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. 2015 Oct 5;73(9):ftv082. doi: 10.1093/femspd/ftv082

Immunity and immune modulation in Trypanosoma cruzi infection

Fabíola Cardillo 1, Rosa Teixeira de Pinho 2, Paulo Renato Zuquim Antas 2, José Mengel 2,3,*
Editor: Patricia Bozza
PMCID: PMC4626602  PMID: 26438729

Abstract

Chagas disease is caused by the protozoan Trypanosoma cruzi. The parasite reaches the secondary lymphoid organs, the heart, skeletal muscles, neurons in the intestine and esophagus among other tissues. The disease is characterized by mega syndromes, which may affect the esophagus, the colon and the heart, in about 30% of infected people. The clinical manifestations associated with T. cruzi infection during the chronic phase of the disease are dependent on complex interactions between the parasite and the host tissues, particularly the lymphoid system that may either result in a balanced relationship with no disease or in an unbalanced relationship that follows an inflammatory response to parasite antigens and associated tissues in some of the host organs and/or by an autoimmune response to host antigens. This review discusses the findings that support the notion of an integrated immune response, considering the innate and adaptive arms of the immune system in the control of parasite numbers and also the mechanisms proposed to regulate the immune response in order to tolerate the remaining parasite load, during the chronic phase of infection. This knowledge is fundamental to the understanding of the disease progression and is essential for the development of novel therapies and vaccine strategies.

Keywords: Trypanosoma cruzi, memory T cell, regulatory T cell, gamma delta T cell, interleukin-17, myeloid-derived suppressor cell (MDSC)

This article reviews the immune mechanisms responsible for the control of parasite numbers as well as the mechanisms that control the immune response, avoiding tissue damage and disease.

Graphical Abstract Figure.

Graphical Abstract Figure.

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This article reviews the immune mechanisms responsible for the control of parasite numbers as well as the mechanisms that control the immune response, avoiding tissue damage and disease.

INTRODUCTION

The intracellular protozoan parasite Trypanosoma cruzi causes Chagas’ disease in humans (Koberle 1968; Andrade, Gollob and Dutra 2014). The infection is characterized by an acute phase resulting in parasitemia that resolves upon the appearance of an effective immune response (Cardillo et al. 2002). In humans and mice, the acute infection is characterized by high parasitemia that increases after 1–8 weeks following infection, depending on the T. cruzi strain (Cardillo et al. 1996). However, the immune response induced during the acute infection is not sufficient to completely eradicate the pathogen, thus resulting in chronic infection (Albareda et al. 2006). The chronic form of the disease mainly affects the peripheral autonomous nervous system in the gastrointestinal tract and heart and the heart muscle in approximately 30% of the infected patients (Koberle 1968; Andrade, Gollob and Dutra 2014). The chronic infection may be accompanied by additional autoimmune mechanisms triggered by the parasite and its persistence (dos Santos et al. 1992; Mengel and Rossi 1992; Bonney and Engman 2008, 2015; Cunha-Neto et al. 2011). Yet, the majority (about 70%) of the patients that progress to the chronic phase remain clinically asymptomatic in the chronic phase of the infection. This condition characterizes the indeterminate form, known as early-indeterminate disease, usually seen in infected children and adolescents, and late-indeterminate disease, generally observed in infected adults (Umezawa et al. 2001).

In this review, we discuss the molecules, cells and possible mechanisms involved in the potentiation and/or the control/downregulation of the immune response during T. cruzi infection.

CELLS AND MOLECULES THAT PROMOTE IMMUNITY IN THE ACUTE PHASE OF T. CRUZI INFECTION

Initial IFN-γ production prior to the generation of T-cell-mediated adaptive immunity is known to occur during the course of many infections and may be important in the development of resistance to many intracellular infections such as Leishmania, Salmonella, Toxoplasma and T. cruzi (Locksley and Scott 1991; Ramarathinam, Niesel and Klimpel 1993; Sher et al. 1993; Cardillo et al. 1996). Natural killer cells may be the major cell type responsible for IFN-γ production in the early stages of T. cruzi infection and their activation requires the presence of live parasites (Cardillo et al. 1996). In addition, innate or adaptive immune cells, such as dendritic cells, macrophages, NKT lymphocytes, γδ T cells and B cells, may contribute to host resistance (Locksley and Scott 1991; Sher et al. 1993; Cardillo et al. 1996; Galli et al. 2003, 2007; Takahashi and Strober 2008).

Dendritic cells (DCs) and/or macrophages act as professional antigen-presenting cells and are central in the initiation and development of immunity or tolerance (Lanzavecchia and Sallusto 2001; Steinman, Hawiger and Nussenzweig 2003). Trypomastigotes are responsible for the generation of regulatory DCs in vitro (Sher et al. 1993; Poncini et al. 2008; da Costa et al. 2014). The production of TNF-α, IFN-γ, IL-12, IL-22, IL-6, IL-10 and CCL2 and the expression of CD40, CD80, MHC-II, PD-L1, CCR5 and CCR7 may be different, depending on the T. cruzi strain used for stimulation (Poveda et al. 2014; da Costa et al. 2014). These results strongly argue that DCs, monocytes and macrophages are active players in the modulation of the adaptive immune response to T. cruzi (Rezende-Oliveira, Sarmento and Rodrigues 2012; Pinho et al. 2014) and may be useful to manipulate immunity/tolerance either before or during the infection (Poncini et al. 2015; Rampazo et al. 2015).

NK1.1+ cells may participate in generating memory T cells, since their depletion in acute infection diminished the generation of the activated/memory T cells in the spleen of T. cruzi-infected mice (Cardillo et al. 2002). In fact, this resulted in larger numbers of T cells expressing CD69, without the corresponding formation of effector T cells (Cardillo et al. 2004). Furthermore, the depletion of NK1.1+ cells caused an earlier appearance of anti-T. cruzi IgM antibodies and less isotype switching to IgG at later time points, suggesting a diminished T-cell-helper response (Cardillo et al. 2002). However, these studies did not discriminate between CD3– and CD3+ NK cells, as they were performed with depleting monoclonal antibodies to the NK1.1 molecule.

Other studies using CD1 and/or V alpha 14 knockout mice have shown that natural killer T cells (NKT cells) may play more discrete or opposing functions during the acute phase of T. cruzi infection (Duthie et al. 2002; Procopio et al. 2002; Miyahira et al. 2003; Duthie et al. 2005a,b), but the net results point to a role of these cells in resistance to T. cruzi infection. However, the mechanisms by which these cells contribute to the immune response to acute infection are not clear yet and might also involve a regulatory function, dampening T-cell hyperactivation, and IFN-γ and NO production (Cardillo et al. 2004). Activated NK cells, bearing a particular phenotype (CD16 + CD56–), were found to increase during the acute phase of Chagas’ disease in children (Sathler-Avelar et al. 2003). However, the exact mechanism used by NK cells to help in the control of the infection in humans is not clear. The mechanism might rely on the secretion of cytokines such as IFN-γ and TNF-α by parasite activated NK cells, thus amplifying the innate and/or the adaptive immune responses (Andrade, Gollob and Dutra 2014).

Another T-cell lineage that might be involved in up- or downregulation of the immune response to T. cruzi during the acute phase of the infection is the γδ T lymphocyte (Cardillo et al. 1993; Nomizo et al. 2006). γδ T cells are not homogeneous and their functions may vary depending on T-cell receptor usage and different stimulatory conditions (Chien and Hampl 2000; Chien, Meyer and Bonneville 2014). A small subpopulation, bearing the Vγ1 chain, is found in the thymus and in the secondary lymphoid organs such as the spleen, lymph nodes and the GALT of the adult mouse (Azuara et al. 1997, 2001; Azuara, Lembezat and Pereira 1998; Azuara and Pereira 2000). Part of this subset also expresses NK1.1 molecules (Azuara et al. 1997) and the administration of a monoclonal antibody to the Vγ1 chain results in increased susceptibility to T. cruzi infection (Nomizo et al. 2006). These cells appear to function as helpers for conventional CD4 T cells, increasing the formation of memory T cells and their IFN-γ production. Taken together, the previously mentioned studies show that the NK1.1+ cell subset is composed by different lineages, having complex functions (Werner et al. 2011). In spite of this, these cells may function by helping conventional T cells to fully differentiate into memory cells, since in their absence conventional T cells might accumulate in an early stage of activation. This would lead to elevated production of inflammatory cytokines and oxygen-containing toxic molecules in peripheral lymphoid organs, since these cells do not migrate efficiently to infected tissues and are ineffective parasite killers in infected tissues. The overall result would be immune hyperactivation accompanied by poor parasite growth control and early death of the host (Cardillo et al. 2004).

B lymphocytes are also required to mount an effective immune response to T. cruzi, helping in the control of the infection (Cardillo et al. 2007; Sullivan et al. 2015). The disease in C57BL/6 muMT KO mice is more severe than in control mice, with higher parasitemia levels and a poor generation of central and effector memory CD4+ and CD8+ T cells in the spleen. During early stages of the T. cruzi infection, B cells are fundamental to trigger T-cell functions related to the Th1 pathway that favor the control of parasite growth (Cardillo et al. 2007). Therefore, in the absence of mature B cells, the immune system is unable to generate and/or maintain central and effector memory CD8+ T cells and to instruct a Th1 functional pattern of T-cell cytokines, since the levels of proinflammatory cytokines such as IFN-γ and IL-12 are reduced in spleen cell supernatants from mice lacking mature B cells (Cardillo et al. 2007). Tissue inflammatory responses in these mice are much less intense in the acute phase of the infection, which is consistent with a deficit in the generation of effector T cells. Furthermore, the preponderant cell type in the skeletal muscle inflammatory infiltrate is the CD4+ T cell, contrary to what is observed in B-cell-sufficient mice, where CD8+ T cells dominate in the inflammatory infiltrate (Cardillo et al. 2007). Adoptively transferred splenic B cells induce increased numbers of both effector/memory splenic CD4 and CD8 T cells, during early chronic infection (Cardillo et al. in preparation). Accordingly, it has been reported that the development, maintenance and functional activities of memory CD8+ T cells during immune responses are dependent on the generation of memory CD4+ T cells and B cells (Williams et al. 2006; Sullivan et al. 2015). Besides, it has been described that B cells may themselves produce many different cytokines upon stimulation, including IFN-γ, IL-10, IL-12, IL-17 and BAFF/BLyS (O'Garra et al. 1990; Mengel et al. 1992; Pang et al. 1992; Veras et al. 2006; Wojciechowski et al. 2009; Amezcua Vesely et al. 2012; Bermejo et al. 2013). In addition, in the chronic phase of T. cruzi infection one may speculate that B cells modulate the immune response through IL-10 production, since the transfer of B cells from IL-10 knockout mice to mu knockout mice helps to control the acute infection, but also leads to an increased inflammatory heart disease in the chronic phase (Cardillo et al. in preparation). Regarding this topic and until recently, virtually no report addressed the real phenotypic markers of B cells producing IL-10, in humans. Thus, the CD19+ CD5+ CD1d+ IL-10+ B cells were found to be increased in chronic chagasic patients. In addition, a higher expression of CD21 and CD24 on the surface of circulating CD19+ B cells has been shown in those patients. The study also showed that the expression of MHC-II (HLA-DR), CD80, CD86, caspase-3, granzyme B and intracellular IL-10 and TGF-β by CD19+ B cells was higher in patients with chronic Chagas disease (Fares et al. 2013).

In summary, in T. cruzi experimental infection, with the Tulahuen strain, the development and function of memory CD8+ and CD4+ T cells are greatly modulated by NK1.1+ and B cells, since lower numbers of memory T cells are formed in acute infection when these subsets are absent. In addition, high parasite load has been observed in NK1.1 cell- or B-cell-depleted mice, indicating that the conversion of activated to effector memory cells is an important step in the control of infection levels and mortality.

The initial magnitude of CD8+ T-cell responses appears to be one of the critical factors in determining the final size of the antigen-specific memory T-cell pool (Olivieri, Cotta-De-Almeida and Araujo-Jorge 2002; Williams et al. 2006; Bixby and Tarleton 2008; Bustamante, Bixby and Tarleton 2008; Miyahira 2008). Central memory CD8+ T cells, expressing high levels of CD44 and CD62L and reduced expression of KLRG1, a marker of repetitive antigen stimulation and cell exhaustion (Bustamante, Bixby and Tarleton 2008), are detectable in the late acute phase among the parasite-specific CD8+ T cells, being related to the low parasite load found in the chronic phase of T. cruzi infection. Therefore, it seems that the central memory CD8+ T-cell population increases as the infection becomes chronic and this pool may be important to dynamically replace cells in the memory/effector T-cell pool, as previously suggested (Sallusto et al. 2010). Interestingly, treatment with benznidazole during the acute phase of the infection lowers the parasitemia and also induces a stable pool of central memory CD8+ T cells (Olivieri, Cotta-De-Almeida and Araujo-Jorge 2002; Bixby and Tarleton 2008). In addition, an increase in total effector/memory CD8+ T cells in T. cruzi-infected subjects has been reported (Leavey and Tarleton 2003; Fiuza et al. 2009). However, the authors also claimed that these cells would be dysfunctional and this could be a consequence of a gradual clonal exhaustion in the CD8+ T-cell population, perhaps as a result of continuous antigenic stimulation by persistent parasites (Leavey and Tarleton 2003). This study also showed an increase in the numbers of effector memory CD8+ T cells as the disease progresses, suggesting that the central memory T-cell pool could be, in fact, a source of effector memory T cells. Consequently, its depletion may worsen the disease by increasing tissue parasite load during the chronic phase of the infection, since the accumulation of effector/memory CD8 T cells would be less effective in controlling the infection because they would be functionally exhausted. However, in another series of experiments, resistance in the acute phase of murine T. cruzi infection correlated with higher percentages of effector/memory T cells prior to infection (Cardillo et al. 2002). This was the case for mature/aged or thymectomized mice, where T cells are submitted to homeostatic expansion due to thymic hypofunction and acquire memory/effector markers (Cardillo, Nomizo and Mengel 1998; Cardillo et al. 2002). In fact, the levels of effector/memory T cells could be inversely correlated with host susceptibility, since the higher the numbers of effector/memory T cells found in mature/aged or thymectomized mice, the lower their susceptibility (Cardillo et al. 1993, 2002). Therefore, it appears that effector/memory T cells are required to control infection, but a pool of central memory T cells is also important to replenish exhausted effector/memory T cells. The restricted availability of reagents to follow parasite specific T cells has hampered more detailed studies, aiming at the evaluation of memory T cells during the acute Chagas’ disease. However, after culturing mononuclear cells from chronic patients with T. cruzi extracts, we have found a preferential in vitro expansion of CD4 + Vβ5+ T cells. In addition, we have shown a decrease in Vβ5 expression in the CD4± T-cell population freshly isolated from acutely infected chagasic individuals, probably reflecting tissue redistribution rather than depletion, whereas CD4 + Vβ5+ T cells were found to be increased in a subset of chronic chagasic patients (Costa et al. 2000). As a whole, the results showed a differential Vβ-TCR usage in different stages of the disease, and that parasite antigens stimulate a portion of the T-cell repertoire with preferential usage of Vβ5-TCR. Therefore, CD4 + Vβ5+ T cells are a unique population of CD4 T cells to be analyzed in future studies, regarding the dynamics of memory T-cell formation in humans.

HOW (AUTO)IMMUNITY IS CONTROLLED DURING T. CRUZI INFECTION

As pointed out above, T. cruzi induces a strong immune response against its own components, but the infection also induces a measurable immune response to host self-antigens (dos Santos et al. 1992; Bonney and Engman 2008; Bonney and Engman 2015). Antigenic mimicry between parasite antigens and host antigens may underlie the reasons for the anti-host autoimmune response (Wood et al. 1982; Duranti et al. 1999; Cunha-Neto et al. 2006). However, antigenic mimicry and immune crossreactivity among parasite antigens and host antigens are not always deleterious and may even be beneficial to a balanced parasite/host relationship (Pontes-de-Carvalho et al. 2013; Massilamany, Gangaplara and Reddy 2015). Therefore, a malfunction of regulatory immune mechanisms may also be involved in the autoimmune responses during the infection (Cardillo et al. 1993, Cardillo, Nomizo and Mengel 1998; Mariano et al. 2008). It is debatable whether the autoimmune response found during the T. cruzi infection is actually the causative factor leading to organ damage during the chronic phase of the disease (Cunha-Neto et al. 2011). However, both the immune response to parasite antigens and host self-antigens are not dissociated and occur concomitantly (Gattass et al. 1988; Cunha-Neto et al. 2011), and therefore should both be considered as promoters of tissue lesion during infection. A similar condition is found in autoimmune inflammatory bowel diseases (IBD), which ameliorate with the use of antibiotics, suggesting a role for bacteria as an important factor for the disease initiation or persistence (Sokol 2014). Yet, in IBD there is a considerable overlap between immunity and autoimmunity (Cassinotti et al. 2014). This means that it is not just an infection per se that may trigger autoimmunity, but an infection that is inappropriately dealt with (Sester et al. 2015). Nevertheless, in most of the chronically T. cruzi-infected patients, a perfectly balanced immune response is achieved and pathology is never manifested (Rassi, Rassi and Marin-Neto 2010). In addition, it has been described that susceptibility to T. cruzi infection might reflect an overreactive host immune response that kills most of the susceptible individuals without being effective in the control of the parasite load (Nascimento et al. 2002; Cardillo et al. 2004). In any of the cases described above, regulatory mechanisms are at the core of the problem, either dealing with resistance/susceptibility in acute infection or health/disease during the chronic phase.

Many cells and molecules have being described to have regulatory/suppressor activity during T. cruzi infection (Cardillo et al. 1993; Lopes and Reis 1994; Abrahamsohn and Coffman 1995; Pinge-Filho et al. 1999; Cuervo et al. 2011). For instance, splenic adherent cells or macrophages were described to suppress T-cell responses in vitro, by the release of mediators such as prostaglandins (Pinge-Filho et al. 1999) and nitric oxide (Abrahamsohn and Coffman 1995). More recently, myeloid-derived suppressor cells (MDSCs) were claimed to be responsible for controlling or suppressing immune responses during acute T. cruzi infection (Cuervo et al. 2011; Goni, Alcaide and Fresno 2002; Arocena et al. 2013).

In another series of experiments, using mice of the BALB/c genetic background, we were the first to demonstrate that γδ T cells were involved in the suppression of immune responses during the acute phase of T. cruzi infection in vitro and in vivo (Cardillo et al. 1993; Cardillo, Nomizo and Mengel 1998). The in vivo depletion of γδ T cells by an anti-δ monoclonal antibody (Costa et al. 2015) raised the levels of IFN-γ produced by αβ T cells in the acute infection similarly to the in vivo blocking of IL-17 (Matta Guedes et al. 2010), and promoted the recovery of a third party humoral immune response to ovalbumin during the acute T. cruzi infection (Cardillo, Nomizo and Mengel 1998). The γδ T-cell suppressor activity was absent in the spleens of thymectomized and aged mice, suggesting that those cells were dependent upon an intact thymic function (Cardillo et al. 1993; Cardillo, Nomizo and Mengel 1998). Thymic output of naïve T cells clearly downmodulated effector responses, since the continuous administration of thymocytes to either aged mice, young thymectomized mice or total spleen cell-reconstituted athymic mice markedly decreased splenic cell proliferation to non-specific stimulation and increased parasitism in recipient T. cruzi-infected mice (Cardillo, Nomizo and Mengel 1998). More recently, one study described that T cells bearing the Vγ4 TCR chain were responsible for producing large amounts of IL-17, resulting in an increase of MDSCs that had the ability to downregulate pathogen-responsive T cells, contributing to parasite persistence (Kong et al. 2014). Additionally, these Vγ4 T cells are produced and exported by the thymus as IL-17 producers (Schmolka et al. 2013). Some γδ T-cell subpopulations, again through the production of IL-17, were also implicated in the augmentation of MDSC numbers in tumor microenvironments, either in mice or humans, promoting tumor growth by opposing cancer immunosurveillance (Rei et al. 2014; Wu et al. 2014). It should be pointed out that most, if not all, γδ T cells in lymphoid organs of the murine BALB/c background produced only IL-17 and no IFN-γ, in contrast to other mouse strains where these cytokines are produced by different γδ T-cell subpopulations (Wakita et al. 2010). Consequently, the overall function of γδ T cells during T. cruzi infection might be dependent on the genetic background where both T. cruzi and mouse strains should be considered. Therefore, it seems that a subpopulation of γδ T cells, producing high levels of IL-17, is the candidate to modulate the numbers of MDSCs that might be the final suppressor cells in the acute phase of T. cruzi infection.

It should be pointed out that the mechanisms described above are easily detected along the acute phase of the infection and vanish after parasite growth is controlled or during the chronic phase of the disease. Therefore, they are less likely to perform these regulatory functions during the chronic infection and in fact, there is no evidence that these mechanisms are operative after the infection is controlled.

The contribution of other regulatory cell populations such as Tr1 and Treg (CD4 + CD25 + Foxp3+) T cells to the immune response modulation, during the acute infection, is not clear yet. It has been shown that IL-10 may function to increase host survival and also to help in the control of parasite load in some models (Hunter et al. 1997; Roffe et al. 2012). However, the exact source of IL-10 has not been studied in detail. In addition, high levels of IL-10 were recently related to protection against cardiomyopathy in human subjects, indicating that this cytokine is of critical importance in the regulation of the immune response during T. cruzi infection (Dutra et al. 2014). The role of CD4 + CD25 + Foxp3+ Treg cells has also been evaluated and early mouse studies where these cells were depleted by monoclonal antibodies to CD25 indicated that their role in the regulation of immunity during the acute phase of the T. cruzi infection is rather limited (Kotner and Tarleton 2007; Sales et al. 2008). On the contrary, recent findings in humans have shown an increased percentage of Treg cells in chagasic subjects in the indeterminate chronic phase (free of disease) when compared to patients with heart damage, suggesting an important role for Tregs in Chagas disease (de Araujo et al. 2011). Moreover, it has been recently demonstrated, using a nondepleting monoclonal antibody to CD25, that regulatory CD4 + CD25 + Foxp3+ T cells may also help to control the adaptive immune response, during the acute infection, in mice (Nihei et al. 2014). The immunomodulatory activity of the nondepleting monoclonal antibody to CD25 was similar to that which has been described for humans (Huss et al. 2015) and encompassed a delayed increase of Treg frequencies and an augmented production of IL-10 and TNF-α by T cells. Interestingly, it was demonstrated that TNF-α levels are significantly higher in Chagas' disease patients with severe ventricular arrhythmias and in patients with dilated cardiomyopathy, suggesting that this cytokine could be detrimental to the heart (Ferreira et al. 2003). However, in one study, using the mouse model, in vivo blockade of TNF-α during the chronic phase of T. cruzi infection aggravated cardiomyopathy, suggesting that TNF-α would have a protective role (Bilate et al. 2007). In fact, it has been recently shown that TNF-α is cardioprotective in both mice and humans (Papathanasiou et al. 2015). In addition and more importantly, there was a clear indication that the functional activity of Treg cells might be of crucial importance during the acute and chronic phases of the infection, decreasing tissue destruction and pathology (Nihei et al. 2014; Bonney et al. 2015). Therefore, the notion concerning the manipulation of Treg cells either by antibodies or even interleukins such as IL-2 (Kosmaczewska 2014) might open up a new avenue for therapeutic strategies in Chagas' disease.

CONCLUDING REMARKS

The study of acute and chronic phases of infection with intracellular pathogens, such as T. cruzi, allows the elucidation of the mechanisms and conditions that may be targeted to reprogram the host immune system, either by using tools that interfere with components of the regulatory arm of the immune system machinery (Nihei et al. 2014) or by improving therapeutic vaccine strategies (Pereira et al. 2015). This knowledge would certainly result in a better understanding of the necessary balance to achieve or reestablish the health of the host during T. cruzi infection, thus providing new strategies to treat Chagas' disease, besides the use of drugs that kills the parasite in vivo, sterilizing the host—a difficult task to achieve because the available treatments are not always efficient, having many toxic collateral effects, so that clinical researchers have not reached a consensus about them after more than 30 years of their clinical use and in addition, parasite resistance to these drugs is common and well documented (Bestetti and Restini 2014; Molina, Salvador and Sanchez-Montalva 2014; Molina et al. 2014; Rassi, Rassi and Marin-Neto 2014; Zingales et al. 2015). Of note, the authors of a randomized, double-blind, placebo-controlled trial in which trypanocidal therapy with benznidazole was evaluated in patients with established Chagas' cardiomyopathy concluded that this type of treatment significantly reduced serum parasite detection but did not significantly reduce cardiac clinical deterioration through 5 years of follow-up (Morillo et al. 2015).

Acknowledgments

We thanks Drs Owen Williams and Lain Pontes de Carvalho for their critical review of the manuscript.

FUNDING

This work was supported by CNPq, PAPES/FIOCRUZ and FOG-FMP/FASE. PRZA is granted with CNPq and FAPERJ research fellowships (PQ-2 and JCNE, respectively).

Conflict of interest. None declared.

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