{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T01:42:29Z","timestamp":1783129349503,"version":"3.54.6"},"reference-count":60,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Programa de Apoyo a Proyectos de Investigaci\u00f3n e Innovaci\u00f3n Tecnol\u00f3gica (PAPIIT)","award":["IN 218119"],"award-info":[{"award-number":["IN 218119"]}]},{"name":"Programa de Apoyo a Proyectos de Investigaci\u00f3n e Innovaci\u00f3n Tecnol\u00f3gica (PAPIIT)","award":["IN 214522"],"award-info":[{"award-number":["IN 214522"]}]},{"name":"Divisi\u00f3n de Investigaci\u00f3n, Facultad de Medicina, UNAM","award":["IN 218119"],"award-info":[{"award-number":["IN 218119"]}]},{"name":"Divisi\u00f3n de Investigaci\u00f3n, Facultad de Medicina, UNAM","award":["IN 214522"],"award-info":[{"award-number":["IN 214522"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>L-arginine metabolism through arginases and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of Chagas disease. Infection with Trypanosoma cruzi can cause a wide spectrum of disease, ranging from acute forms contained by the host immune response to chronic ones, such as the chronic chagasic cardiomyopathy. Here, we analyzed, in an in vitro model, the ability of two T. cruzi isolates, with different degrees of virulence, to regulate the metabolism of L-arginine through arginase 1 (Arg-1) and NOS2 in macrophages and through arginase 2 (Arg-2) and NOS2 in cardiomyocytes. Stimulation of bone marrow-derived macrophages (BMM\u03a6), obtained from CD1 mice, with TNF-\u03b1 + IFN-\u03b3 induced their polarization into classically activated macrophages (CAM\u03a6), which expressed functional NOS2, while stimulation with IL-4 induced their polarization into alternatively activated macrophages (AAM\u03a6), which expressed functional Arg-1. Interestingly, stimulation of cardiomyocytes, obtained from hearts of CD1 neonatal mice, with TNF-\u03b1 + IFN-\u03b3 or IL-4 also resulted in functional NOS2 and arginase expression, as observed in CAM\u03a6 and AAM\u03a6, but Arg-2 was the arginase isoform expressed instead of Arg-1. We observed that infection of BMM\u03a6 with the more virulent T. cruzi isolate (QRO) importantly diminished NOS2 expression and nitric oxide (NO) production in CAM\u03a6, allowing parasite survival, while infection with the less virulent isolate (CI2) did not diminish NOS2 activity and NO production in CAM\u03a6 to a great extent, which resulted in parasite killing. Regarding Arg-1, infection of BMM\u03a6 with the QRO isolate significantly induced Arg-1 expression and activity in AAM\u03a6, which resulted in a higher parasite load than the one in the unstimulated BMM\u03a6. Even though infection with CI2 isolate did not increase Arg-1 expression and activity in AAM\u03a6, the parasite load was higher than the one in the unstimulated BMM\u03a6 but at a lesser magnitude than that observed during infection with the QRO isolate. On the other hand, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with TNF-\u03b1 + IFN-\u03b3 inhibited NOS2 expression and NO production, leading to amelioration of infection. Surprisingly, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with IL-4 strongly inhibited Arg-2 expression and function, which resulted in parasite loads similar to those observed in unstimulated cardiomyocytes. Our results suggest that T. cruzi isolates that exhibit variable virulence or pathogenicity degrees differentially regulate L-arginine metabolism through Arg-1\/2 and NOS2 in macrophages and cardiomyocytes.<\/jats:p>","DOI":"10.3390\/pathogens13100878","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T12:02:10Z","timestamp":1728388930000},"page":"878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Differential Regulation of L-Arginine Metabolism through NOS2 and Arginases during Infection with Trypanosoma cruzi"],"prefix":"10.3390","volume":"13","author":[{"given":"Arturo A.","family":"Wilkins-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Unidad de Investigaci\u00f3n UNAM-INC, Divisi\u00f3n de Investigaci\u00f3n, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico-Instituto Nacional de Cardiolog\u00eda \u201cIgnacio Ch\u00e1vez\u201d, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8490-5293","authenticated-orcid":false,"given":"Paz Mar\u00eda","family":"Salazar-Schettino","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda de Par\u00e1sitos, Departamento de Microbiolog\u00eda y Parasitolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeca G.","family":"Manning-Cela","sequence":"additional","affiliation":[{"name":"Departamento de Biomedicina Molecular, Centro de Investigaci\u00f3n y de Estudios Avanzados del IPN, Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4414-6437","authenticated-orcid":false,"given":"Laila","family":"Guti\u00e9rrez-Kobeh","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n UNAM-INC, Divisi\u00f3n de Investigaci\u00f3n, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico-Instituto Nacional de Cardiolog\u00eda \u201cIgnacio Ch\u00e1vez\u201d, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lidani, K.C.F., Andrade, F.A., Bavia, L., Damasceno, F.S., Beltrame, M.H., Messias-Reason, I.J., and Sandri, T.L. 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