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Free Radic Biol Med ; 129: 227-236, 2018 12.
Article in English | MEDLINE | ID: mdl-30248443

ABSTRACT

Elderly organisms are more susceptible to infectious diseases. However, the impact of aging on antiparasitic mechanisms, especially the nitric oxide pathway, is poorly understood. Using an integrated in vivo and in vitro model, we compared the severity of Trypanosoma cruzi infection in young and elderly (8 or 72 weeks old) mice. Forty C57BL/6 mice were randomized into four groups: Y-inf, young infected; Yn-inf, young uninfected; A-inf, aged infected; An-inf, aged uninfected. Parasitemia was measured daily, and animals were euthanized after 15 days of infection. Trypanosoma cruzi-induced inflammatory processes were analyzed in blood and heart samples, as well as in bone marrow-derived macrophages (BMDMs) co-cultured with splenocytes isolated from young or elderly mice. Our results indicated upregulated IgG2b and IL-17 production in elderly animals, which was not sufficient to reduce parasitemia, parasitic load and myocarditis to levels observed in young animals. The higher susceptibility of elderly mice to T. cruzi infection was accompanied by reduced cardiac inducible nitric oxide synthase (iNOS) gene expression, nitric oxide (NO) and IFN-γ levels, as well as an antagonistic upregulation of arginase-1 expression and arginase activity. The same responses were observed when BMDMs co-cultured with splenocytes from elderly mice were stimulated with T. cruzi antigens. Our findings indicate that elderly mice were more susceptible to T. cruzi infection, which was potentially related to an attenuated response to antigenic stimulation, inhibition of iNOS gene expression and NO production, and antagonistic upregulation of arginase gene expression and activity, which created favorable conditions for heart parasitism and myocarditis development.


Subject(s)
Aging/genetics , Arginase/genetics , Chagas Cardiomyopathy/genetics , Chagas Disease/genetics , Nitric Oxide Synthase Type II/genetics , Parasitemia/genetics , Trypanosoma cruzi/pathogenicity , Aging/immunology , Animals , Antigens, Protozoan/pharmacology , Arginase/blood , Chagas Cardiomyopathy/immunology , Chagas Cardiomyopathy/parasitology , Chagas Disease/immunology , Chagas Disease/parasitology , Coculture Techniques , Gene Expression Regulation , Heart/parasitology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Immunoglobulin G/blood , Immunoglobulin G/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interleukin-10/blood , Interleukin-10/genetics , Interleukin-17/blood , Interleukin-17/genetics , Macrophages/drug effects , Macrophages/immunology , Macrophages/parasitology , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/blood , Parasitemia/immunology , Severity of Illness Index , Signal Transduction , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/parasitology , Trypanosoma cruzi/immunology
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