The role of inflammasome in the clinical progression of chronic Chagas disease

01.01.2020 bis 31.12.2021

Chagas disease (CD), caused by Trypanosoma cruzi, is considered the parasitic disease with the highest socioeconomic impact in Latin America. According to the World Health Organization, there are 6-8 million people infected in the world, and the international movement of people contributed to CD become emerging in non-endemic regions (Europe and USA). Although most individuals remain in the asymptomatic form throughout life, 2-5% of the patients progress each year to one of the symptomatic forms: cardiomyopathy, mega-digestive syndromes, or both. Up to date, there are no markers capable of indicating which patients will progress from the asymptomatic to the symptomatic forms, which makes CD a great concern in the international public health scenario. Although the mechanisms involved in the pathogenesis of CD are unclear, the development and severity of the disease are associated with immune-mediated mechanisms that facilitate the maintenance of latent infections, maintaining a balance between the immune response of host and survival of the parasite. Among the components of innate immunity that can act in the pathophysiology of CD, the inflammasome is a multiprotein intracellular complex responsible for promoting the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18. As an important component in the inflammasome complex, there is a set of NRLP receptors, such as NLRP1 and NLRP3, that belongs to the family of the leucine-rich repeat containing proteins (also known as NOD-like receptors, NLRs). Triggered by the signaling of PAMPs (pathogen-associated molecular patterns) and cytoplasmic DAMPs (danger-associated molecular patterns), both NLRP1 and NLRP3 form multiprotein complexes that lead to the activation and release of IL-1β and IL-18. The activation/formation of this complex is mediated by harmful stimuli, such as pathogens, dead cells or irritants, that induces the production of pro-inflammatory cytokines and cell recruitment for immune response and tissue repair, with possible influence on cardiac remodeling. An imbalance in the activity of inflammasome has been reported in metabolic, immunologic and inflammatory disorders, as well as parasitic infections. In addition, the inflammasomes were also considered critical determinants of host resistance to T. cruzi infection in an animal model, suggesting that the host-parasite interaction may provide an important role for the inflammasome in the cardiac remodeling observed in patients with chronic Chagas cardiomyopathy. We intend to characterize the patients clinically and also identify clinical, serological and genetic markers, including inflammasome proteins (NLRP1 and NLRP3) and related cytokines (IL-1β and IL-18), associated with the development and progression of chagasic cardiomyopathy in 10-years followed-up patients with chronic CD attending the outpatient department for Chagas Disease of the Clinical Hospital (Hospital de Clínicas - HC), Federal University of Paraná (Universidade Federal do Paraná - UFPR), Southern Brazil. Actually, this outpatient department attends among 600 patients and is a reference center for chronic CD follow up of the Brazilian Unified Health System (Sistema Único de Saúde- SUS).