An effective innate immune recognition of the intracellular protozoan parasite Trypanosoma cruzi is critical for host resistance against Chagas disease, a severe and chronic illness that affects millions of people in Latin America. In this study, we evaluated the participation of nucleotide-binding oligomerization domain (Nod)-like receptor proteins in host response to T. cruzi infection and found that Nod1-dependent, but not Nod2-dependent, responses are required for host resistance against infection. Bone marrow-derived macrophages from Nod1−/− mice showed an impaired induction of NF-κB–dependent products in response to infection and failed to restrict T. cruzi infection in presence of IFN-γ. Despite normal cytokine production in the sera, Nod1−/− mice were highly susceptible to T. cruzi infection, in a similar manner to MyD88−/− and NO synthase 2−/− mice. These studies indicate that Nod1-dependent responses account for host resistance against T. cruzi infection by mechanisms independent of cytokine production.
BackgroundChagas disease is a neglected disease caused by the intracellular parasite Trypanosoma cruzi. Around 30% of the infected patients develop chronic cardiomyopathy or megasyndromes, which are high-cost morbid conditions. Immune response against myocardial self-antigens and exacerbated Th1 cytokine production has been associated with the pathogenesis of the disease. As IL-17 is involved in the pathogenesis of several autoimmune, inflammatory and infectious diseases, we investigated its role during the infection with T. cruzi.Methodology/Principal FindingsFirst, we detected significant amounts of CD4, CD8 and NK cells producing IL-17 after incubating live parasites with spleen cells from normal BALB/c mice. IL-17 is also produced in vivo by CD4+, CD8+ and NK cells from BALB/c mice on the early acute phase of infection. Treatment of infected mice with anti-mouse IL-17 mAb resulted in increased myocarditis, premature mortality, and decreased parasite load in the heart. IL-17 neutralization resulted in increased production of IL-12, IFN-γ and TNF-α and enhanced specific type 1 chemokine and chemokine receptors expression. Moreover, the results showed that IL-17 regulates T-bet, RORγt and STAT-3 expression in the heart, showing that IL-17 controls the differentiation of Th1 cells in infected mice.Conclusion/SignificanceThese results show that IL-17 controls the resistance to T. cruzi infection in mice regulating the Th1 cells differentiation, cytokine and chemokine production and control parasite-induced myocarditis, regulating the influx of inflammatory cells to the heart tissue. Correlations between the levels of IL-17, the extent of myocardial destruction, and the evolution of cardiac disease could identify a clinical marker of disease progression and may help in the design of alternative therapies for the control of chronic morbidity of chagasic patients.
Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease.
Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1 ؊/؊ mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.Chagas' disease is the most important cause of acquired cardiomyopathy in Latin America and is one of the outcomes resulting from the interaction between the human immune system and the hemoflagellate prokaryote Trypanosoma cruzi. In the natural infection, the flagellated forms in the feces of infected hematophagous insects of the Triatominae subfamily invade the host through skin lesions or intact mucosa. The parasite then proliferates intracellularly and disseminates systemically from the site of inoculation, causing an inflammatory reaction of variable intensity, along with splenomegaly, cardiac parasitism, and myocarditis, which is largely associated with morbidity. More frequently, a chronic asymptomatic infection is established, which eventually leads to dilated cardiomyopathy and heart failure as well as esophageal or intestinal dilatations due to the combined effects of parasite persistence, immune deregulation, autonomic denervation, and microvascular damages (21,30).The immunological mechanisms underlying this silent, relentless infection and heart pathology remain elusive despite several decades of research. It is known that T cell-mediated immune responses are essential to control the parasite replication during the acute phase of the infection (33). The cytokines gamma interferon (IFN-␥), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-␣) strengthen the activation of innate and adaptive ...
Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-γ and TNF-α are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-γ and TNF-α by CD8+ T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL-4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2−/− mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus-induced pancreatitis, which is a major medical condition with unmet clinical needs.
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