Programmed Cell Death Protein 1–PDL1 Interaction Prevents Heart Damage in Chronic Trypanosoma cruzi Infection

Abstract

Chagas disease is a neglected parasitic infection that affects around six to seven million people, mainly in Latin America. About 30–35% of infected people present chronic Chagas cardiomyopathy (CCC), which eventually leads to death. This condition is characterized by local parasite persistence and leukocyte infiltration. In a murine model of CCC, we observed that among infiltrating leukocytes, CD4+ and CD8+ T cells were in higher frequency in the heart of chronically infected mice, although elevated expression of the regulatory molecules programmed cell death protein 1 (PD1) and PDL1 suggested these cells could be inhibited. To investigate if PD1–PDL1 interaction in the heart of chronically infected mice negatively impacts on the local immune response, facilitating parasite persistence, and progression to CCC, we attempted to recover the local immune response by treating chronically infected mice with anti-PD1 and anti-PDL1-blocking antibodies together with irradiated Trypanosoma cruzi, which provides immune response boosting. Irradiated parasites promote expression of costimulatory molecules in dendritic cells and provide specific parasite antigen, which should aid T cell reactivation upon checkpoint blockade. Following treatment, there was an increased frequency of heart-infiltrating CD4+ and CD8+ T cells with an effector memory phenotype, an increased histopathology score and decreased heart rate, supporting our previous hypothesis of local immunosuppression induced by this pathway during CCC. In addition, blood parasitemia was reduced, which was associated with increased T. cruzi-specific immunoglobulin G 1 antibodies. However, no difference was observed in cytokine production or T. cruzi burden in the hearts of treated mice. Taken together, our results suggest PD1–PDL1 interaction protects the heart from excessive immune response.

An Animal Model of Acute and Chronic Chagas Disease With the Reticulotropic Y Strain of Trypanosoma cruzi That Depicts the Multifunctionality and Dysfunctionality of T Cells

“…Additionally, high parasite loads were observed in colon, heart, liver, and skeletal muscle tissues with moderate inflammatory infiltrate obtained from mice with acute and chronic infections compared with those with low or absent inflammatory infiltrate, suggesting that our experimental model is similar to that of other studies (54, 67). As it was to be expected, reticulotropic strains, such as Y strain, might be involved in increased inflammatory infiltrates in liver and spleen tissues and causes pathology as reported previously (57, 58), but to evaluate the pathological forms of experimental ChD, is important to implement other methodological approaches, such as the measurement of heart rate or the identification of fibrosis in tissue samples (57, 60, 68). However, to date, it has been very difficult to establish the direct relationship among the parasite load, the inflammatory infiltrate and the pathogenesis of ChD as previously described (69).…”

“…In contrast, acute T. cruzi -infected mice treated with anti-CTLA-4 show reduced parasitemia and mortality compared to mice treated with an isotype control (IgG) (92). In chronic experimental models of ChD and in patients with a severe form of chronic ChD, a continuous increase in inhibitory receptor expression and co-expression on T cells from peripheral blood and cells from cardiac tissue has been observed (68, 93). Recently, cardiac tissue cells from mice with a chronic infection and heart failure showed high levels of PD-1 and PD-L1 expression at 330 dpi (68).…”

“…In chronic experimental models of ChD and in patients with a severe form of chronic ChD, a continuous increase in inhibitory receptor expression and co-expression on T cells from peripheral blood and cells from cardiac tissue has been observed (68, 93). Recently, cardiac tissue cells from mice with a chronic infection and heart failure showed high levels of PD-1 and PD-L1 expression at 330 dpi (68). Moreover, mice treated with anti-PD-1 show reduced parasitemia, increased numbers of cardiac T cells with an effector memory phenotype, and increased deterioration of cardiac function compared with infected mice treated with an isotype control (IgG) (68).…”

“…Recently, cardiac tissue cells from mice with a chronic infection and heart failure showed high levels of PD-1 and PD-L1 expression at 330 dpi (68). Moreover, mice treated with anti-PD-1 show reduced parasitemia, increased numbers of cardiac T cells with an effector memory phenotype, and increased deterioration of cardiac function compared with infected mice treated with an isotype control (IgG) (68). Remarkably, in the present study, acute T. cruzi -infected mice expressed inhibitory receptors, such as 2B4 (CD244), CD160, CTLA-4, and PD-1, at higher levels and exhibited higher co-expression of these molecules at 10 dpi than at 30 dpi, suggesting that the transient increase in inhibitory receptor expression and co-expression on T cells from acute T. cruzi -infected mice is related to immune regulation in an acute inflammatory microenvironment.…”

NLRP3 and mTOR Reciprocally Regulate Macrophage Phagolysosome Formation and Acidification Against Vibrio vulnificus Infection

“…Vibrio vulnificus is a Gram-negative bacterium that causes primary septicemia, inflammation-mediated septic shock, and necrotizing wound infection ( Blake et al, 1979 ; Park and Lee, 2018 ; Baker-Austin and Oliver, 2020 ). Cases of V. vulnificus infection have been reported worldwide, including the United States, China, Australia, Germany, Korea, and Japan ( Zhao et al, 2015 ; Heng et al, 2017 ). Infection with this bacterium is related to V. vulnificus contaminated raw seafood consumption or an open wound that was exposed to warm seawater containing this bacteria ( Baker-Austin and Oliver, 2020 ).…”