Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Abstract

The infection with the protozoan parasite Trypanosoma cruzi causes Chagas disease, a neglected tropical disease in Latin America and an imported emerging disease worldwide. Chronic Chagasic cardiomyopathy (CCC), a progressive inflammatory and fibrosing disease, is the most prominent clinical form of Chagas disease, culminating in heart failure and high rates of sudden death. CCC pathogenesis is influenced by both host and parasite factors and is proposed to be mostly immune‐driven. Chemokines are crucial players in orchestrating immune cell recruitment to infected tissues and inflammation. Herein, we investigated inflammatory chemokine receptor expression on circulating T cells in patients stratified by CCC severity. Compared to asymptomatic individuals, we found increased percentages of effector CD4+ T cells and central memory CD4+ and CD8+ T cells expressing CCR5 in patients with structural cardiopathy, but normal global ventricular function and no symptoms of chronic heart failure. Even naïve T cells expressed CCR5 in these patients. In contrast, reduced frequencies of CD4+ and CD8+ effector T cells expressing CXCR3 were observed in patients presenting with severe heart disease. Patients with increased left ventricular diameter, heart enlargement, and insufficiency had higher frequencies of CCR5+ effector and effector memory CD8+ T cells. Moreover, the percentage of effector CCR5+ CD8+ T cells was increased in patients with a reduced ejection fraction. Our results show that high expression CCR5 and low expression of CXCR3 on circulating T cells are associated with worse prognosis, possibly reflecting immune‐mediated cardiac remodeling of CCC.

Phenotypic and Functional Signatures of Peripheral Blood and Spleen Compartments of Cynomolgus Macaques Infected With T. cruzi: Associations With Cardiac Histopathological Characteristics

“…Therefore, the involvement of CCR5 in the recruitment of regulatory T-cells (Huehn and Hamann, 2005) indicates a dual role for this receptor, not only inducing but also resolving inflammatory response. Previous studies have tried to decipher whether CCR5 plays a role in the development of cardiac injuries or if it is a protective biomarker in Chagas disease (Talvani et al, 2004;Nogueira et al, 2012;de Oliveira et al, 2016;Miranda et al, 2017;Roffe et al, 2019). CCR5 + Tcells have been found in association with T. cruzi nests and antigens in heart tissue during murine acute infection, suggesting a direct anti-parasitic role (Marino et al, 2004) as well as its involvement in immunopathological mechanisms (Marino et al, 2005).…”

“…Chronic Chagas cardiomyopathy (CCC) may involve a complex variety of immunological events leading to distinct histopathological features (Reis et al, 1993;Higuchi et al, 2003;Fonseca et al, 2007). Many specific cell populations and cytokines involved in the immunopathological mechanisms underlying cardiac Chagas disease have been identified (Reis et al, 1993;Higuchi et al, 2003;Fonseca et al, 2007;Costa et al, 2009;Cunha-Neto and Chevillard, 2014;Ferreira et al, 2014;Roffe et al, 2019). Despite the many well-described immunological factors involved in CCC, their hypothetical interactions that might lead to different cardiac pathologies are still not well understood.…”

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

“…Therefore, CCR5 has two basic conflicting effects on Chagas disease: it is protective in the acute phase and acts as a facilitator of disease‐related inflammation in chronic infection (Oliveira et al, 2016). Interestingly, the potential use of pharmacological CCR5 modulators to treat Chagas disease has already been suggested by different authors (Machado et al, 2005; Marino et al, 2005; Medeiros et al, 2009; Roffe et al, 2019). In the opposite direction, Silva et al (2007) demonstrated that CCR5 has no relevant role in T. cruzi infection‐related meningoencephalitis.…”

“…Moreover, a body of evidence supports the involvement of the CCR5 protein (Batista et al, 2018; Dutra, Rocha, & Teixeira, 2005; Hardison et al, 2006; Kroll‐Palhares et al, 2008; Machado et al, 2005; Marino et al, 2005; Medeiros et al, 2009; Roffe et al, 2019; Roffê et al, 2010; Silva et al, 2007), as well as gene variants of CCR5 and CCR5 ligands (Batista et al, 2018; Calzada et al, 2001; Flórez et al, 2012; Machuca et al, 2014; Oliveira et al, 2015, 2016) on varied aspects of Chagas disease, mainly associated to the development of Chagas heart disease. For example, animal‐based evidence pointed to a protective role of CCR5 in controlling T. cruzi replication and maintaining a protective immune response in acute infection (Hardison et al, 2006).…”

“…For example, animal‐based evidence pointed to a protective role of CCR5 in controlling T. cruzi replication and maintaining a protective immune response in acute infection (Hardison et al, 2006). On the other hand, CCR5 may participate in the inflammation and heart damage observed in Chagas heart disease (Batista et al, 2018; Roffe et al, 2019), suggesting that CCR5 deficiency might play a protective role against Chagas‐associated cardiomyopathy. Therefore, CCR5 has two basic conflicting effects on Chagas disease: it is protective in the acute phase and acts as a facilitator of disease‐related inflammation in chronic infection (Oliveira et al, 2016).…”