Adipose Tissue in Chagas Disease: A Neglected Component of Pathogenesis

Abstract

Chagas disease (CD), caused by the protozoan T. cruzi, is a serious public health issue with high morbidity and mortality rates. Approximately 7 million people are infected, mostly in Latin America. The pathogenesis is multifactorial and poorly elucidated, particularly regarding the role of adipose tissue (AT). This review aims to explore the complex relationship between T. cruzi and AT, focusing on the possible role of this tissue in CD, as well as to explore the impact of diet on the progression of the disease. T. cruzi infects adipocytes, affecting their function. Chronic infection alters adipose physiology, contributing to systemic inflammation and metabolic disturbances. Adipokines are dysregulated, while markers of inflammation and oxidative stress increase within AT during CD. Additionally, the immune response and clinical aspects of CD may be influenced by the host's diet. High-fat diets (HFDs) impact parasite burden and cardiac pathology in murine models. The complex interaction among T. cruzi infection, AT dysfunction, and dietary factors underscore the complexity of CD pathogenesis. Despite accumulating evidence suggesting the role of AT in CD, further research is needed to elucidate its clinical implications. Understanding the bidirectional relationship between AT and T. cruzi infection may offer insights into disease progression and potential therapeutic targets, highlighting the importance of considering adipose physiology in CD management strategies.

Keywords: T. cruzi; adipocytes; high-fat diet; pathophysiology.

Figure 1

Main theories on the pathogenesis of Chagas disease. According to the parasite persistence theory, T. cruzi replicates within host cells, causing the rupture of infected cells and releasing antigens that trigger the host’s immune response, leading to inflammation. The autoimmune theory suggests that the immune system targets the host’s own tissues, causing chronic inflammation through the following mechanisms: molecular mimicry, bystander activation, and potentially T. cruzi kinetoplast DNA (kDNA) integration. Erythrocytes (https://beta.scidraw.io/drawing/634), heart (https://beta.scidraw.io/drawing/277), intestine (https://beta.scidraw.io/drawing/296), adipocyte (https://doi.org/10.5281/zenodo.3926133), myocyte (https://doi.org/10.5281/zenodo.3926129), and macrophage (https://beta.scidraw.io/drawing/221) were obtained from https://scidraw.io/. Accessed on 19 February 2025.

Figure 2

Main types of adipocytes. There are three main types of adipocytes, each differing functionally and morphologically. White adipocytes are large and contain a single lipid droplet and few mitochondria. Their primary function is energy storage. Brown adipocytes have numerous small lipid droplets and a high number of mitochondria. Their main function is thermogenesis. Beige (or brite) adipocytes display intermediary characteristics, highlighting the remarkable plasticity of adipose tissue. Adipocyte (https://doi.org/10.5281/zenodo.3926133) and mitochondria (https://doi.org/10.5281/zenodo.7590755) were obtained from https://scidraw.io/. Accessed on 19 February 2025.

Figure 3

Impact of a high-fat diet on some variables analyzed in the acute and/or chronic phases of T. cruzi infection according to key studies. The upper section presents the results of experiments conducted during the acute phase of T. cruzi infection, while the bottom section corresponds to the chronic phase. In each section, the top panel compares infected animals fed with a high-fat diet (HFD) to those fed with a standard diet (SD), and the bottom panel compares infected and uninfected mice fed an HFD. The red box indicates an increase in the variable, the blue box indicates a decrease, and the gray box indicates no change. It is important to note that differences in results may be attributed to variations in experimental protocols. All studies were performed in murine models [17,63,70,71,72,73,74,75]. WAT: white adipose tissue. TNF-α: tumor necrosis factor-alpha. IFN-γ: interferon-gamma. AT: adipose tissue. NE: Not evaluated. *: Increase in 120 dpi. #: Decrease in 160 dpi.

Figure 4

Consequences of the interaction between T. cruzi and white adipose tissue. In the acute phase of infection, adipose tissue is a target for T. cruzi. In the chronic phase, it serves as a reservoir for the parasite, contributing to the persistence of the infection. The inflammation triggered by T. cruzi persists in adipose tissue, leading to several effects, including oxidative stress, adipocyte apoptosis, an imbalance in pro- and anti-inflammatory factors, as well as impaired adipogenesis and lipolysis. These effects are influenced by the parasite’s genetics and the host’s immune response. Together, these factors contribute to the development of chronic Chagas cardiomyopathy. ROS: reactive oxygen species. Heart (https://beta.scidraw.io/drawing/277) and macrophage (https://beta.scidraw.io/drawing/221) were obtained from https://scidraw.io/. Accessed on 19 February 2025.