Monocyte glycolysis determines CD8+ T cell functionality in human Chagas disease

Abstract

dinucleotide (NADH) and flavin adenine dinucleotide, which donate electrons to the electron transport chain to fuel oxidative phosphorylation (OXPHOS), the process by which 32 ATP molecules are generated in the mitochondria.In inflammatory settings, OXPHOS is inhibited by nitric oxide (NO) production in monocyte-derived inflammatory dendritic cells (moDCs) in an autocrine manner. In the absence of an active respiratory chain, sustained glycolytic metabolism is essential for moDC survival and function (9). Furthermore, NO production seems to be central in orchestrating HIF-1α responses by inducing its stabilization and transcriptional activation (10).Chagas disease, a complex pathological condition resulting from Trypanosoma cruzi infection, has become one of the most frequent causes of heart failure, cardio-embolic stroke, and sudden death in Latin America (11). The acute phase lasts 2-3 months and is characterized by detectable parasitemia and active parasite replication within target tissues. However, clinical symptoms are usually mild and nonspecific, and the vast majority of acute infections are never detected. During this phase, cell-mediated immunity controls parasite levels, but it is insufficient to completely clear the infection; most individuals remain infected for life. People who survive the acute phase enter a chronic asymptomatic phase (indeterminate stage), which is generally symptomless and may last from 10 to 30 years. Approximately 30% of patients in this period, also recognized as "silent," may develop heart abnormalities (12) that could give rise to the cardiac form of chronic infection. Although antiparasitic therapy is clearly recommended for acute Chagas disease, the treatment of patients in the chronic stage is controversial. This is largely due to a lack of large, randomized trials and incomplete understanding of pathological immune mechanisms developed during this stage. After decades of controversies, it is widely accepted nowadays that parasite persistence is a necessary and sufficient condition for the sustained inflammatory responses underlying the progression of cardiac lesions of chronic Chagas disease (13-18). Thus, one of the main challenges in understanding Chagas myocarditis immunopathology is to find out why, despite a robust immune response during the acute phase of the infection, the parasite is not completely eliminated, being able to sustain a pathological inflammatory environment.Cell-mediated immunity involves activation of phagocytes and of cytotoxic T lymphocytes (CTLs). In this sense, we have recently reported increased IL-1β plasma levels concomitant with enhanced frequency of NO-producing leukocytes and the surface nitration of CTLs associated with decreased functionality of this T cell compartment in the peripheral blood from patients with Chagas disease in the indeterminate phase (19). In this study, we went deeper by exploring how metabolism affects the monocyte compartment and T cell functionality during this human infectious disease. We have found that the nonc...

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…membrane is a platform for the NLRP3 inflammasome [266]. There exist several known signal transduction pathways between the cell and its mitochondria [267] The glycolytic pathway is vital for monocyte function and monocyte-derived cells' differentiation and functions (see Table 8): (i) the glycolytic pathway influences monocyte differentiation into macrophages and dendritic cells [261,[276][277][278]; (ii) glycolysis is upregulated in monocytes in response to infection and is important for effector functions [279][280][281], and the Akt-mTOR-HIF-1-α pathway seems especially important [268,[276][277][278]; (iii) trained monocytes are mainly glycolytic [94,245,282].…”

“…Ctype lectin signalling seems to trigger glycolysis when challenged by pathogens, and both glycolysis and the pentose phosphate pathway are then required for ROS production/ [279] Monocytes in Chagas patients are mainly glycolytic, and monocyte glycolysis determines CD8+ T-cell functionality . [280] CD14 + monocytes from rheumatoid arthritis patients express IL-1β, TNFα, IL-6, IL-27, CXCL10, and CXCL11, and are highly glycolytic, with increased expression of HIF1α, HK, and PFKFB3, which is mediated by STAT3. [281] Amino acid transporter SLC7A5 and mediated amino acid uptake in monocytes influence cytokine production, and inhibition of SLC7A5 is associated with the downregulation of glycolysis during LPS activation.…”

Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID‐19 pneumonia

“…For ATP production, monocytes rely both on oxidative phosphorylation (OXPHOS) and glycolysis (Kramer et al , 2014). However, under conditions that diverge from normal physiology, including inflammation or hypoxia, monocytes activate transcriptional responses that modulate or change cellular metabolism and induce a preferential use of one of the two pathways (Sanmarco et al , 2019). Recent studies have shown that monocyte bioenergetics and inflammatory phenotype can change in response to different infections or pathological stimuli such as hypoxia (Yamada et al , 2020).…”

HIF-1α and CD73 expression in cardiac leukocytes correlates with the severity of myocarditis in end-stage Chagas disease patients

“…In contrast, circulating T-lymphocytes display reduced expression of CD39 and CD73 ecto-enzymes in T. cruzi-chronically infected asymptomatic patients, 65 which also exhibit increased plasmatic ATP levels in comparison with control noninfected donors. 66 and diminish local parasite burden. 33 Considering the limited regenerative capacity of cardiomyocytes, CD73-derived adenosine could be a critical metabolite to protect the heart from excessive inflammation.…”

“…76 inflammatory environment. 66 Interestingly, HIF-1 also drives the expression of adenosine A2B receptor (ADORA2B) by direct binding to the receptor promoter. 77 During a chronic infection, low levels of adenosine chronically signaling through ADORA2A may contribute to immunosuppression, thereby increasing the impact of infection.…”