Brain-Thymus Connections in Chagas Disease.

BACKGROUND: The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. SUMMARY: The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease. KEY MESSAGES: During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.

Outcomes of patients in Chagas disease of the central nervous system: a systematic review.

Chagas disease is a parasitic infection caused by the protozoan Trypanosoma cruzi. One of the complications of the disease is the infection of the central nervous system (CNS), as it can result from either the acute phase or by reactivation during the chronic phase, exhibiting high mortality in immunocompromised patients. This systematic review aimed to determine clinical and paraclinical characteristics of patients with Chagas disease in the CNS. Articles were searched from PubMed, Scopus and LILACS until January 2023. From 2325 articles, 59 case reports and 13 case series of patients with Chagas in the CNS were retrieved from which 138 patients were identified. In this population, 77% of the patients were male, with a median age of 35 years old, from which most of them came from Argentina and Brazil. Most of the individuals were immunocompromised from which 89% were HIV-positive, and 54 patients had an average of 48 cells per mm3 CD4+ T cells. Motor deficits and seizures were the most common manifestation of CNS compromise. Furthermore, 90 patients had a documented CNS lesion by imaging from which 89% were supratentorial and 86% were in the anterior/middle cranial fossa. The overall mortality was of 74%. Among patients who were empirically treated with anti-toxoplasma drugs, 70% died. This review shows how Chagas disease in the CNS is a devastating complication requiring prompt diagnosis and treatment to improve patients' outcomes.

Trypanosoma cruzi screening in people living with HIV in the UK.

People living with HIV (PLWH) are at higher risk of reactivation of Chagas disease, a neglected tropical disease, caused by Trypanosoma cruzi. There are no data from UK HIV clinics on the prevalence of T. cruzi. We implemented T. cruzi screening at our clinic as part of routine care for PLWH with epidemiological risk factors. Among 86 patients screened, none had positive serology: one seropositive patient was identified due to increased clinician awareness. Implementing T. cruzi screening as part of routine clinical care was feasible, though labour intensive and identified at-risk individuals.

Ursolic acid-rich extract presents trypanocidal action in vitro but worsens mice under experimental acute Chagas disease.

Chagas disease is a neglected tropical disease with only two drugs available for treatment and the plant Cecropia pachystachya has several compounds with antimicrobial and anti-inflammatory activities. This study aimed to evaluate a supercritical extract from C. pachystachya leaves in vitro and in vivo against Trypanosoma cruzi. A supercritical CO2 extraction was used to obtain the extract (CPE). Cytotoxicity and immunostimulation ability were evaluated in macrophages, and the in vitro trypanocidal activity was evaluated against epimastigotes and trypomastigotes forms. In vivo tests were done by infecting BALB/c mice with blood trypomastigotes forms and treating animals orally with CPE for 10 days. The parasitemia, survival rate, weight, cytokines and nitric oxide dosage were evaluated. CPE demonstrated an effect on the epi and trypomastigotes forms of the parasite (IC50 17.90 ± 1.2 µg/mL; LC50 26.73 ± 1.2 µg/mL) and no changes in macrophages viability, resulting in a selectivity index similar to the reference drug. CPE-treated animals had a worsening compared to non-treated, demonstrated by higher parasitemia and lower survival rate. This result was attributed to the anti-inflammatory effect of CPE, demonstrated by the higher IL-10 and IL-4 values observed in the treated mice compared to the control ones. CPE demonstrated a trypanocidal effect in vitro and a worsening in the in vivo infection due to its anti-inflammatory activity.

Histology and histochemistry of the accessory gland of the female reproductive tract of Rhodnius neglectus Lent, 1954 (Hemiptera: Reduviidae).

Rhodnius neglectus is a wild triatomine, vector of the protozoan Trypanosoma cruzi, which causes Chagas' disease, and feeds on the blood of small mammals, being essential for its growth and reproduction. Accessory glands of the female reproductive tract are important in insect reproduction, but their anatomy and histology in R. neglectus are poorly studied. The aim of this work was to describe the histology and histochemistry of the accessory gland of the female reproductive tract of R. neglectus. The reproductive tract of five females of R. neglectus was dissected and the accessory glands transferred to Zamboni's fixative solution, dehydrated in a crescent series of ethanol, embedded in historesin, sectioned at 2 µm thick, stained with toluidine blue for histological analysis or mercury bromophenol blue for detection of total proteins. The accessory gland R. neglectus is tubular, without branches, opening in the dorsal region of the vagina and differing along its length in proximal and distal regions. In the proximal region, the gland is lined by the cuticle with a layer of columnar cells associated with muscle fibers. In the distal region of the gland, the epithelium has spherical secretory cells with terminal apparatus and conducting canaliculi opening in the lumen through pores in the cuticle. Proteins were identified in the gland lumen, terminal apparatus, nucleus and cytoplasm of secretory cells. The histology of the R. neglectus gland is similar to that found in other species of this genus, but with variations in the shape and size of its distal region.

Transcriptomic analysis of the adaptation to prolonged starvation of the insect-dwelling Trypanosoma cruzi epimastigotes.

Trypanosoma cruzi is a digenetic unicellular parasite that alternates between a blood-sucking insect and a mammalian, host causing Chagas disease or American trypanosomiasis. In the insect gut, the parasite differentiates from the non-replicative trypomastigote forms that arrive upon blood ingestion to the non-infective replicative epimastigote forms. Epimastigotes develop into infective non-replicative metacyclic trypomastigotes in the rectum and are delivered via the feces. In addition to these parasite stages, transitional forms have been reported. The insect-feeding behavior, characterized by few meals of large blood amounts followed by long periods of starvation, impacts the parasite population density and differentiation, increasing the transitional forms while diminishing both epimastigotes and metacyclic trypomastigotes. To understand the molecular changes caused by nutritional restrictions in the insect host, mid-exponentially growing axenic epimastigotes were cultured for more than 30 days without nutrient supplementation (prolonged starvation). We found that the parasite population in the stationary phase maintains a long period characterized by a total RNA content three times smaller than that of exponentially growing epimastigotes and a distinctive transcriptomic profile. Among the transcriptomic changes induced by nutrient restriction, we found differentially expressed genes related to managing protein quality or content, the reported switch from glucose to amino acid consumption, redox challenge, and surface proteins. The contractile vacuole and reservosomes appeared as cellular components enriched when ontology term overrepresentation analysis was carried out, highlighting the roles of these organelles in starving conditions possibly related to their functions in regulating cell volume and osmoregulation as well as metabolic homeostasis. Consistent with the quiescent status derived from nutrient restriction, genes related to DNA metabolism are regulated during the stationary phase. In addition, we observed differentially expressed genes related to the unique parasite mitochondria. Finally, our study identifies gene expression changes that characterize transitional parasite forms enriched by nutrient restriction. The analysis of the here-disclosed regulated genes and metabolic pathways aims to contribute to the understanding of the molecular changes that this unicellular parasite undergoes in the insect vector.

mTOR signaling inhibition decreases lysosome migration and impairs the success of Trypanosoma cruzi infection and replication in cardiomyocytes.

Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi) and, among all the chronic manifestations of the disease, Chronic Chagas Cardiomyopathy (CCC) is the most severe outcome. Despite high burden and public health importance in Latin America, there is a gap in understanding the molecular mechanisms that results in CCC development. Previous studies showed that T. cruzi uses the host machinery for infection and replication, including the repurposing of the responses to intracellular infection such as mitochondrial activity, vacuolar membrane, and lysosomal activation in benefit of parasite infection and replication. One common signaling upstream to many responses to parasite infection is mTOR pathway, previous associated to several downstream cellular mechanisms including autophagy, mitophagy and lysosomal activation. Here, using human iPSC derived cardiomyocytes (hiPSCCM), we show the mTOR pathway is activated in hiPSCCM after T. cruzi infection, and the inhibition of mTOR with rapamycin reduced number of T. cruzi 48 h post infection (hpi). Rapamycin treatment also reduced lysosome migration from nuclei region to cell periphery resulting in less T. cruzi inside the parasitophorous vacuole (PV) in the first hour of infection. In addition, the number of parasites leaving the PV to the cytoplasm to replicate in later times of infection was also lower after rapamycin treatment. Altogether, our data suggest that host's mTOR activation concomitant with parasite infection modulates lysosome migration and that T. cruzi uses this mechanism to achieve infection and replication. Modulating this mechanism with rapamycin impaired the success of T. cruzi life cycle independent of mitophagy.

A qualitative exploration of knowledge of Chagas disease among adolescents in rural Ecuador.

INTRODUCTION: Chagas disease (CD) is a neglected tropical disease that affects 6 to 7 million people worldwide. In South America, CD is a major health problem in several regions, causing more than 12 000 deaths per year. CD is caused by a parasite called Trypanosoma cruzi, mostly transmitted through the contaminated feces of certain species of triatomine bug, commonly known as the 'kissing bug'. CD is endemic in Loja province in the southern region of Ecuador, where triatomines have been found in 68% of communities. Previous promotion of healthy practices in Loja province have included educational programs directed toward youth to affirm cultural and social norms that support health and prevent CD transmission. The present study was designed to evaluate current knowledge related to CD among youth in the three communities of Loja province following previous intervention programs. METHODS: A descriptive, qualitative approach was applied using individual semi-structured interviews with 14 young people (eight females, six males) from three rural communities in Loja province. Interviews assessed knowledge about CD transmission, knowledge about the parasite-vector-disease pathway, and the role of youth in preventing Chagas disease in their communities. RESULTS: Following a thematic analysis of the data, the study results showed there is cursory knowledge of the triatomine insect that can carry the causative parasite for CD. Participants were able to generally talk about the vector, habitat and prevention practices for triatomine infestation. Nevertheless, limited understanding of transmission dynamics in the parasite-vector-disease pathway itself was found. One major finding was that prevention practices were not correctly applied or followed, increasing the risk of exposure in the community. Youth also articulated that CD is stigmatized in their communities, which may be a barrier for prevention efforts. CONCLUSION: Gaps in knowledge about the parasite-vector-disease pathway were identified among youth. Overall, youth responses indicated positive regard for prevention practices and a desire to be involved in prevention programs. Developing educational programs focusing on CD transmission may be needed to improve control and prevention of this parasitic disease. The implications of these findings are discussed for developing effective control programs in the region.

Transcriptional changes during metacyclogenesis of a Colombian Trypanosoma cruzi strain.

During its life cycle, Trypanosoma cruzi undergoes physiological modifications in order to adapt to insect vector and mammalian host conditions. Metacyclogenesis is essential, as the parasite acquires the ability to infect a variety of mammalian species, including humans, in which pathology is caused. In this work, the transcriptomes of metacyclic trypomastigotes and epimastigotes were analyzed in order to identify differentially expressed genes that may be involved in metacyclogenesis. Toward this end, in vitro induction of metacyclogenesis was performed and metacyclic trypomastigotes obtained. RNA-Seq was performed on triplicate samples of epimastigotes and metacyclic trypomastigotes. Differential gene expression analysis showed 513 genes, of which 221 were upregulated and 292 downregulated in metacyclic trypomastigotes. The analysis showed that these genes are related to biological processes relevant in metacyclogenesis. Within these processes, we found that most of the genes associated with infectivity and gene expression regulation were upregulated in metacyclic trypomastigotes, while genes involved in cell division, DNA replication, differentiation, cytoskeleton, and metabolism were mainly downregulated. The participation of some of these genes in T. cruzi metacyclogenesis is of interest, as they may be used as potential therapeutic targets in the design of new drugs for Chagas disease.

Resisting an invasion: A review of the triatomine vector (Kissing bug) defense strategies against a Trypanosoma sp infection.

Triatomines are an important group of insects in the Americas. They serve as transmission vectors for Trypanosoma cruzi, the etiologic agent responsible for the deadly Chagas disease in humans. The digenetic parasite has a complex life cycle, alternating between mammalian and insect hosts, facing different environments. In the insect vector, the metacyclic trypomastigote (non-replicative) and epimastigote (replicative) stages face a set of insect-mediated environmental changes, such as intestinal pH, body temperature, nutrient availability, and vector immune response. These insects have the ability to differentiate between self and non-self-particles using their innate immune system. This immune system comprises physical barriers, cellular responses (phagocytosis, nodules and encapsulation), humoral factors, including effector mechanisms (antimicrobial peptides and prophenoloxidase cascade) and the intestinal microbiota. Here, we consolidate and synthesize the available literature to describe the defense mechanisms deployed by the triatomine vector against the parasite, as documented in recent years, the possible mechanisms developed by the parasite to protect against the insect's specific microenvironment and innate immune responses, and future perspectives on the Triatomine-Trypanosome interaction.

Central nervous system commitment in Chagas disease.

The involvement of the central nervous system (CNS) during human acute and chronic Chagas disease (CD) has been largely reported. Meningoencephalitis is a frequent finding during the acute infection, while during chronic phase the CNS involvement is often accompanied by behavioral and cognitive impairments. In the same vein, several studies have shown that rodents infected with Trypanosoma cruzi (T. cruzi) display behavior abnormalities, accompanied by brain inflammation, in situ production of pro-inflammatory cytokines and parasitism in diverse cerebral areas, with involvement of microglia, macrophages, astrocytes, and neurons. However, the mechanisms used by the parasite to reach the brain remain now largely unknown. Herein we discuss the evidence unravelling the CNS involvement and complexity of neuroimmune interactions that take place in acute and chronic CD. Also, we provide some clues to hypothesize brain infections routes in human and experimental acute CD following oral infection by T. cruzi, an infection route that became a major CD related public health issue in Brazil.

IL-1ß is not critical to chronic heart dysfunction in mice with Chagas disease.

Long after Trypanosoma cruzi infection, 40% of individuals develop a progressive chronic chagasic cardiomyopathy (CCC), with systolic dysfunction and arrhythmias. Since we previously showed IL-1ß mediates the development of systolic dysfunction and cardiac arrhythmias in diabetes mellitus and cardiorenal syndrome, and IL-1ß remains elevated in Chagas disease patients, here we tested the role of IL-1ß in CCC using a mouse model. Mice deficient in IL-1R expression (Il-1r-/- ) survived acute T. cruzi infection with greater parasitemia than controls but did not lose weight as wild-type (WT) did. At the chronic stage, WT presented prolonged ventricular repolarization intervals (QJ), while Il-1r-/- presented intervals like noninfected controls. Infected Il-1r-/- and WT did not differ in stroke volume (SV), the incidence of cardiac arrhythmias on electrocardiography (EKG), whole heart action potential duration (APD), or the incidence of triggered activity after S1-S2 protocol, which is a measure of susceptibility to cardiac arrhythmias. We also treated chronically infected WT mice with an IL-1R antagonist, anakinra. Treatment shortened the QJ interval but did not improve the SV or the incidence of cardiac arrhythmias on EKG. Anakinra failed to reduce triggered activity following the electrical extra-stimulation protocol. In conclusion, the absence of functional IL-1ß/IL-1R signaling did not prevent or reverse the decrease of SV or the incidence of cardiac arrhythmias induced by chronic T. cruzi infection, implying this is not a critical mechanism in generating or maintaining CCC. Since similar cardiac abnormalities were previously credited to IL-1ß signaling, ruling out this mechanism is important to discourage further attempts of IL-1ß blockade as a therapeutical measure.

Epidemiological-clinical profile and mortality in patients coinfected with Trypanosoma cruzi/HIV: experience from a Brazilian reference center.

BACKGROUND: The recent urbanization of Chagas disease (CD) has contributed to a greater risk of coexistence with human immunodeficiency virus (HIV) and AIDS. METHODS: This retrospective observational study included patients who were followed at INI-Fiocruz between July 1986 and October 2021. All patients underwent an assessment protocol that included sociodemographic profile, epidemiological history, and clinical evaluation. Descriptive data analyses included reports of the medians and frequencies of variables of interest. Differences in medians between groups were tested using the Mann-Whitney U test. Differences in frequency were tested using Fisher's exact test. RESULTS: Among 2201 patients, 11 (0.5%) were identified with Trypanosoma cruzi/HIV coinfection. Of these, 63.6% were women with a median age of 51.0 years old. Two patients had the indeterminate form of CD, six had the cardiac form, two had the digestive form and one had the cardio-digestive form. Half of the patients were undergoing antiretroviral treatment at the time of coinfection diagnosis with a median CD4+ count of 350 cells/µL and a viral load of 1500 copies/µL. Four patients underwent a xenodiagnosis test at coinfection diagnosis, which all yielded positive results; two of them presented high parasitemia under the risk of reactivation. Prophylaxis for CD reactivation was administered to four patients; two with ketoconazole and two with benznidazole. Six patients died after a median follow-up of 22.5 months, with AIDS being the most common cause of death. Only one case of reactivation was observed. CONCLUSIONS: Early diagnosis and prompt treatment of CD reactivation dramatically reduced mortality. Identification of Trypanosoma cruzi/HIV co-infection is crucial to planning a close follow-up of coinfected patients.

Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature.

BACKGROUND: Chronic Chagas Cardiomyopathy (CCC) usually develops between 10 and 20 years after the first parasitic infection and is one of the leading causes of end-stage heart failure in Latin America. Despite the great inter-individual variability in CCC susceptibility (only 30% of infected individuals ever present CCC), there are no known predictors for disease development in those chronically infected. METHODOLOGY/PRINCIPAL FINDINGS: We describe a new susceptibility locus for CCC through a GWAS analysis in the SaMi-Trop cohort, a population-based study conducted in a Chagas endemic region from Brazil. This locus was also associated with CCC in the REDS II Study. The newly identified locus (rs34238187, OR 0.73, p-value 2.03 x 10-9) spans a haplotype of approximately 30Kb on chromosome 18 (chr18: 5028302-5057621) and is also associated with 80 different traits, most of them blood protein traits significantly enriched for immune-related biological pathways. Hi-C data show that the newly associated locus is able to interact with chromatin sites as far as 10Mb on chromosome 18 in a number of different cell types and tissues. Finally, we were able to confirm, at the tissue transcriptional level, the immune-associated blood protein signature using a multi-tissue differential gene expression and enrichment analysis. CONCLUSIONS/SIGNIFICANCE: We suggest that the newly identified locus impacts CCC risk among T cruzi infected individuals through the modulation of a downstream transcriptional and protein signature associated with host-parasite immune response. Functional characterization of the novel risk locus is warranted.

Gp35/50 mucin molecules of Trypanosoma cruzi metacyclic forms that mediate host cell invasion interact with annexin A2.

Host cell invasion is a critical step for infection by Trypanosoma cruzi, the agent of Chagas disease. In natural infection, T. cruzi metacyclic trypomastigote (MT) forms establish the first interaction with host cells. The gp35/50 mucin molecules expressed in MT have been implicated in cell invasion process, but the mechanisms involved are not well understood. We performed a series of experiments to elucidate the mode of gp35/50-mediated MT internalization. Comparing two parasite strains from genetically divergent groups, G strain (TcI) and CL strain (TcVI), expressing variant forms of mucins, we demonstrated that G strain mucins participate in MT invasion. Only G strain-derived mucins bound to HeLa cells in a receptor-dependent manner and significantly inhibited G strain MT invasion. CL strain MT internalization was not affected by mucins from either strain. HeLa cell invasion by G strain MT was associated with actin recruitment and did not rely on lysosome mobilization. To examine the involvement of annexin A2, which plays a role in actin dynamic, annexin A2-depleted HeLa cells were generated. Annexin A2-deficient cell lines were significantly more resistant than wild type controls to G strain MT invasion. In a co-immunoprecipitation assay, to check whether annexin A2 might be the receptor for mucins, protein A/G magnetic beads crosslinked with monoclonal antibody to G strain mucins were incubated with detergent extracts of MT and HeLa cells. Binding of gp35/50 mucins to annexin A2 was detected. Both G strain MT and purified mucins induced focal adhesion kinase activation in HeLa cells. By confocal immunofluorescence microscopy, colocalization of invading G strain MT with clathrin was visualized. Inhibition of clathrin-coated vesicle formation reduced parasite internalization. Taken together, our data indicate that gp35/50-mediated MT invasion is accomplished through interaction with host cell annexin A2 and clathrin-dependent endocytosis.

A fat body transcriptome analysis of the immune responses of Rhodnius prolixus to artificial infections with bacteria.

BACKGROUND: Rhodnius prolixus is an important vector of Trypanosoma cruzi, the causal agent of Chagas disease in humans. Despite the medical importance of this and other triatomine vectors, the study of their immune responses has been limited to a few molecular pathways and processes. Insect immunity studies were first described for holometabolous insects such as Drosophila melanogaster, and it was assumed that their immune responses were conserved in all insects. However, study of the immune responses of triatomines and other hemimetabolous insects has revealed discrepancies between these and the Drosophila model. METHODS: To expand our understanding of innate immune responses of triatomines to pathogens, we injected fifth instar nymphs of R. prolixus with the Gram-negative (Gr-) bacterium Enterobacter cloacae, the Gram-positive (Gr+) bacterium Staphylococcus aureus, or phosphate-buffered saline (PBS), and evaluated transcript expression in the fat body 8 and 24 h post-injection (hpi). We analyzed the differential expression of transcripts at each time point, and across time, for each treatment. RESULTS: At 8 hpi, the Gr- bacteria-injected group had a large number of differentially expressed (DE) transcripts, and most of the changes in transcript expression were maintained at 24 hpi. In the Gr+ bacteria treatment, few DE transcripts were detected at 8 hpi, but a large number of transcripts were DE at 24 hpi. Unexpectedly, the PBS control also had a large number of DE transcripts at 24 hpi. Very few DE transcripts were common to the different treatments and time points, indicating a high specificity of the immune responses of R. prolixus to different pathogens. Antimicrobial peptides known to be induced by the immune deficiency pathway were induced upon Gr- bacterial infection. Many transcripts of genes from the Toll pathway that are thought to participate in responses to Gr+ bacteria and fungi were induced by both bacteria and PBS treatment. Pathogen recognition receptors and serine protease cascade transcripts were also overexpressed after Gr- bacteria and PBS injections. Gr- injection also upregulated transcripts involved in the metabolism of tyrosine, a major substrate involved in the melanotic encapsulation response to pathogens. CONCLUSIONS: These results reveal time-dependent pathogen-specific regulation of immune responses in triatomines, and hint at strong interactions between the immune deficiency and Toll pathways.

Quantitative 3D Imaging of Trypanosoma cruzi-Infected Cells, Dormant Amastigotes, and T Cells in Intact Clarified Organs.

Chagas disease is a neglected pathology that affects millions of people worldwide, mainly in Latin America. The Chagas disease agent, Trypanosoma cruzi (T. cruzi), is an obligate intracellular parasite with a diverse biology that infects several mammalian species, including humans, causing cardiac and digestive pathologies. Reliable detection of T. cruzi in vivo infections has long been needed to understand Chagas disease's complex biology and accurately evaluate the outcome of treatment regimens. The current protocol demonstrates an integrated pipeline for automated quantification of T. cruzi-infected cells in 3D-reconstructed, cleared organs. Light-sheet fluorescent microscopy allows for accurately visualizing and quantifying of actively proliferating and dormant T. cruzi parasites and immune effector cells in whole organs or tissues. Also, the CUBIC-HistoVision pipeline to obtain uniform labeling of cleared organs with antibodies and nuclear stains was successfully adopted. Tissue clearing coupled with 3D immunostaining provides an unbiased approach to comprehensively evaluate drug treatment protocols, improve the understanding of the cellular organization of T. cruzi-infected tissues, and is expected to advance discoveries related to anti-T. cruzi immune responses, tissue damage, and repair in Chagas disease.

Trypanosoma cruzi modulates lipid metabolism and highjacks phospholipids from the midgut of Rhodnius prolixus.

Chagas disease is potentially life-threatening and caused by the protozoan parasite Trypanosoma cruzi. The parasite cannot synthesize some lipids and depends on the uptake of these lipids from its vertebrate and invertebrate hosts. To achieve this, T. cruzi may need to modify the physiology of the insect host for its own benefit. In this study, we investigated the interaction of T. cruzi (Y strain) with its insect vector Rhodnius prolixus and how it manipulates the vector lipid metabolism. We observed a physiological change in lipid flux in of infected insects. In the fat body of infected insects, triacylglycerol levels decreased by 80.6% and lipid storage droplet-1(LSD-1) mRNA levels were lower, when compared to controls. Lipid sequestration by infected midguts led to increased levels of 5' AMP-activated protein kinase (AMPK) phosphorylation and activation in the fat body, inhibiting the synthesis of fatty acids and stimulating their oxidation. This led to reduced lipid levels in the fat body of infected insets, despite the fact that T. cruzi does not colonize this tissue. There was a 3-fold increase, in lipid uptake and synthesis in the midgut of infected insects. Finally, our results suggest that the parasite modifies the lipid flux and metabolism of its vector R. prolixus through the increase in lipid delivery from the fat body to midgut that are then scavenge by T cruzi.

Role of Virulence Factors of Trypanosomatids in the Insect Vector and Putative Genetic Events Involved in Surface Protein Diversity.

Trypanosomatids are flagellate protozoans that can infect several invertebrate and vertebrate hosts, including insects and humans. The three most studied species are the human pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. which are the causative agents of Human African Trypanosomiasis (HAT), Chagas disease and different clinical forms of leishmaniasis, respectively. These parasites possess complex dixenous life cycles, with zoonotic and anthroponotic stages, and are transmitted by hematophagous insects. To colonize this myriad of hosts, they developed mechanisms, mediated by virulence factors, to infect, propagate and survive in different environments. In insects, surface proteins play roles in parasite attachment and survival in the insect gut, whilst in the mammalian host, the parasites have a whole group of proteins and mechanisms that aid them invading the host cells and evading its immune system components. Many studies have been done on the impact of these molecules in the vertebrate host, however it is also essential to notice the importance of these virulence factors in the insect vector during the parasite life cycle. When inside the insect, the parasites, like in humans, also need to survive defense mechanisms components that can inhibit parasite colonization or survival, e.g., midgut peritrophic membrane barrier, digestive enzymes, evasion of excretion alongside the digested blood meal, anatomic structures and physiological mechanisms of the anterior gut. This protection inside the insect is often implemented by the same group of virulence factors that perform roles of immune evasion in the mammalian host with just a few exceptions, in which a specific protein is expressed specifically for the insect vector form of the parasite. This review aims to discuss the roles of the virulence molecules in the insect vectors, showing the differences and similarities of modes of action of the same group of molecules in insect and humans, exclusive insect molecules and discuss possible genetic events that may have generated this protein diversity.

Selenium, TGF-Beta and Infectious Endemic Cardiopathy: Lessons from Benchwork to Clinical Application in Chagas Disease.

For over 60 years, selenium (Se) has been known as an essential microelement to many biological functions, including cardiovascular homeostasis. This review presents a compilation of studies conducted in the past 20 years related to chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, a neglected disease that represents a global burden, especially in Latin America. Experimental and clinical data indicate that Se may be used as a complementary therapy to prevent heart failure and improve heart function. Starting from the main questions "Is Se deficiency related to heart inflammation and arrhythmogenesis in CCC?" and "Could Se be recommended as a therapeutic strategy for CCC?", we show evidence implicating the complex and multidetermined CCC physiopathology, discussing its possible interplays with the multifunctional cytokine TGF-ß as regulators of immune response and fibrosis. We present two new proposals to face this global public health challenge in vulnerable populations affected by this parasitic disease: fibrosis modulation mediated by TGF-ß pathways and the possible use of selenoproteins as antioxidants regulating the increased reactive oxygen stress present in CCC inflammatory environments. We assess the opportunity to consider the beneficial effects of Se in preventing heart failure as a concept to be applied for CCC patients.