Response to Infection by Trypanosoma cruzi in a Murine Model

Abstract

Cardiopathy is a common, irreversible manifestation of the chronic phase of Chagas disease; however, there is controversy as to how the causes for progression from the acute to the chronic phase are defined. In this work, the presence of the parasite is correlated with the occurrence of cell infiltration and fibrosis in cardiac tissues, as well as IgG detection and disease progression in a murine model. Fifty CD1 mice were infected intraperitoneally with Trypanosoma cruzi , while 30 control were administered with saline solution. Parasitemia levels were determined, and IgG titers were quantified by ELISA. At different times, randomly selected mice were euthanized, and the heart was recovered. Cardiac tissue slides were stained with HE and Masson trichrome stain. A significant increase in parasitemia levels was observed after 15 days post-infection (dpi), with a maximum of 4.1 × 10 6 parasites on 33 dpi, ending on 43 dpi; amastigote nests were observed on 15–62 dpi. Histological analysis revealed lymphocytic infiltration and fibrotic lesions from 8 dpi until the end of the study, on 100 dpi. The presence of plasma cells in the myocardium observed on 40–60 dpi, accompanied by seropositivity to ELISA on 40–100 dpi, was regarded as the hallmark of the transition phase. Meanwhile, the chronic phase, characterized by the absence of amastigotes, presence of cell infiltration, fibrotic lesions, and seropositivity, started on 62 dpi. A strong correlation between parasitemia and the presence of amastigote nests was found ( r 2 = 0.930), while correlation between the presence of fibrosis and of amastigote nests was weak ( r 2 = 0.306), and that between fibrosis and lymphocyte infiltration on 100 dpi was strong ( r 2 = 0.899). The murine model is suitable to study Chagas disease, since it can reproduce the chronic and acute phases of the human disease. The acute phase was determined to occur on 1–60 dpi, while the chronic phase starts on 62 dpi, and fibrotic damage is a consequence of the continuous inflammatory infiltration; on the other hand, fibrosis was determined to start on the acute phase, being more apparent in the chronic phase, when Chagas disease-related cardiopathy is induced.

Immunopathological Mechanisms Underlying Cardiac Damage in Chagas Disease

“…The presence and replication by binary fission of intracellular amastigotes in the myocardiocyte and its ensuing lysis cause inflammation, the release of cellular components, and finally the destruction of cardiac tissue [ 36 ]. A direct correlation between the presence of the parasite and tissue inflammation has been reported [ 37 ], even when only the presence of T. cruzi antigens or DNA has been confirmed in chronic lesions [ 38 ]. The infection can affect skeletal, cardiac, and smooth muscle, as well as neuronal tissue.…”

“…This process, either constructive or reconstructive, favors cardiac remodeling, which is a progressive mechanism in response to acute or chronic damage, regardless of its etiology. Remodeling leads to changes in the heart size, shape, and function, and it is clinically associated with a poor prognosis in patients with heart failure [ 37 , 88 ].…”

Main Cardiac Histopathologic Alterations in the Acute Phase of Trypanosoma cruzi Infection in a Murine Model

“…In the acute phase, after the primary infection, myocardial involvement is described with intracellular replication of the parasite in myocytes, lysis, and the onset of an inflammatory process that progresses to the fibrosis which characterizes the chronic phase [ 3 , 4 ]. Various studies have directly related myocardial fibrosis to the inflammatory response, consisting primarily of lymphocytes and macrophages [ 5 , 6 ].…”

“…In the acute phase, after the primary infection, myocardial involvement is described with intracellular replication of the parasite in myocytes, lysis, and the onset of an inflammatory process that progresses to the fibrosis which characterizes the chronic phase [3,4]. Various directly related myocardial fibrosis to the inflammatory response, consisting primarily of lymphocytes and macrophages [5,6]. Several mammalian species were used to study the pathogenesis of cardiac lesions in Chagas disease; however, there are no descriptions of the presence of histopathological alterations after primary infection that would allow us to determine the onset of fibrosis generation during the acute phase and its progression to the chronic phase of the disease, for which it is distinctive.…”

Induction of Autophagy by Ursolic Acid Promotes the Elimination of Trypanosoma cruzi Amastigotes From Macrophages and Cardiac Cells

“…Macrophages may either suppress T. cruzi replication or provide a favorable environment where the parasite can reproduce and be distributed to other tissues within the body ( Peluffo et al., 2004 ; Holzmuller et al., 2018 ). However, cardiac cells are one of the main targets of T. cruzi , in which the parasite establishes its replicative niche to form the amastigote nests that are present in the heart of the chronic patients ( De Alba-Alvarado et al., 2020 ).…”