Chagas disease: still many unsolved issues

Abstract

Over the past 20 years, the immune effector mechanisms involved in the control of Trypanosoma cruzi, as well as the receptors participating in parasite recognition by cells of the innate immune system, have been largely described. However, the main questions on the physiopathology of Chagas disease remain unanswered: "Why does the host immune system fail to provide sterile immunity?" and "Why do only a proportion of infected individuals develop chronic pathology?" In this review, we describe the mechanisms proposed to explain the inability of the immune system to eradicate the parasite and the elements that allow the development of chronic heart disease. Moreover, we discuss the possibility that the inability of infected cardiomyocytes to sense intracellular T. cruzi contributes to parasite persistence in the heart and the development of chronic pathology.

Figure 1

Expression of PD-L1 by infiltrating leukocytes in a chronically infected heart. C3H/HePAS mice were infected with 4 × 10⁵ Sylvio X10/4 trypomastigotes obtained from LLCMK2 cultures. At day 400 postinfection, mice were sacrificed, and the heart tissue was digested with collagenase to isolate the infiltrating leukocytes. PD-L1 expression was analyzed by flow cytometry. Heart leukocytes from a pool of age-matched noninfected mice were also included.

Figure 2

Parasite persistence is not the necessary outcome of heart infection by T. cruzi parasites. C57BL/6 mice were infected with 10³ T. cruzi blood trypomastigotes of the Y strain. At days 18 (a) and 180 (b) postinfection, mice were sacrificed, and the heart tissue was formalin-fixed, included in paraffin, and stained with hematoxylin/eosin. Arrow in the figure shows an amastigote nest, which is magnified at the insert. Bars in figures correspond to 200 μm and to 100 μm at the insert.

Figure 3

Lack of sensing of amastigote nests could contribute to parasite perpetuation and pathology in the chronically infected heart. Lack of sensing could occur independently of the origin of cardiomyocyte-invading trypomastigotes, that is, from a local ruptured nest or metastasis from a distant niche. The heart picture shown corresponds to a C3H/HePAS mouse infected for more than 200 days with 10⁶ Sylvio X10/4 trypomastigotes. The tissue section was stained with hematoxylin-eosin. Bar corresponds to 100 μm (reproduced from C. R. F. Marinho, Microbes and Infection [64] with permission from Elsevier).