Perspectives on Adipose Tissue, Chagas Disease and Implications for the Metabolic Syndrome

The contribution of adipose tissue an autocrine and endocrine organ in the pathogenesis of infectious disease and metabolic syndrome is gaining attention. Adipose tissue and adipocytes are one of the major targets of T. cruzi infection. Parasites are detected 300 days postinfection in adipose tissue. Infection of adipose tissue and cultured adipocytes triggered local expression of inflammatory mediators resulting in the upregulation of cytokine and chemokine levels. Adipose tissue obtained from infected mice display an increased infiltration of inflammatory cells. Adiponectin, an adipocyte specific protein, which exerts antiinflammatory effects, is reduced during the acute phase of infection. The antiinflammatory regulator peroxisome proliferator activated receptor-γ (PPAR-γ) is downregulated in infected cultured adipocytes and adipose tissue. T. cruzi infection is associated with an upregulation of signaling pathways such as MAPKs, Notch and cyclin D, and reduced caveolin-1 expression. Adiponectin null mice have a cardiomyopathy and thus we speculate that the T. cruzi-induced reduction in adiponectin contributes to the T. cruzi-induced cardiomyopathy. While T. cruzi infection causes hypoglycemia which correlates with mortality, hyperglycemia is associated with increased parasitemia and mortality. The T. cruzi-induced increase in macrophages in adipose tissue taken together with the reduction in adiponectin and the associated cardiomyopathy is reminiscent of the metabolic syndrome

Trypanosoma cruzi Utilizes the Host Low Density Lipoprotein Receptor in Invasion

Trypanosoma cruzi, an intracellular protozoan parasite that causes Chagas disease in humans and results in the development of cardiomyopathy, is a major health problem in endemic areas. This parasite can invade a wide variety of mammalian cells. The mechanisms by which these parasites invade their host cells are not completely understood. Our study highlights, for the first time, that the Low Density Lipoprotein receptor (LDLr) is important in the invasion and the subsequent fusion of the parasitophorous vacuole with host lysosomes. We demonstrate that T. cruzi directly binds to LDLr, and inhibition or disruption of LDLr significantly decreases parasite entry. Additionally, we have determined that this cross-linking triggers the accumulation of LDLr and phosphotidylinositol phosphates in coated pits, which initiates a signaling cascade that results in the recruitment of lysosomes, possibly via the sorting motif in the cytoplasmic tail of LDLr, to the site of adhesion/invasion. Studies of infected CD1 mice demonstrate that LDLs accumulate in infected heart and that LDLr co-localize with internalized parasites. Overall, this study demonstrates that LDLr and its family members, engaged mainly in lipoprotein transportation, are also involved in T. cruzi entry into host cells and this interaction likely contributes to the progression of chronic cardiomyopathy

Bradykinin B2 Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses

Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B2 receptors (B2R). Here we report that C57BL/6.B2R−/− mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R+/+ mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.]) in B2R−/− heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-γ-producing CD4+ and CD8+ T cells in the spleen of B2R−/− and wild-type mice. However, production of IFN-γ by effector T cells isolated from B2R−/− heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-γ-producing (CD4+CD44+ and CD8+CD44+) T cells both in the spleen and heart while B2R−/− mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R−/− mice was linked to upregulated secretion of IL-17 and TNF-α by antigen-responsive CD4+ T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c+ DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B2R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c+ DCs isolated from B2R+/+ spleen, but not by DCs from B2R−/− mice. Notably, adoptive transfer of B2R+/+ CD11c+ DCs (intravenously) into B2R−/− mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed TH17 responses. Collectively, our results demonstrate that activation of B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection

Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection

Chagas' disease is caused by infection with the parasite Trypanosoma cruzi. We report that infected, but not uninfected, human endothelial cells (ECs) released thromboxane A2 (TXA2). Physical chromatography and liquid chromatography-tandem mass spectrometry revealed that TXA2 is the predominant eicosanoid present in all life stages of T. cruzi. Parasite-derived TXA2 accounts for up to 90% of the circulating levels of TXA2 in infected wild-type mice, and perturbs host physiology. Mice in which the gene for the TXA2 receptor (TP) has been deleted, exhibited higher mortality and more severe cardiac pathology and parasitism (fourfold) than WT mice after infection. Conversely, deletion of the TXA2 synthase gene had no effect on survival or disease severity. TP expression on somatic cells, but not cells involved in either acquired or innate immunity, was the primary determinant of disease progression. The higher intracellular parasitism observed in TP-null ECs was ablated upon restoration of TP expression. We conclude that the host response to parasite-derived TXA2 in T. cruzi infection is possibly an important determinant of mortality and parasitism. A deeper understanding of the role of TXA2 may result in novel therapeutic targets for a disease with limited treatment options

Recent Developments in the Interactions Between Caveolin and Pathogens

The role of caveolin and caveolae in the pathogenesis of infection has only recently been appreciated. In this chapter, we have highlighted some important new data on the role of caveolin in infections due to bacteria, viruses and fungi but with particular emphasis on the protozoan parasites Leishmania spp., Trypanosoma cruzi and Toxoplasma gondii. This is a continuing area of research and the final chapter has not been written on this topic

Energy transfer in “parasitic” cancer metabolism: Mitochondria are the powerhouse and Achilles' heel of tumor cells

It is now widely recognized that the tumor microenvironment promotes cancer cell growth and metastasis via changes in cytokine secretion and extra-cellular matrix remodeling. However, the role of tumor stromal cells in providing energy for epithelial cancer cell growth is a newly emerging paradigm. For example, we and others have recently proposed that tumor growth and metastasis is related to an energy imbalance. Host cells produce energy-rich nutrients via catabolism (through autophagy, mitophagy and aerobic glycolysis), which are then transferred to cancer cells, to fuel anabolic tumor growth. Stromal cell derived L-lactate is taken up by cancer cells and is used for mitochondrial oxidative phosphorylation (OXPHOS), to produce ATP efficiently. However, “parasitic” energy transfer may be a more generalized mechanism in cancer biology than previously appreciated. Two recent papers in Science and Nature Medicine now show that lipolysis in host tissues also fuels tumor growth. These studies demonstrate that free fatty acids produced by host cell lipolysis are re-used via β-oxidation (β-OX) in cancer cell mitochondria. Thus, stromal catabolites (such as lactate, ketones, glutamine and free fatty acids) promote tumor growth by acting as high-energy onco-metabolites. As such, host catabolism via autophagy, mitophagy and lipolysis may explain the pathogenesis of cancer-associated cachexia and provides exciting new druggable targets for novel therapeutic interventions. Taken together, these findings also suggest that tumor cells promote their own growth and survival by behaving as a “parasitic organism.” Hence, we propose the term “parasitic cancer metabolism” to describe this type of metabolic-coupling in tumors. Targeting tumor cell mitochondria (OXPHOS and β-OX) would effectively uncouple tumor cells from their hosts, leading to their acute starvation. In this context, we discuss new evidence that high-energy onco-metabolites (produced by the stroma) can confer drug resistance. Importantly, this metabolic chemo-resistance is reversed by blocking OXPHOS in cancer cell mitochondria, with drugs like Metformin, a mitochondrial “poison.” In summary, parasitic cancer metabolism is achieved architecturally by dividing tumor tissue into at least two well-defined opposing “metabolic compartments:” catabolic and anabolic