Abstract
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi (T. cruzi), is the main parasitic disease in the Western Hemisphere. Unfortunately, its physiopathology is not completely understood, and cardiomegaly development is hard to predict. Trying to explain tissue lesion and the fact that only a percentage of the infected individuals develops clinical manifestations, a variety of mechanisms have been suggested as the provokers of CD, such as parasite persistence and autoimmune responses. However, holistic analysis of how parasite and host-related elements may connect to each other and influence clinical outcome is still scarce in the literature. Here, we investigated murine models of CD caused by three different pathogen strains: Colombian, CL Brener and Y strains, and employed parasitological and immunological tests to determine parasite load, antibody reactivity, and cytokine production during the acute and chronic phases of the disease. Also, we developed a quantitative PCR (qPCR) protocol to quantify T. cruzi kDNA minicircle integration into the mammalian host genome. Finally, we used a correlation analysis to interconnect parasite- and host-related factors over time. Higher parasite load in the heart and in the intestine was significantly associated with IgG raised against host cardiac proteins. Also, increased heart and bone marrow parasitism was associated with a more intense leukocyte infiltration. kDNA integration rates correlated to the levels of IgG antibodies reactive to host cardiac proteins and interferon production, both influencing tissue inflammation. In conclusion, our results shed light into how inflammatory process associates with parasite load, kDNA transfer to the host, autoreactive autoantibody production and cytokine profile. Altogether, our data support the proposal of an updated integrative theory regarding CD pathophysiology.
Highlights
Chagas disease (CD) is an endemic disease in South and Central America, caused by the protozoan Trypanosoma cruzi
Parasite detection in the bone marrow was negative in 40% of the mice infected with the Colombian strain, 10% of the animals infected with CL Brener, and 30% of the animals infected with Y strain, revealing a more heterogeneous parasite infection of bone marrow (Supplementary Figure S2)
Despite the observed differences in the percentage of animals with positive quantitative PCR (qPCR) parasite genome amplification, we only verified statistically significant difference when comparing the bone marrow samples of animals infected with the Colombian versus CL Brener strains (p = 0.008), and when comparing the intestine samples of animals infected with the Y versus Colombian and CL Brener strains (p < 0.05)
Summary
Chagas disease (CD) is an endemic disease in South and Central America, caused by the protozoan Trypanosoma cruzi. It is considered a neglected tropical endemic by WHO, yet it threatens 25 million people worldwide and causes significant morbidity and mortality with more than 10,000 deaths per year (World Health Organization, 2018). Infection persists with low parasitemia and the disease progresses to an unpredictable chronic phase, which begins with no symptoms but can evolve to cardiac, digestive, or mixed (both cardiac and digestive) forms in about 30–40% of the patients, requiring complex treatment (Gironès et al, 2005; Costa et al, 2017; Zrein et al, 2018)
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