Current understanding of immunity to Trypanosoma cruzi infection and pathogenesis of Chagas disease

Abstract

Chagas disease caused by Trypanosoma cruzi remains an important neglected tropical disease and a cause of significant morbidity and mortality. No longer confined to endemic areas of Latin America, it is now found in non-endemic areas due to immigration. The parasite may persist in any tissue, but in recent years, there has been increased recognition of adipose tissue both as an early target of infection and a reservoir of chronic infection. The major complications of this disease are cardiomyopathy and megasyndromes involving the gastrointestinal tract. The pathogenesis of Chagas disease is complex and multifactorial involving many interactive pathways. The significance of innate immunity, including the contributions of cytokines, chemokines, reactive oxygen species, and oxidative stress, has been emphasized. The role of the components of the eicosanoid pathway such as thromboxane A(2) and the lipoxins has been demonstrated to have profound effects as both pro- and anti-inflammatory factors. Additionally, we discuss the vasoconstrictive actions of thromboxane A(2) and endothelin-1 in Chagas disease. Human immunity to T. cruzi infection and its role in pathogen control and disease progression have not been fully investigated. However, recently, it was demonstrated that a reduction in the anti-inflammatory cytokine IL-10 was associated with clinically significant chronic chagasic cardiomyopathy.

Fig. 1. Heart of a patient with chronic chagasic cardiomyopathy

(A) Shown is 4-chamber enlargement of the heart in a chagasic patient. Apical aneurysm is marked with an arrow (printed with permission from the Armed Forces Institute of Pathology). (B) H&E-stained myocardium from a patient with chronic chagasic cardiomyopathy showing fibrosis and chronic inflammation (arrow). (C) Myocardium of the same patient sample stained with Masson’s trichrome showing significant fibrosis (blue color, marked by arrow). H&E (D) and Masson’s trichrome (E) staining of the myocardium of an uninfected healthy donor are shown for comparison. Arrow-heads in all panels mark the myocardium.

Fig. 2. Macrophages in adipose tissue

Immunohistochemical analysis using antibody against ionized calcium-binding adaptor molecule 1 (Iba1) of adipose tissue obtained from mice. (A) Brown adipose tissue (BAT), obtained from the interscapluar region and white adipose tissue obtained from the subcutaneous region (WAT). Note the increase in macrophages in the infected adipose tissue. (B) Macrophage-specific F4/80 messenger RNA (mRNA) demonstrating the increase in macrophages in both BAT and WAT, as determined by real-time quantitative polymerase chain reaction. Con=control; Inf=infected (reproduced from Nagajyothi et al. Journal of Infectious Disease [45] with permission from the Journal and the Oxford University Press).

Fig. 3. Oxidative stress in Chagas disease

T. cruzi infection elicits generation of superoxide (O₂^•−) through activation of NADPH oxidase in phagocytic cells. T. cruzi invasion of other cells elicits intracellular Ca⁺² flux affecting mitochondrial membrane potential and results in increased leakage of electrons from the electron transport chain to molecular oxygen and formation of O₂^•− and other reactive oxygen species (ROS). Two pathways of ROS signaling of the NFκB pathway are envisioned. One, ROS directly promotes phosphorylation and transport of p65 (RelA) and p50 to nucleus, assembly of transcription complex, and expression of proinflammatory cytokines (e.g. IL-1β, TNF-α). Two, ROS-mediated oxidation of DNA may signal activation of poly (ADP-ribose) polymerase (PARP-1). PARP-1 cleaves NAD⁺ to form ADP-ribose and polymerizes the latter onto nuclear acceptor proteins (e.g. histones), transcription factors, and PARP itself, and contributes to DNA repair and genomic stability. Binding of poly ADP-ribose (PAR) molecules activates NF-κB transcription complex and inflammatory cytokine gene expression. The feed-back loop of ROS generation and cytokine gene expression contribute to persistence of inflammatory responses and oxidative damage, and progressive evolution of cardiomyopathy in Chagas disease.

Fig. 4. Progression of human Chagas disease

Following infection with T. cruzi the majority of individuals develop parasitemia associated with a robust cellular and humoral immune response involving cells of the innate and adaptive immune response. This stage can present with severe clinical features ranging from high fever to arrhythmia and death. Upon successful control of the initial infection by the immune response, parasitemia wanes and symptoms subside, as the individual enters the chronic phase of Chagas disease. Here the majority of individuals enter the indeterminate (asymptomatic) clinical form, associated with a balanced inflammatory and regulatory immune response (low inflammatory index). Approximately 30% of the individuals will progress to the cardiac clinical form of disease associated with a higher inflammatory state. Cell types referred in the figure: CD4, CD8 and double negative (DN) T cells, macrophages (MΦ), Natural killer (NK) cells, CD5 (IgM-secreting) B cells. The increased inflammation refers to data demonstrating an up regulation of the inflammatory response (cytokines, chemokines).