA; Corresponding authorDepartment of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USADepartment of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USA; Corresponding authorSummary: Poly(ADP-ribose) polymerase 1 (PARP1) inhibition improved the ventricular function in Chagas disease (CD). Here, we uncovered that Parp1 depletion enhances cardiac health by regulating CD8+T cell response against Trypanosoma cruzi (Tc) infection. For this, Parp1−/− and wild-type (WT) mice were challenged with Tc and euthanized at acute and chronic phases of parasite replication and CD development, respectively. Parp1−/− mice controlled the chronic parasite persistence and associated inflammatory pathology more effectively than WT mice. Parp1−/− enhanced the maturation and stability of metabolically reprogrammed CD8+ effector and memory T cells with increased cytotoxic effects against the parasite. Mechanistically, PARP1 depletion enhanced the NFATc1 translocation to Pdcd1 promoter in CD8+T cells, altered the PD1:PDL1 stoichiometric ratio between CD8+T and antigen-presenting cells, and promoted CD8+T cell longevity and function during chronic Tc infection. We conclude that molecular and chemical inhibitors of PARP1 would offer a potential therapy to arrest CD pathogenesis.http://www.sciencedirect.com/science/article/pii/S2589004225011873molecular biologyimmunologymicrobiologycell biology |
| spellingShingle | Imran H. Chowdhury Nandadeva Lokugamage Nisha J. Garg PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection iScience molecular biology immunology microbiology cell biology |
| title | PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection |
| title_full | PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection |
| title_fullStr | PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection |
| title_full_unstemmed | PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection |
| title_short | PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection |
| title_sort | parp1 nfatc1 pd1 pathway of maturation and stability of cd8 t cells is beneficial against chronic trypanosoma cruzi infection |
| topic | molecular biology immunology microbiology cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225011873 |
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