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Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy

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Chevillard, Christophe [1] ; Nunes, Joao Paulo Silva [2, 3, 4] ; Frade, Amanda Farage [3, 4, 5] ; Almeida, Rafael Ribeiro [2, 3, 4] ; Pandey, Ramendra Pati [2, 3, 4] ; Nascimento, Marilda Savoia [2, 3, 4] ; Kalil, Jorge [2, 3, 4] ; Cunha-Neto, Edecio [2, 3, 4]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Aix Marseille Univ, INSERM UMR 1090, TAGC, Marseille - France
[2] Univ Sao Paulo, Fac Med, Disciplina Imunol Clin & Alergia, Sao Paulo - Brazil
[3] Univ Sao Paulo, Fac Med, Hosp Clin, Lab Imunol, Inst Coracao, Sao Paulo - Brazil
[4] INCT, Inst Invest Immunol III, Sao Paulo - Brazil
[5] Brazil Univ, Dept Bioengn, Sao Paulo - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Citações Web of Science: 3

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi and affects over 8 million people worldwide. In spite of a powerful innate and adaptive immune response in acute infection, the parasite evades eradication, leading to a chronic persistent infection with low parasitism. Chronically infected subjects display differential patterns of disease progression. While 30% develop chronic Chagas disease cardiomyopathy (CCC)-a severe inflammatory dilated cardiomyopathy-decades after infection, 60% of the patients remain disease-free, in the asymptomatic/indeterminate (ASY) form, and 10% develop gastrointestinal disease. Infection of genetically deficient mice provided a map of genes relevant for resistance to T. cruzi infection, leading to the identification of multiple genes linked to survival to infection. These include pathogen resistance genes (PRG) needed for intracellular parasite destruction, and genes involved in disease tolerance (protection against tissue damage and acute phase death-DTG). All identified DTGs were found to directly or indirectly inhibit IFN-gamma production or Th1 differentiation. We hypothesize that the absolute need for DTG to control potentially lethal IFN-gamma PRG activity leads to T. cruzi persistence and establishment of chronic infection. IFN-gamma production is higher in CCC than ASY patients, and is the most highly expressed cytokine in CCC hearts. Key DTGs that downmodulate IFN-gamma, like IL-10, and Ebi3/IL27p28, are higher in ASY patients. Polymorphisms in PRG and DTG are associated with differential disease progression. We thus hypothesize that ASY patients are disease tolerant, while an imbalance of DTG and IFN-gamma PRG activity leads to the inflammatory heart damage of CCC. (AU)

Processo FAPESP: 16/15209-0 - Novas terapias para Doença de Chagas: repurposing (reposicionamento) de drogas com efeito na invasão da célula hospedeira pelo T. cruzi, potenciação do efeito do benzonidazol em cepas resistentes e em modelo de cardiopatia chagásica crônica em hamsters
Beneficiário:Edecio Cunha Neto
Linha de fomento: Auxílio à Pesquisa - Pesquisa em Políticas Públicas para o SUS
Processo FAPESP: 14/50890-5 - INCT 2014: Investigação em Imunologia
Beneficiário:Jorge Elias Kalil Filho
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 13/50302-3 - Identificação de uma assinatura genética preditiva / prognóstica na Doença de Chagas: abordagem de biologia de sistemas
Beneficiário:Edecio Cunha Neto
Linha de fomento: Auxílio à Pesquisa - Regular