Abstract
Background: Archaeal genes present in Trypanosoma cruzi may represent symbionts that would explain development of heart failure in 30% of Chagas disease patients. Extracellular vesicles in peripheral blood, called exosomes (< 0.1 μm) or microvesicles (>0.1 μm), present in larger numbers in heart failure, were analyzed to determine whether they are derived from archaea in heart failure Chagas disease.Methods: Exosomes and microvesicles in serum supernatant from 3 groups were analyzed: heart failure Chagas disease (N = 26), asymptomatic indeterminate form (N = 21) and healthy non-chagasic control (N = 16). Samples were quantified with transmission electron microscopy, flow cytometer immunolabeled with anti-archaemetzincin-1 antibody (AMZ 1, archaea collagenase) and probe anti-archaeal DNA and zymography to determine AMZ1 (Archaeal metalloproteinase) activity.Results: Indeterminate form patients had higher median numbers of exosomes/case vs. heart failure patients (58.5 vs. 25.5, P < 0.001), higher exosome content of AMZ1 antigens (2.0 vs. 0.0; P < 0.001), and lower archaeal DNA content (0.2 vs. 1.5, P = 0.02). A positive correlation between exosomes and AMZ1 content was seen in indeterminate form (r = 0.5, P < 0.001), but not in heart failure patients (r = 0.002, P = 0.98). Higher free archaeal DNA (63.0 vs. 11.1, P < 0.001) in correlation with exosome numbers (r = 0.66, P = 0.01) was seen in heart failure but not in indeterminate form (r = 0.29, P = 0.10). Flow cytometer showed higher numbers of AMZ1 microvesicles in indeterminate form (64 vs. 36, P = 0.02) and higher archaeal DNA microvesicles in heart failure (8.1 vs. 0.9, P < 0.001). Zymography showed strong% collagenase activity in HF group, mild activity in IF compared to non-chagasic healthy group (121 ± 14, 106 ± 13 and 100; P < 0.001).Conclusions: Numerous exosomes, possibly removing and degrading abnormal AMZ1 collagenase, are associated with indeterminate form. Archaeal microvesicles and their exosomes, possibly associated with release of archaeal AMZ1 in heart failure, are future candidates of heart failure biomarkers if confirmed in larger series, and the therapeutic focus in the treatment of Chagas disease.
Highlights
Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi), an endemic infection in Latin America (Strasen et al, 2014; Bocchi et al, 2017), having two distinct phases: acute and chronic
We investigated whether serum microvesicles and exosomes containing archaeal DNA or archaeal collagenase are related to heart failure (HF) in Chagas disease patients
Microvesicles surrounded by a double membrane containing archaeal DNA were seen in myocardiocytes and at the extracellular matrix surrounded by macrophages and lymphocytes, suggesting that they would be the cause of myocarditis in the absence of T.cruzi (Higuchi et al, 2009)
Summary
Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi), an endemic infection in Latin America (Strasen et al, 2014; Bocchi et al, 2017), having two distinct phases: acute and chronic. Our previous studies with endomyocardial biopsies from chagasic patients showed that HF patients have lymphocytic myocarditis (Pereira Barretto et al, 1986), with lymphocytes injuring non-T. cruzi infected myocytes (Higuchi et al, 1987) These patients have myocardium with T. cruzi antigens (Higuchi et al, 1993; Bellotti et al, 1996), and DNA (Jones et al, 1993), but in too scarce amount to explain the intensity of inflammatory infiltrate with unbalanced immune response (Cunha-Neto et al, 1995; Gao et al, 2003), suggesting that other factors beyond the parasite may be interfering (Higuchi et al, 1997; MarinNeto et al, 2007). Extracellular vesicles in peripheral blood, called exosomes (0.1 μm), present in larger numbers in heart failure, were analyzed to determine whether they are derived from archaea in heart failure Chagas disease
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