title: Perforin-expressing cytotoxic cells contribute to chronic cardiomyopathy in Trypanosoma cruzi infection.
abstract: Understanding the dual participation of the immune response in controlling the invader and at the same time causing tissue damage might contribute to the design of effective new vaccines and therapies for Chagas disease. Perforin, a cytolytic protein product of killer cells, is involved in resistance to acute Trypanosoma cruzi infection. However, the contribution of perforin in parasite control and chronic chagasic cardiomyopathy is unclear. Perforin-positive cells were detected in the heart tissue during the acute and chronic phases of infection of C57BL/6 mice inoculated with low dose (10(2) parasites) of the Colombian T. cruzi strain. This protocol led to acute phase survival in both wild-type and perforin null (pfp(-/-)) mice lineages. During the chronic infection, parasitism and inducible nitric oxide synthase (iNOS) as well as interleukin (IL)-4+ and, mainly, interferon (IFN)-gamma+ cells were more elevated in the heart tissue of pfp(-/-) mice. Higher levels of circulating NO and anti-parasite immunoglobulin (Ig)G2c and IgG3, paralleled by a prominent frequency of IFN-gamma+ and IL-10+ splenocytes, were present in pfp(-/-)-infected mice. Therefore, although the perforin-dependent pathway plays a role, it is not crucial for anti-T. cruzi immunity and acute phase survival of mice infected with a low inoculum. Further, perforin deficiency resulted in lower activity of creatine kinase-muscle brain isoform (CK-MB) isoenzyme in serum and a more restricted connexin 43 loss, both of which are markers of the cardiomyocyte lesion. Moreover, perforin deficiency hampered the development of severe electrocardiographic abnormalities. Hence, our results corroborate that perforin-bearing cytotoxic cells might contribute to cardiomyocyte lesion and heart dysfunction during chronic T. cruzi infection, shedding light on immunopathogenesis of chronic chagasic cardiomyopathy.
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Jaline Coutinho
authors.initials: JC
authors.lastname: Silverio
authors.forename: Luzia Maria
authors.initials: LM
authors.lastname: de-Oliveira-Pinto
authors.forename: Andréa Alice
authors.initials: AA
authors.lastname: da Silva
authors.forename: Gabriel Melo
authors.initials: GM
authors.lastname: de Oliveira
authors.forename: Joseli
authors.initials: J
authors.lastname: Lannes-Vieira
mesh_terms: D000208:Acute Disease; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000276:immunology* / Q000469:parasitology / Q000503:physiopathology / Q000517:prevention & control; D002908:Chronic Disease; D018031:Connexin 43 / Q000378:metabolism; D052279:Creatine Kinase, MB Form / Q000097:blood; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology* / Q000469:parasitology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000469:parasitology; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D000913:Antibodies, Protozoan; D018031:Connexin 43; C543076:GJA1 protein, mouse; D007074:Immunoglobulin G; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D052279:Creatine Kinase, MB Form