Correlation of Parasite Burden, kDNA Integration, Autoreactive Antibodies, and Cytokine Pattern in the Pathophysiology of Chagas Disease

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.

IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease

“…Although the mechanisms that lead to the development of CCC are still intriguing due to the fact that not all infected patients develop heart anomalies, the relevance of parasite persistence as a trigger is presently acknowledged ( 8 – 10 , 46 – 48 ). However, the understanding of the involvement of the different components of the inflammatory response and CCC is still unclear.…”

“…Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, triggers both innate (1)(2)(3), and adaptive (4)(5)(6) immune responses that aim at the control of the parasite load both in tissues and peripheral blood [Reviewed in (7)]. However, these mechanisms do not succeed in the complete eradication of the parasite, which results in parasite persistence (8)(9)(10)(11)(12).…”

“…The inflammatory response is characterized by the recruitment of mononuclear cells to the heart and other tissues, and increased systemic and local inflammatory mediators, including cytokines like IL-1β, IL-6, and TNFα and enzymes like iNOS, involved in the production of NO, or matrix metalloproteinases like MMP-9, that contribute to tissue remodeling ( 17 – 19 ). Despite the low levels of parasite load observed during the chronic phase of infection, its persistence plays a crucial role to uphold the inflammatory reaction leading to heart anomalies and remodeling ( 10 , 20 ).…”

Neuronal Parasitism, Early Myenteric Neurons Depopulation and Continuous Axonal Networking Damage as Underlying Mechanisms of the Experimental Intestinal Chagas' Disease

“…The damage of myenteric neurons characterizes the chronic phase of the intestinal CD (Adad et al, 2013 ; Jabari et al, 2014 ). However, as the parasitism is very low in the lesions of digestive Chagas disease (da Silveira et al, 2005 ; Wesley et al, 2019 ), it has been suggested that chronic neuronal destruction might be due to the immune response that follows the infection, as proposed for heart lesions (Teixeira et al, 2011 ). It is not possible to determine when and how exactly this denervation occurs during the asymptomatic 20–30 years that follow the post-acute phase in humans.…”

The Stem Cell Revolution Revealing Protozoan Parasites’ Secrets and Paving the Way towards Vaccine Development

“…The chronic phase of Chagas disease starts without evident clinical manifestations either remaining stable in time or progressing to organ damage, mainly cardiomyopathy or megaviscera in as many as a third of infected people. The progress of Chagas disease is unpredictable and the development of clinical symptoms depends on a wide variety of factors from both the host and the parasite [ 46 ]. Development of effective treatment and diagnosis is difficult and hampered by the lack of tools particularly to examine the host factors involved in the disease.…”