A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease

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Gomes dos Santos, Alexandra ^[1] ; Watanabe, Elieser Hitoshi ^{[2, 3]} ; Ferreira, Daiane Tomomi ^{[2, 4]} ; Oliveira, Jamille ^[1] ; Nakanishi, Erika Shimoda ^{[2, 4]} ; Oliveira, Claudia Silva ^[1] ; Bocchi, Edimar ^[5] ; Novaes, Cristina Terra Gallafrio ^[6] ; Cruz, Fatima ^[5] ; Carvalho, Noemia Barbosa ^[6] ; Sato, Paula Keiko ^{[2, 4]} ; Yamashiro-Kanashiro, Edite Hatsumi ^{[7, 2, 4]} ; Pontillo, Alessandra ^[8] ; de Freitas, Vera Lucia Teixeira ^{[1, 2, 4]} ; Onuchic, Luiz Fernando ^{[2, 3]} ; Shikanai-Yasuda, Maria Aparecida ^{[1, 2, 4]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Dept Infect & Parasit Dis, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Dept Med, Div Nephrol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med, Dept Med, Div Mol Med, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Hosp Clin, Lab Immunol LIM 48, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Fac Med, Hosp Clin, Heart Inst, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Fac Med, Hosp Clin, Div Infect Dis, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Inst Med Trop, Sao Paulo - Brazil

^[8] Univ Sao Paulo, Inst Ciencias Biomed ICB, Dept Immunol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 11, OCT 22 2020.
• Citações Web of Science: 0

Resumo

Background Chagas disease caused by Trypanosoma cruzi (T. cruzi) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between IL1B, IL6, IL17A, or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy. Methods Two hundred twenty-six patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR. Results Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24-0.86, P = 0.015). Original findings included associations between IL17A rs2275913 AA and IL18 s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07-0.97, P = 0.044; and OR = 0.35, 95% CI 0.14-0.87, P = 0.023, respectively). IL18 rs1946518 AA and IL1B rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class >= 2 (OR = 0.21, 95% CI 0.06-0.68, P = 0.009; and OR = 0.48, 95% CI 0.24-0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) <45% for IL18 rs1946518 AA (OR = 0.22, 95% CI 0.05-0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23-0.96, P = 0.039), NYHA class >= 2 (OR = 0.15, 95% CI 0.06-0.39, P < 0.001), and LVEF < 45% (OR = 0.03, 95% CI 0.00-0.25, P = 0.001). Digestive involvement was negatively associated with NYHA >= 2 and LVEF < 45% (OR = 0.20, 95% CI 0.09-0.47, P < 0.001; and OR = 0.24, 95% CI 0.09-0.62, P = 0.004, respectively). Conclusions Our data support a protective role of IL17A AA, IL18 AA, and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies. (AU)

• Processo FAPESP: 19/06363-4 - Efeito modulador de TORID sobre a ativação patológica do inflamassoma: uma abordagem genética
• Beneficiário: Alessandra Pontillo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/50273-0 - Monitoramento de pacientes imunodeprimidos com Doenças de Chagas: níveis de parasitemia e associação com o perfil, poliformismo de citonas sobrevidas e características dos isolados Trypanosoma cruzi em transplante de órgãos, uso de drogas imunossupressoras e co-infecção com o vírus da imunodeficiência humana
• Beneficiário: Maria Aparecida Shikanai Yasuda
• Modalidade de apoio: Auxílio à Pesquisa - Regular