Materiały źródłowe

• #1 Pathology and Pathogenesis of Chagas Heart Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7373119/

  Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. […] The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. […] Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host-parasite equation. […] Current thinking is that the inflammation in the heart develops over years from indolent, low-grade processes that depend, at least in part, on the few parasites that persist in the heart.

• #1 Chagas Disease – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/extraintestinal-protozoa/chagas-disease

  Chagas disease is caused by Trypanosoma cruzi. Infection is transmitted to humans when bitten by Triatominae (reduviid, kissing, or assassin) bugs in South and Central America, Mexico, and very rarely in the US. […] Chagas disease is most commonly spread when a Triatominae bug bites an infected person or animal, then bites another person. While biting, infected bugs deposit feces containing metacyclic trypomastigotes on the skin. These infective forms enter through the bite wound or penetrate the conjunctivae or mucous membranes. […] The parasites invade macrophages at the site of entry and transform into amastigotes that multiply by binary fission; the amastigotes develop into trypomastigotes, enter the bloodstream and tissue spaces, and infect other cells. Cells of the reticuloendothelial system, myocardium, muscles, and nervous system are most commonly involved. […] Chronic Chagas disease develops in 20 to 30% of patients after the chronic indeterminate phase, which may last years or decades. The parasites are probably present in chronic disease; an autoimmune reaction also may contribute to organ damage. The main effects are cardiac and gastrointestinal.

• #1 Chagas Disease (American Trypanosomiasis): Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/214581-overview

  An inflammatory lesion called a chagoma caused by T cruzi may appear at the site of entry in patients with acute Chagas disease. Histologic changes may include interstitial edema, lymphocytic infiltration, and reactive hyperplasia of adjacent lymph nodes due to intracellular parasitism of muscle and other subcutaneous tissues. […] The pathogenesis of cardiac and gastrointestinal lesions of chronic Chagas disease was a focus of debate for decades. Beginning more than 20 years ago, however, convincing evidence has shown that low levels of parasites in chronically affected tissue, detectable with molecular methods, provoke a chronic inflammatory response that eventually leads to the pathologic changes observed microscopically and organ dysfunction.

• #1 Chagas disease – Wikipedia

  https://en.wikipedia.org/wiki/Chagas_disease

  Chagas disease is caused by infection with the protozoan parasite T. cruzi, which is typically introduced into humans through the bite of triatomine bugs, also called „kissing bugs”. […] Inside a host cell, the parasite transforms into a replicative form called an amastigote, which undergoes several rounds of replication. […] The replicated amastigotes transform back into trypomastigotes, which burst the host cell and are released into the bloodstream. […] Over many years, cycles of parasite replication and immune response can severely damage these tissues, particularly the heart and digestive tract. […] In the acute phase of the disease, signs and symptoms are caused directly by the replication of T. cruzi and the immune system’s response to it. […] During chronic Chagas disease, long-term organ damage develops over years due to continued replication of the parasite and damage from the immune system.

• #1 Chagas disease pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Chagas_disease_pathophysiology

  The hallmark of Chagas disease is inflammation. Acutely following transmission, a state of parasitemia, characterized by parasitic replication and host immune responses, is responsible for the development of clinical manifestations. Following the acute phase, it is thought that Chagas disease causes a state of low-grade persistent inflammation that eventually results in the development of chronic disease, manifested by multisystem involvement. […] The pathogenesis of chronic Chagas disease is poorly understood, but is thought to be caused by either persistent parasites that were not eliminated by the host during the acute phase or development of autoimmune destructive processes. […] Inflammation is the hallmark of Chagas disease. Early host immune responses include the activation of B-cell and T-cell (CD4+ and CD8+) lymphocytes that result in the production of anti-trypanosoma antibodies and direct cytotoxicity. It is thought that host immune mechanisms simultaneously contribute to the elimination of the parasite and host tissue damage. The early response causes a state of systemic inflammation reaction that either subsides and resolves or persists as a low-grade silent inflammation and manifests as a chronic disease.

• #1 Chagas disease: Current perspectives on a forgotten disease | Revista Médica del Hospital General de México

  https://www.elsevier.es/en-revista-revista-medica-del-hospital-general-325-articulo-chagas-disease-current-perspectives-on-S0185106316301123

  Chagas disease is a parasitic zoonosis caused by Trypanosoma cruzi, a protozoan whose transmission to humans is primarily vector-borne. […] The production of virulence factors by T. cruzi during the acute phase strongly inhibits the response of the host’s immune system, thereby inducing anergia and clonal deletion of T lymphocytes, along with a strong polyclonal stimulation of B lymphocytes that secrete antibodies with a low affinity towards T. cruzi antigens. This promotes persistence of the infection and its progression towards the chronic phase of the disease. […] Within the chronic phase, the mechanisms behind the transition from the asymptomatic phase to the symptomatic phase have not yet been fully elucidated. However, it is believed that there are many factors involved, such as differences between T. cruzi strains, parasite load, infection time, genetic background, and host immune response.

• #1 Chagas Heart Disease Pathogenesis: One Mechanism or Many?

  https://eurekaselect.com/public/article/12606

  Chagas heart disease (CHD), caused by the protozoan parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis in the world. The etiology of CHD is unclear and multiple mechanisms have been proposed to explain the pathogenesis of the disease. This review describes the proposed mechanisms of CHD pathogenesis and evaluates the historical significance and evidence supporting each. […] Although the majority of CHD-related pathologies are currently attributed to parasite persistence in the myocardium and autoimmunity, there is strong evidence that CHD develops as a result of additive and even synergistic effects of several distinct mechanisms rather than one factor.

• #1 Chagas disease pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Chagas_disease_pathophysiology

  The true mechanism that result in chronic manifestations of the disease is poorly understood, but it is thought that chronic Chagas disease may be caused by either pathogenic inflammatory responses against residual and persistent T. cruzi pathogens or autoimmune mechanisms. […] Chronic inflammation typically results in end-organ damage by inducing local and diffuse tissue necrosis and fibrosis. […] The pathogenic mechanisms responsible for cardiac lesions developing during the chronic phase of Chagas disease are not completely understood. However, four mechanisms are believed to play a role, neurogenic disturbances, microvascular derangements, parasite-dependent damage, and immune-mediated tissue injury. […] Most investigators now believe that parasite persistence is a critical factor in causing inflammation and in initiating and progressing chronic myocarditis.

• #1 Pathogenesis of Chagas’ Disease: Parasite Persistence and Autoimmunity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3131057/

  The theory of parasite persistence is a consequence of the early detection of nests of T. cruzi amastigotes in the heart of a child who died of acute Chagas’ disease, which suggests that the disease stems directly from a microbial infection. […] The autoimmune theory of Chagas’ disease is based on the demonstration of the accelerated cytotoxic interaction of T. cruzi-immune lymphocytes with nonparasitized allogeneic heart cells. Lymphocytes from rabbits with cryptic T. cruzi infections produce accelerated rejection with the destruction of embryonic heart tissue. These immune lymphocytes adhere to myofibers and lyse parasite-free target heart cells in 2 h, whereas control rabbit nonimmune lymphocytes require 72 h and overadhering to the target cells. […] The kDNA integrates into specific loci encoding proteins with important functions: the PARP-1, CLEC5, CITb-109, and HLA haplotype genes, encoding a major histocompatibility complex class 1 antigen, are silenced by the kDNA integrations. The rupture of the ORFs of the ADAM gene, involved in myogenesis and neurogenesis, has been observed. Additionally, the kDNA integrates into a LINE present at the ORF of the CLEC5A gene 7 q.33 locus in the chromosome illustrated in Fig. 11, which encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) family, which promotes cell adhesion, cell-cell signaling, glycoprotein turnover, and proimmune response-mediated proinflammatory cytokines.

• #1 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  A direct role for heart parasitism has been proposed after the identification of T. cruzi antigen and DNA in CCC hearts by immunohistochemical and PCR techniques. […] In addition, T. cruzi-specific CD8+ T cells have been isolated from endomyocardial biopsies of a CCC patient, providing evidence for the recruitment and expansion of T. cruzi-specific T cells in the myocardium. […] However, the scarcity of T. cruzi in inflammatory lesions of CCC led early investigators to suggest that tissue damage had an autoimmune nature. […] In this paper, we will review the immunologic, transcriptomic/proteomic, and genetics studies of the pathogenesis of Chagas disease. […] CCC is one of the few examples of post-infectious autoimmunity in humans, where infectious episodes with an established pathogen clearly triggers antigenic mimicry with host self-antigens, in association to target organ immune damage.

• #1 Pathology and Pathogenesis of Chagas Heart Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7373119/

  Innate and adaptive immune responses may contribute to heart damage and increase the risk of heart failure through inducing sustained inflammation, fibrosis, and oxidative stress injury, leading to the disruption of myofibrils, myocyte necrosis, microvascular dysfunction, autonomic dysfunction, and cardiac hypertrophy and fibrosis. […] The absence or paucity of parasites in the hearts of those who succumb to Chagas heart disease has been a conspicuous feature of the disease since it was first described. […] The recent development of luminescent parasite systems now permits longitudinal and noninvasive assessment of host parasitism in experimental animals, and it is hoped that these models will be valuable both for assessing the mechanisms of pathogenesis and for developing new and more effective therapies.

• #1

  https://www.jci.org/articles/view/118969

  Heart tissue destruction in chronic Chagas’ disease cardiomyopathy (CCC) may be caused by autoimmune recognition of heart tissue by a mononuclear cell infiltrate decades after Trypanosoma cruzi infection. […] Indirect evidence suggests there is molecular mimicry between T. cruzi and heart tissue. […] Furthermore, cardiac myosin-B13 crossreactive antibodies are present in 100% CCC patients vs 14% asymptomatic T. cruzi-seropositive individuals (P = 2.3 x 10(-6)), suggesting a role for molecular mimicry between cardiac myosin and B13 in CCC pathogenesis. […] Together with the association of myosin-B13 crossreactive antibodies with CCC, the present data strongly suggest the relevance of molecular mimicry between cardiac myosin and the T. cruzi protein B13 in the pathogenesis of heart lesions in chronic Chagas’ disease cardiomyopathy.

• #1 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  The discrepancy between the parasitism and inflammation suggested that tissue-damaging T cells were of autoimmune nature, possibly elicited by cross-reactive immune responses with T. cruzi parasite. […] Direct experimental evidence of autoimmunity in CCC and experimental models has been documented over the last 25 years. […] The existence of degenerate intramolecular recognition, with multiple low-homology, cross-reactive epitopes in a single autoantigenic protein may have implications in increasing the magnitude of the autoimmune response in CCC and other autoimmune diseases. […] Autoimmune and T. cruzi-specific responses secondary to parasite persistence are not incompatible or mutually exclusive in Chagas disease, and a combination of these types of immune responses could be involved in the establishment of heart tissue lesions.

• #1 Pathogenesis of Chagas’ Disease: Parasite Persistence and Autoimmunity

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3131057/

  Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas’ disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas’ disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. […] The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8+ , and CD8+ T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas’ disease is a genetically driven autoimmune disease.

• #1 Pathology and Pathogenesis of Chagas Heart Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7373119/

  The inflammatory infiltrate is composed primarily of lymphocytes and macrophages, with smaller numbers of natural killer cells, dendritic cells, and granulocytes. […] The chronic phase of the disease likely represents, at least in part, a slowly progressive, cyclical reaction to the presence of intramyocardial parasites, which results in a smoldering, ongoing inflammatory reaction, myocardial cell necrosis and dropout, and fibrosis that develop over years to decades. […] Many of the mechanisms of the pathogenesis of Chagas heart disease have been described and defined in detail in humans and experimental animals. […] Most proposed mechanisms require the presence of T. cruzi somewhere in the host, whether in the heart or elsewhere, to produce and/or propagate cardiac pathology. […] Disease outcome is determined by a highly complex interplay between the virulence of the T. cruzi strain and the genetic susceptibility of the individual, with both parasite virulence and host susceptibility varying with the parasite-host combination.

• #1 Immunopathological Mechanisms Underlying Cardiac Damage in Chagas Disease

  https://www.mdpi.com/2076-0817/12/2/335

  Several theories have been advanced on the development of lesions in heart disease. Among them, the presence of autoimmune phenomena and the persistence of the parasite stand out, without being mutually exclusive. […] The inflammatory process in Chagas disease starts in the acute phase, with the production of proinflammatory cytokines to recruit and induce the activation of monocytes to the site of infection. This process is important to control parasite replication through a Th1-type response, characterized by the production of interleukins (IL) such as IL-1, interferon gamma (IFN-γ), and the tumor necrosis factor alpha (TNF-α). […] Fibrosis in cardiac tissue is a significant increase in the volume of collagen. It gradually produces scar tissue, which affects the overall cardiac function in the severe manifestations of the chronic phase of Chagas disease.

• #1 Cytokine Profiling in Chagas Disease: Towards Understanding the Association with Infecting Trypanosoma cruzi Discrete Typing Units (A BENEFIT TRIAL Sub-Study) | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091154

  The aim of this study was to evaluate the different cytokine profiles in Chagasic patients with and without chronic cardiomyopathy to correlate these cytokine profiles in patients infected with the different T.cruzi DTUs in order to establish whether these factors may be involved in the pathogenesis of Chagas disease. Our results show that specific anti-inflammatory and pro-inflammatory cytokine modulation is correlated with the clinical presentation of chronic patients with Chagas disease and suggests the occurrence of specific immune responses, probably associated to different T. cruzi DTUs. […] An important finding of this study was a switch between the anti-inflammatory cytokines IL-13, IL-5 and IL-10 and pro-inflammatory cytokines IL-2, IL-6, IL-9 and IL-12 among CARD and NON-CARD groups. These findings suggest that regulation (differential regulation of cytokine synthesis) may play an important role in the development of Chagas cardiomyopathy.

• #1 Cytokine Profiling in Chagas Disease: Towards Understanding the Association with Infecting Trypanosoma cruzi Discrete Typing Units (A BENEFIT TRIAL Sub-Study) | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091154

  The anti-inflammatory/pro-inflammatory cytokine profile switch found between patients with Chagas cardiomyopathy and those infected but still in the NON-CARD stage of the disease is compatible with the hypothesis that the progression of human Chagas disease from asymptomatic to severe forms, is related with a lack of adequate immune modulation. […] The relationship of the genetic variability of the parasite and host characteristics with pathogenesis is increasingly recognized as an important factor in the understanding of Chagas disease. […] In summary, pro-inflammatory profile is associated to CARD patients and anti-inflammatory profile to NON-CARD patients. The fact that the levels of cytokines were different for patients infected with different parasite DTUs suggests a specific immune response, probably associated to DTUs. A novel contribution of this study is the possibility of using IL-12, IFN-, IL-6 and IL-1 as prognostic biomarkers of Chagas Disease. Future studies should be carried out covering the geographical wide-range of DTUs and other human populations, in order to validate these cytokines as biomarkers as well as finding the plausible association between DTUs-epitope and Chagas Disease clinical manifestations.

• #1 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  Chagas disease, or American trypanosomiasis, is a parasitic infection caused by the flagellate protozoan Trypanosoma cruzi. […] In chronic phase, mortality is primarily due to the rhythm disturbances and congestive heart failure that result from the chronic inflammatory cardiomyopathy (CCC) due to the persistence presence of parasites in the heart tissue. […] Mechanisms underlying differential progression to CCC are still incompletely understood. […] Since the bulk of evidence indicates the inflammatory infiltrate is a significant effector of heart tissue damage. […] This review aims to summarize the major recent advances in the understanding of the immunopathogenesis of Chagas disease cardiomyopathy. […] CCC is an inflammatory cardiomyopathy that can be accompanied by heart electric conduction defects, arrhythmias and thromboembolism.

• #1 Immunopathological Mechanisms Underlying Cardiac Damage in Chagas Disease

  https://www.mdpi.com/2076-0817/12/2/335

  In Chagas disease, the mechanisms involved in cardiac damage are an active field of study. The factors underlying the evolution of lesions following infection by Trypanosoma cruzi and, in some cases, the persistence of its antigens and the host response, with the ensuing development of clinically observable cardiac damage, are analyzed in this review. […] Most of the mechanisms involved in evading the immune response occur in the acute phase, when trypomastigotes establish contact with immune cells of the vertebrate host. The parasite has evolved mechanisms to survive processes such as phagocytosis and the complement system, in addition to interfering with lymphocyte maturation. […] The presence and replication by binary fission of intracellular amastigotes in the myocardiocyte and its ensuing lysis cause inflammation, the release of cellular components, and finally the destruction of cardiac tissue.

• #1 Enhanced Platelet Adherence and Aggregation in Chagas’ Disease: A Potential Pathogenic Mechanism for Cardiomyopathy in: The American Journal of Tropical Medicine and Hygiene Volume 43 Issue 3 (1990)

  https://www.ajtmh.org/abstract/journals/tpmd/43/3/article-p274.xml

  Spasm and thrombosis of the coronary microcirculation has been implicated in the pathogenesis of the cardiomyopathy of Chagas’ disease. […] We demonstrate that increases in platelet adherence and aggregation accompany Trypanosoma cruzi infection and may contribute to the observed microvascular pathology. […] These data support the hypothesis that heightened platelet reactivity and endothelial cell dysfunction are associated with acute Chagas’ disease and may cause coronary microvascular spasm and/or occlusion.

• #1 Chagas disease – Wikipedia

  https://en.wikipedia.org/wiki/Chagas_disease

  In the heart, colon, and esophagus, chronic disease leads to a massive loss of nerve endings. […] Loss of nerves impairs the movement of food through the digestive tract, which can lead to blockage of the esophagus or colon and restriction of their blood supply. […] The parasite can insert kinetoplast DNA into host cells, an example of horizontal gene transfer.

• #1 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  Several studies suggest that heart failure due to CCC may have a worse prognosis with 50% shorter survival when compared to other cardiomyopathies of different etiologies such as ischemic cardiomyopathy and idiopathic dilated cardiomyopathy. […] Significantly, a key difference between CCC and such cardiomyopathies is inflammation/myocarditis, present in greater intensity among CCC patients. […] The major histopathological feature attending dilated cardiomyopathy in CCC is the presence of a diffuse myocarditis, with intense cardiomyocyte damage and hypertrophy, and significant fibrosis, in the presence of very scarce T. cruzi forms. […] Since it is known that T. cruzi establishes a lifelong, low-grade infection, the possibility that chronic myocardial inflammation and tissue damage in CCC are a consequence of recognition of parasite antigen on target tissue must be entertained.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240520/New-mechanism-discovered-for-Chagas-disease-induced-heart-damage.aspx

  Jyothi Nagajyothi, Ph.D. and her laboratory at the Hackensack Meridian Center for Discovery and Innovation (CDI) have identified what may be the main mechanism for how chronic Chagas Disease, a parasitic infection affecting millions of people worldwide, can cause irreversible and potentially fatal heart damage. […] The culprit is in the adipose (fat tissue) which the parasite Trypanosoma cruzi destroys in the course of infection, releasing smaller particles which induce the dysfunction of heart tissue, conclude the scientists in the journal iScience, a Cell Press open-access journal. […] The latest study utilized both in-vitro and in-vivo models to delineate the molecular pathway triggered by infection-induced adipocyte apoptosis (cell death) and the subsequent response elicited by the released extracellular vesicles known as adipomes.

• #1 Fat Tissue Regulates the Pathogenesis and Severity of Cardiomyopathy in Murine Chagas Disease | bioRxiv

  https://www.biorxiv.org/content/10.1101/2020.11.25.397596v1

  Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. […] These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease. […] The molecular mechanisms underlying CCC pathogenesis, progression and severity are complex, multi-factorial and not completely understood. […] Loss of fat cells increased cardiac lipid load and deregulated cardiac lipid metabolism leading to mitochondrial oxidative stress and endoplasmic reticulum stress and severe CCC. […] In addition, loss of fat cells increased cardiac parasite load during acute infection and altered immune signalling in the hearts of infected mice during chronic infection. These discoveries underscore the importance of adipose tissue in the development of CCC.

• #1 Chagas Disease – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/extraintestinal-protozoa/chagas-disease

  Cardiac disease usually manifests with conduction abnormalities including right bundle branch block or left anterior fascicular block. Chronic cardiomyopathy often follows with flaccid enlargement of all chambers, apical aneurysms, and progression of lesions in the conduction system. Patients may present with heart failure, syncope, sudden death due to heart block or ventricular arrhythmia, or thromboembolism. […] Gastrointestinal disease manifests with symptoms resembling achalasia or Hirschsprung disease. Chagas megaesophagus manifests as dysphagia and may lead to pulmonary infections caused by aspiration or to severe undernutrition. Megacolon may result in long periods of obstipation and intestinal volvulus.

• #1 Megacolon – Wikipedia

  https://en.wikipedia.org/wiki/Megacolon

  Megacolon can be associated with Chagas disease. Chagas disease is caused by Trypanosoma cruzi, a flagellate protozoan transmitted by the assassin bug. […] There are several theories on how megacolon (and also megaesophagus) develops in Chagas disease. The Austrian-Brazilian physician and pathologist Fritz Kberle was the first to propose the neurogenic hypothesis based on the documented destruction of the myenteric plexus in the walls of the intestinal tracts of Chagas patients. In this, the destruction of the autonomic nervous system innervation of the colon leads to a loss of the normal smooth muscle tone of the wall and subsequent gradual dilation. […] Neurons were strongly reduced all over the digestive tract; megacolon appeared only when there was a reduction of over 80% of the number of neurons; these pathologies appeared as a result of the disruption of the neurally integrated control of peristalsis (muscular annular contraction) in those parts where a strong force is necessary to impel the luminal bolus of feces; idiopathic megacolon and Chagas megacolon appear to have the same cause, namely the degeneration of the myenteric plexus. […] Why T. cruzi causes the destruction, however, remains to be determined. There is evidence for the presence of specific neurotoxins as well as a disorderly immune system reaction.

• #1 Technological advances in the serological diagnosis of Chagas disease in dogs and cats: a systematic review | Parasites & Vectors | Full Text

  https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-022-05476-4

  During this phase electrocardiogram abnormalities become more evident. […] Other lesions are associated with fibrosis and cardiomyocyte necrosis, possibly caused by the inflammatory processes that trigger hyalinization and fibrosis. […] Chagasic megaesophagus and megacolon can be observed in both the acute and chronic phases. […] In the acute phase, T. cruzi triggers an inflammatory reaction in the esophagus/colon and causes myenteric denervation. […] Prognosis may be unpredictable and the survival rate of chronically infected, untreated dogs is variable. […] The development of commercial diagnostic tools to detect past exposure to T. cruzi in dogs and cats would be useful from both veterinary and public health perspectives.

• #1 CDC – DPDx – American Trypanosomiasis

  https://www.cdc.gov/dpdx/trypanosomiasisamerican/index.html

  Trypanosoma cruzi, is a parasitic protozoan that is the causative agent of Chagas disease (American trypanosomiasis). Currently, six distinct lineages of T. cruzi are classified into discrete typing units (TcI-VI), which vary in their geographic occurrence, host specificity, and pathogenicity. […] Inside the host, the trypomastigotes invade cells near the site of inoculation, where they differentiate into intracellular amastigotes. The amastigotes multiply by binary fission and differentiate into trypomastigotes, and then are released into the circulation as bloodstream trypomastigotes. […] The symptomatic chronic form (determinate form) may not occur for years or even decades after initial infection. This may include cardiac or gastrointestinal involvement, which occasionally occur together. The many complications of chronic Chagas disease can be fatal. Amastigote invasion of smooth muscle can lead to megaesophagus, megacolon, and dilated cardiomyopathy. […] Trypomastigotes of T. cruzi are the only stage found circulating in human blood or CSF. In tissue, the parasite forms amastigotes characterized by a single nucleus and kinetoplast. The amastigotes of T. cruzi are morphologically indistinguishable from those of Leishmania spp.

• #1 The End Justifies the Means: Chagas Disease from a Perspective of the Host–Trypanosoma cruzi Interaction

  https://www.mdpi.com/2075-1729/14/4/488

  The neglected Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi. […] The complex interaction between the parasite and the host outlines the etiology and progression of CD. The unique characteristics and high adaptability of T. cruzi, its mechanisms of persistence, and evasion of the immune system seem to influence the course of the disease. […] Despite the efforts to uncover the pathology of CD, there are many gaps in understanding how it is established and reaches chronicity. […] Here, we discuss the main factors that contribute to the pathogenesis of CD, from the molecular peculiarities of the parasite and its virulence factors to pathogen–host interactions and the immune response. […] The pathogenesis of CD comprises an acute phase and a chronic phase. […] Failure of the host to eliminate the infection leads to the persistence of the parasite in tissues (either through continuous cycles of cellular entry and exit or through sporadic local infections or reactivation of dormant parasites), resulting in direct and immune-mediated tissue damage.

• #1

  https://link.springer.com/article/10.1007/s11897-022-00568-9

  Chagas disease is a neglected anthropozoonosis of global importance with significant cardiovascular-associated mortality. This review focuses on the Trypanosoma cruzi reinfections role in chronic Chagas cardiomyopathy pathogenesis. We discuss and summarize the available data related to pathology, pathogenesis, diagnosis, and treatment of reinfections. […] Reinfections influence the genetic and regional diversity of T. cruzi, tissue tropism, modulation of the hosts immune system response, clinical manifestations, the risk for congenital infections, differences in diagnostics performances, response to antiparasitic therapy, and the natural history of the disease. […] Evidence has shown that higher anti-T. cruzi antibodies are correlated with an increased rate of cardiomyopathy and death, suggesting that a higher parasite exposure related to reinfections may lead to worse outcomes. […] Based on the existing literature, reinfections may play a role in developing and exacerbating chronic Chagas cardiomyopathy and are linked to worse outcomes.

• #1 Increased heart fibrosis and acute infection in a murine Chagas disease model associated with organophosphorus pesticide metabolite exposure | Scientific Reports

  https://www.nature.com/articles/s41598-019-54218-7

  Some reports suggest that exposure to organophosphorus (OP) pesticides increases the incidence of infections. […] Chagas cardiomyopathy (CC) is one of the chronic manifestations of Trypanosoma cruzi infection; approximately 30% of chronically infected individuals develop CC 20-30 years after the initial parasitic infection. […] The pathogenesis of CC is not completely understood, but it has been suggested that the development of myocardial damage is due to parasitic invasion and the severe immune inflammatory response that follows, leading to fibrosis and cellular hypertrophy. […] The inflammatory mechanisms induced by infection of Trypanosoma cruzi, combined with exposure to EtDAPs, lead to cardiac fiber destruction and myocarditis and induce an exacerbated initial reparative response (fibrosis) due to the cardiac remodeling associated with the development of CC, which is linked with HF and sudden death.

• #1 Increased heart fibrosis and acute infection in a murine Chagas disease model associated with organophosphorus pesticide metabolite exposure | Scientific Reports

  https://www.nature.com/articles/s41598-019-54218-7

  Our results demonstrate, for the first time, that a single exposure to a low level of DEDTP or DEP is enough to modify the development of an infection, such as with Trypanosoma cruzi. […] We suggest that the elimination of parasites is reduced because M are subsequently reprogrammed to switch to the immunosuppressive/tissue-repairing phenotype of M2 cells (mainly M2a and M2d), which contributes to uncontrolled parasite replication. […] The exposure to DAPs increases the parasite burden of an infection such as Trypanosoma cruzi and induces the M2 polarization of macrophages, increasing fibrosis and inflammation in tissues such as that of the heart.

• #1 Role of vasoactive mediators in the pathogenesis of Chagas’ disease

  https://www.imrpress.com/journal/FBL/8/5/10.2741/1103

  This review focuses on the vascular pathogenesis of Chagas’ disease, the cardiomyopathy caused by infection with the parasitic protozoa Trypanosoma cruzi. Recent studies strongly suggest that T. cruzi infection is linked to functional changes in the activity of two potent vasoactive peptidergic mediators, endothelin-1, a vasoconstrictor, and kinins, a group of vasodilator and pro-inflammatory peptides related to bradykinin. Understanding the molecular mechanisms underlying disturbances of vascular homoeostasis induced by T. cruzi may provide opportunities for therapeutic intervention and amelioration of heart pathology.

• #1 Heme crystallization in a Chagas disease vector acts as a redox-protective mechanism to allow insect reproduction and parasite infection | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006661

  Heme crystallization as hemozoin represents the dominant mechanism of heme disposal in blood feeding triatomine insect vectors of the Chagas disease. […] Here, we demonstrate that selective blockage of heme crystallization in vivo by the antimalarial drug quinidine, caused systemic heme overload and redox imbalance in distinct insect tissues, assessed by spectrophotometry and fluorescence microscopy. […] Importantly, egg production, oviposition, and total T. cruzi parasite counts in R. prolixus were significantly reduced by quinidine treatment. […] Altogether, these data underscore the importance of heme crystallization as the main redox regulator for triatomine vectors, indicating the dual role of hemozoin as a protective mechanism to allow insect fertility, and T. cruzi life-cycle.

• #1 Heme crystallization in a Chagas disease vector acts as a redox-protective mechanism to allow insect reproduction and parasite infection | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006661

  This remarkable effect on oogenesis was sustained along the full blood digestion and reproductive cycle, in both insect colonies. […] Interestingly, QND strongly reduced T. cruzi parasite loads in R. prolixus digestive tract (by ~ 75%) 15 days after blood meal. […] These data indicate that the effect on the parasites is not due to the QND administration per se. […] Therefore, we concluded that reductions in T. cruzi counts in triatomine midgut were most likely a consequence of the cytotoxic effect of excessive free heme on trypomastigotes rather than in epimastigotes. […] Collectively, our data highlight the dual role of Hz as a key protective mechanism, with striking beneficial outputs for both triatomine vector and for T. cruzi.

• #1 The End Justifies the Means: Chagas Disease from a Perspective of the Host–Trypanosoma cruzi Interaction

  https://www.mdpi.com/2075-1729/14/4/488

  The targeting of T. cruzi strains for lodging in certain organs could be determined by the host’s genetic background. […] The distribution of parasites in tissues in the acute and chronic phase and the parasite persistence pathways are schematically represented. […] The microenvironment of infection is of great importance, as T. cruzi secretes factors into the environment where infected cells respond by releasing other factors. […] The invasive effects may come from the increase in intracellular Ca2+ and the rearrangement of the host cell cytoskeleton caused by EVs. […] The complex communication between parasite–host through secreted molecules and extracellular vesicles also participates in the pathogenesis of CD.

• #1 Achievements and challenges in controlling Chagas disease

  https://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S1665-11462011000200006

  The pathogenesis of both acute and chronic phases has been under intense examination in recent years. One focus of research has been the origin of tissue damage in chronic illness—a critical question because it is highly pertinent to treatment strategies for chronic disease. Another area of inquiry has been the investigation of the immune response to parasite infection with the hope of developing novel therapeutic targets within the inflammatory cascade. […] An accurate description of the pathogenetic mechanisms leading to chronic chagasic disease is currently quite controversial. The question of chronic disease pathogenesis is more than academic; it has pressing significance for effective treatment strategies by shedding light on whether there is a need for etiological treatment, more focus on immunomodulatory interventions, or even the use of neurohormonal antagonists. Much of the research has focused on chronic cardiomyopathy, the most common and most serious manifestation of chronic illness. In the past, lack of evidence of parasite persistence in chronic chagasic patients suggested an autoimmune etiology for tissue damage and although more sensitive tests demonstrating parasite presence in both blood and tissue in chronic patients now implicate parasite presence as a direct component of pathological processes, the contribution of autoimmune processes continues to be considered.

• #1 Achievements and challenges in controlling Chagas disease

  https://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S1665-11462011000200006

  Overall, current evidence does not indicate that autoimmune processes are the primary mediator of chronic tissue damage, but immunological mechanisms likely do play a role in the pathogenesis of chronic chagasic cardiopathy. […] The high prevalence of parasites in the blood and tissue of chronic chagasic patients, the association of T. cruzi antigens with cardiac inflammation, and correlation of parasite presence with disease severity points to a primary role of the parasite in the pathogenesis of chronic Chagas cardiomyopathy. Importantly, a recent study showed etiological treatment of chronic and indeterminate phase patients improved clinical cardiac outcomes, reinforcing the centrality of parasite persistence in chronic disease. […] Several unified theories have been proposed; adequacy of immune response to the parasite may determine degree of parasite persistence and subsequent inflammatory response or parasite presence may act as a trigger for autoimmune activation.

• #1

  https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)

  Chagas disease can be treated with benznidazole or nifurtimox. Both medicines kill the parasite and are fully effective in curing the disease if given early, in the acute phase, including in case of congenital transmission. Their efficacy diminishes, however, the longer a person has been infected; also, adverse reactions are more frequent and potentially severe in older age. Treatment is also indicated for patients in whom infection has been reactivated (for example, due to immunosuppression), and during the early chronic phase, including for girls and women of childbearing age (before or after pregnancy) to prevent congenital transmission. […] The large number of triatomine bug species and wild animals (reservoirs) infected with T. cruzi throughout the Americas mean that the infection cannot be eradicated. Instead, the public health targets are elimination of the transmission to humans, early health-care access and life-long follow up of the infected people. […] Innovation, research and development, and evaluation of new diagnostics and medicines can accelerate the path towards the elimination of the disease as a public health problem.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240520/New-mechanism-discovered-for-Chagas-disease-induced-heart-damage.aspx

  By gauging the effect of plasma-derived infection-associated L-adipomes (P-ILA), the scientists found that it regulates immunometabolic signaling amid Chagas infection – and thus induces cardomyopathy. […] „These findings highlight adipomes’ pivotal role in promoting inflammation and impairing myocardial function during cardiac remodeling in Chagas disease,” the authors write. „Furthermore, their research identifies that the composition of adipomes is tailored to the physiological state of adipose tissue. Hence, plasma adipomes can serve as specific biomarkers for disease progression identification.”

• #1 Heme crystallization in a Chagas disease vector acts as a redox-protective mechanism to allow insect reproduction and parasite infection | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006661

  Thus, targeting heme crystallization in insect vectors represents an innovative way for Chagas disease control, by reducing simultaneously triatomine reproduction and T. cruzi transmission. […] Although the regulation of heme homeostasis is critical for both triatomine vectors and T. cruzi parasites, the physiological significance of Hz for these organisms remains unknown. […] We hypothesized that pharmacological blockage of Hz formation in the triatomine insect Rhodnius prolixus might dysregulate the heme/redox homeostasis and disrupt vector/parasite physiology ultimately, with potential effects in CD transmission. […] Taken together, these results indicate that heme crystallization represents the prime redox regulator for triatomine vectors, highlighting the dual role of Hz as a protective mechanism to allow insect reproduction, and T. cruzi infection, opening new possibilities for effective CD control.

• #2 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  Chagas disease, or American trypanosomiasis, is a parasitic infection caused by the flagellate protozoan Trypanosoma cruzi. […] In chronic phase, mortality is primarily due to the rhythm disturbances and congestive heart failure that result from the chronic inflammatory cardiomyopathy (CCC) due to the persistence presence of parasites in the heart tissue. […] Mechanisms underlying differential progression to CCC are still incompletely understood. […] Since the bulk of evidence indicates the inflammatory infiltrate is a significant effector of heart tissue damage. […] This review aims to summarize the major recent advances in the understanding of the immunopathogenesis of Chagas disease cardiomyopathy. […] CCC is an inflammatory cardiomyopathy that can be accompanied by heart electric conduction defects, arrhythmias and thromboembolism.

• #2 Chagas disease – Wikipedia

  https://en.wikipedia.org/wiki/Chagas_disease

  Chagas disease is caused by infection with the protozoan parasite T. cruzi, which is typically introduced into humans through the bite of triatomine bugs, also called „kissing bugs”. […] Inside a host cell, the parasite transforms into a replicative form called an amastigote, which undergoes several rounds of replication. […] The replicated amastigotes transform back into trypomastigotes, which burst the host cell and are released into the bloodstream. […] Over many years, cycles of parasite replication and immune response can severely damage these tissues, particularly the heart and digestive tract. […] In the acute phase of the disease, signs and symptoms are caused directly by the replication of T. cruzi and the immune system’s response to it. […] During chronic Chagas disease, long-term organ damage develops over years due to continued replication of the parasite and damage from the immune system.

• #2 The End Justifies the Means: Chagas Disease from a Perspective of the Host–Trypanosoma cruzi Interaction

  https://www.mdpi.com/2075-1729/14/4/488

  The neglected Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi. […] The complex interaction between the parasite and the host outlines the etiology and progression of CD. The unique characteristics and high adaptability of T. cruzi, its mechanisms of persistence, and evasion of the immune system seem to influence the course of the disease. […] Despite the efforts to uncover the pathology of CD, there are many gaps in understanding how it is established and reaches chronicity. […] Here, we discuss the main factors that contribute to the pathogenesis of CD, from the molecular peculiarities of the parasite and its virulence factors to pathogen–host interactions and the immune response. […] The pathogenesis of CD comprises an acute phase and a chronic phase. […] Failure of the host to eliminate the infection leads to the persistence of the parasite in tissues (either through continuous cycles of cellular entry and exit or through sporadic local infections or reactivation of dormant parasites), resulting in direct and immune-mediated tissue damage.

• #2 Immunopathological Mechanisms Underlying Cardiac Damage in Chagas Disease

  https://www.mdpi.com/2076-0817/12/2/335

  In Chagas disease, the mechanisms involved in cardiac damage are an active field of study. The factors underlying the evolution of lesions following infection by Trypanosoma cruzi and, in some cases, the persistence of its antigens and the host response, with the ensuing development of clinically observable cardiac damage, are analyzed in this review. […] Most of the mechanisms involved in evading the immune response occur in the acute phase, when trypomastigotes establish contact with immune cells of the vertebrate host. The parasite has evolved mechanisms to survive processes such as phagocytosis and the complement system, in addition to interfering with lymphocyte maturation. […] The presence and replication by binary fission of intracellular amastigotes in the myocardiocyte and its ensuing lysis cause inflammation, the release of cellular components, and finally the destruction of cardiac tissue.

• #2 Chagas disease: Current perspectives on a forgotten disease | Revista Médica del Hospital General de México

  https://www.elsevier.es/pt-revista-revista-medica-del-hospital-general-325-articulo-chagas-disease-current-perspectives-on-S0185106316301123

  Chagas disease is a parasitic zoonosis caused by Trypanosoma cruzi, a protozoan whose transmission to humans is primarily vector-borne. […] The production of virulence factors by T. cruzi during the acute phase strongly inhibits the response of the host’s immune system, thereby inducing anergia and clonal deletion of T lymphocytes, along with a strong polyclonal stimulation of B lymphocytes that secrete antibodies with a low affinity towards T. cruzi antigens. This promotes persistence of the infection and its progression towards the chronic phase of the disease. […] In the course of the past few decades, knowledge of the mechanisms of immune response and the pathophysiology of Chagas disease has increased. T. cruzi is known to interact with multiple host cell receptors, including toll-like receptors (TLRs). This leads to the activation of macrophages, neutrophils, and natural killer (NK) cells. These cells result in an intense inflammatory reaction secondary to upregulation of pro-inflammatory cytokines and cause respiratory burst through NAD(P)H oxidase (nicotinamide adenine dinucleotide phosphate oxidase [NOX2]), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO). This releases reactive oxygen species (ROS), such as superoxide (O2), and reactive nitrogen species (RNS), such as nitric oxide (NO), in addition to hypochlorous acid (HOCl).

• #2 Pathology and Pathogenesis of Chagas Heart Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7373119/

  The inflammatory infiltrate is composed primarily of lymphocytes and macrophages, with smaller numbers of natural killer cells, dendritic cells, and granulocytes. […] The chronic phase of the disease likely represents, at least in part, a slowly progressive, cyclical reaction to the presence of intramyocardial parasites, which results in a smoldering, ongoing inflammatory reaction, myocardial cell necrosis and dropout, and fibrosis that develop over years to decades. […] Many of the mechanisms of the pathogenesis of Chagas heart disease have been described and defined in detail in humans and experimental animals. […] Most proposed mechanisms require the presence of T. cruzi somewhere in the host, whether in the heart or elsewhere, to produce and/or propagate cardiac pathology. […] Disease outcome is determined by a highly complex interplay between the virulence of the T. cruzi strain and the genetic susceptibility of the individual, with both parasite virulence and host susceptibility varying with the parasite-host combination.

• #2 Pathogenesis of Chagas disease: time to move on – UEA Digital Repository

  https://ueaeprints.uea.ac.uk/id/eprint/36850/

  Trypanosoma cruzi is the etiologic agent of Chagas disease. The contributions of parasite and immune system for disease pathogenesis remain unresolved and controversial. […] There is now a considerable body of evidence and broad consensus that parasite persistence is requisite for pathogenesis and that antiparasitic immunity can be protective against T. cruzi pathogenesis without eliciting autoimmune pathology. Thus, treatment of chronically infected patients is likely to yield positive outcomes and efforts to understand immunity and vaccine development should be recognized as a priority area of research for Chagas disease.

• #2 WHF IASC Roadmap on Chagas Disease | Global Heart

  https://globalheartjournal.com/articles/10.5334/gh.484

  Thus far, the main factors identified as being related to cardiac damage are: Immune response to antigens of the parasite leading to fibrosing inflammation (T CD8 lymphocyte response), direct damage to myocytes by the presence of the parasite, damage of the neuronal cardiac system, autoantibodies against neuro-receptors, microvascular abnormalities, non-specific damage due presence of eosinophils and neutrophils, and oxidative stress. […] There is growing evidence that parasite persistence is a necessary factor for disease progression.

• #2 Pathogenesis of Chagas disease: time to move on

  https://www.imrpress.com/journal/FBE/4/5/10.2741/e495

  Trypanosoma cruzi is the etiologic agent of Chagas disease. The contributions of parasite and immune system for disease pathogenesis remain unresolved and controversial. […] This viewpoint was adopted by cash-strapped health systems in the developing economies where the disease is endemic and has been repeatedly challenged by researchers and clinicians in recent years and there is now a considerable body of evidence and broad consensus that parasite persistence is requisite for pathogenesis and that antiparasitic immunity can be protective against T. cruzi pathogenesis without eliciting autoimmune pathology. Thus, treatment of chronically infected patients is likely to yield positive outcomes and efforts to understand immunity and vaccine development should be recognized as a priority area of research for Chagas disease.

• #2 Chagas Disease (American Trypanosomiasis): Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/214581-overview

  An inflammatory lesion called a chagoma caused by T cruzi may appear at the site of entry in patients with acute Chagas disease. Histologic changes may include interstitial edema, lymphocytic infiltration, and reactive hyperplasia of adjacent lymph nodes due to intracellular parasitism of muscle and other subcutaneous tissues. […] The pathogenesis of cardiac and gastrointestinal lesions of chronic Chagas disease was a focus of debate for decades. Beginning more than 20 years ago, however, convincing evidence has shown that low levels of parasites in chronically affected tissue, detectable with molecular methods, provoke a chronic inflammatory response that eventually leads to the pathologic changes observed microscopically and organ dysfunction.

• #2 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  Several studies suggest that heart failure due to CCC may have a worse prognosis with 50% shorter survival when compared to other cardiomyopathies of different etiologies such as ischemic cardiomyopathy and idiopathic dilated cardiomyopathy. […] Significantly, a key difference between CCC and such cardiomyopathies is inflammation/myocarditis, present in greater intensity among CCC patients. […] The major histopathological feature attending dilated cardiomyopathy in CCC is the presence of a diffuse myocarditis, with intense cardiomyocyte damage and hypertrophy, and significant fibrosis, in the presence of very scarce T. cruzi forms. […] Since it is known that T. cruzi establishes a lifelong, low-grade infection, the possibility that chronic myocardial inflammation and tissue damage in CCC are a consequence of recognition of parasite antigen on target tissue must be entertained.

• #2 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  The discrepancy between the parasitism and inflammation suggested that tissue-damaging T cells were of autoimmune nature, possibly elicited by cross-reactive immune responses with T. cruzi parasite. […] Direct experimental evidence of autoimmunity in CCC and experimental models has been documented over the last 25 years. […] The existence of degenerate intramolecular recognition, with multiple low-homology, cross-reactive epitopes in a single autoantigenic protein may have implications in increasing the magnitude of the autoimmune response in CCC and other autoimmune diseases. […] Autoimmune and T. cruzi-specific responses secondary to parasite persistence are not incompatible or mutually exclusive in Chagas disease, and a combination of these types of immune responses could be involved in the establishment of heart tissue lesions.

• #2 Pathogenesis of Chagas disease cardiomyopathy

  https://www.wjgnet.com/2220-3176/full/v2/i3/39.htm

  It is likely that the persistence of a parasite which induces strong innate immunity and proinflammatory cytokines may continuously boost the production of potentially pathogenic Th1 T cells cross-reactively recognizing T. cruzi and heart-specific epitopes. […] Such Th1 T cells may migrate to heart tissue in response to locally expressed CXCR3 ligand chemokines. […] Once they reach myocardial tissue, cross-reactive T cells could be activated by cardiac antigen even in the absence of T. cruzi antigens. […] This would elicit local production of Th1 cytokines. […] Local production of Th1 cytokines could exert their pathophysiological role by causing direct inflammatory damage, as well as modulating cardiac cell gene expression. […] Finally, it must be stressed that autoimmune and T. cruzi-specific innate or adaptative responses are not incompatible or mutually exclusive, and it is likely that a combination of both is involved in the pathogenesis of CCC.

• #2 Chagas disease – Wikipedia

  https://en.wikipedia.org/wiki/Chagas_disease

  In the heart, colon, and esophagus, chronic disease leads to a massive loss of nerve endings. […] Loss of nerves impairs the movement of food through the digestive tract, which can lead to blockage of the esophagus or colon and restriction of their blood supply. […] The parasite can insert kinetoplast DNA into host cells, an example of horizontal gene transfer.

• #2 Achievements and challenges in controlling Chagas disease

  https://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S1665-11462011000200006

  Despite the controversy over the primary pathogenetic mechanism, acute and chronic inflammation mediated by the host immune system is undoubtedly important in development of tissue damage. An understanding of the delicate balance between parasite control and inflammatory tissue damage could lead to new therapeutic targets to spare tissue injury. Various studies have outlined the progression of immunologic events. A strong innate response and a polyclonal activation of B and T-cells follow the initial encounter with the parasite, with the induction of cytokines, particularly IFN-γ and TNF-α, and expression of adhesion molecules that promote CD8+ dominant leukocyte recruitment. This inflammatory response leads to an acute myocarditis, and the sustained production of IFN-inducible cytokines establishes a facilitative environment for continued inflammation.

• #2 Cytokine Profiling in Chagas Disease: Towards Understanding the Association with Infecting Trypanosoma cruzi Discrete Typing Units (A BENEFIT TRIAL Sub-Study) | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091154

  The anti-inflammatory/pro-inflammatory cytokine profile switch found between patients with Chagas cardiomyopathy and those infected but still in the NON-CARD stage of the disease is compatible with the hypothesis that the progression of human Chagas disease from asymptomatic to severe forms, is related with a lack of adequate immune modulation. […] The relationship of the genetic variability of the parasite and host characteristics with pathogenesis is increasingly recognized as an important factor in the understanding of Chagas disease. […] In summary, pro-inflammatory profile is associated to CARD patients and anti-inflammatory profile to NON-CARD patients. The fact that the levels of cytokines were different for patients infected with different parasite DTUs suggests a specific immune response, probably associated to DTUs. A novel contribution of this study is the possibility of using IL-12, IFN-, IL-6 and IL-1 as prognostic biomarkers of Chagas Disease. Future studies should be carried out covering the geographical wide-range of DTUs and other human populations, in order to validate these cytokines as biomarkers as well as finding the plausible association between DTUs-epitope and Chagas Disease clinical manifestations.

• #2 WHF IASC Roadmap on Chagas Disease | Global Heart

  https://globalheartjournal.com/articles/10.5334/gh.484

  Chagas Disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, with some of the most serious manifestations affecting the cardiovascular system. […] The predominant and most serious chronic manifestations of CD affect the cardiovascular system. […] The extent of cardiac involvement in the chronic phase of the disease appears to be the result of the parasite-activated immune response, but parasite persistence during the chronic stage of infection is critical. […] The immune response elicited in the acute phase and maintained during the chronic one seems to be influenced by variables such as parasite load during the acute phase, parasite strain, the magnitude of the immune response, and the presence or absence of reinfection. […] A critical knowledge gap exists as to why only 30% of infected individuals will progress to CCC. Several host and parasite factors have been evaluated to understand this phenomenon.

• #2 Chagas disease: Current perspectives on a forgotten disease | Revista Médica del Hospital General de México

  https://www.elsevier.es/en-revista-revista-medica-del-hospital-general-325-articulo-chagas-disease-current-perspectives-on-S0185106316301123

  Some theories have attempted to explain the pathophysiological process of the disease, including: theory of parasite persistence (this is based on the fact that the presence and replication of amastigotes in host cells cause mechanical rupture and waste secretion which attract pro-inflammatory cells); unified neurogenic theory (this is based on the fact that significant neuron loss in the sympathetic and parasympathetic nervous systems is unrelated to the presence of T. cruzi in situ, and is attributed to production and release of a neurotoxin from a parasite nest hidden in the host’s body); and autoimmune theory (this is based on the accelerated cytotoxic interaction that exists between lymphocytes related to the immune response to T. cruzi and allogeneic myocardiocytes not infested with parasites). Each one shows unique discrepancies, which may be explained from a clinical point of view by the difficulty of determining pathogenicity after a prolonged period of time has elapsed between infection with T. cruzi and development of its complications.

• #2 CDC – DPDx – American Trypanosomiasis

  https://www.cdc.gov/dpdx/trypanosomiasisamerican/index.html

  Trypanosoma cruzi, is a parasitic protozoan that is the causative agent of Chagas disease (American trypanosomiasis). Currently, six distinct lineages of T. cruzi are classified into discrete typing units (TcI-VI), which vary in their geographic occurrence, host specificity, and pathogenicity. […] Inside the host, the trypomastigotes invade cells near the site of inoculation, where they differentiate into intracellular amastigotes. The amastigotes multiply by binary fission and differentiate into trypomastigotes, and then are released into the circulation as bloodstream trypomastigotes. […] The symptomatic chronic form (determinate form) may not occur for years or even decades after initial infection. This may include cardiac or gastrointestinal involvement, which occasionally occur together. The many complications of chronic Chagas disease can be fatal. Amastigote invasion of smooth muscle can lead to megaesophagus, megacolon, and dilated cardiomyopathy. […] Trypomastigotes of T. cruzi are the only stage found circulating in human blood or CSF. In tissue, the parasite forms amastigotes characterized by a single nucleus and kinetoplast. The amastigotes of T. cruzi are morphologically indistinguishable from those of Leishmania spp.

• #2 Megacolon – Wikipedia

  https://en.wikipedia.org/wiki/Megacolon

  Megacolon can be associated with Chagas disease. Chagas disease is caused by Trypanosoma cruzi, a flagellate protozoan transmitted by the assassin bug. […] There are several theories on how megacolon (and also megaesophagus) develops in Chagas disease. The Austrian-Brazilian physician and pathologist Fritz Kberle was the first to propose the neurogenic hypothesis based on the documented destruction of the myenteric plexus in the walls of the intestinal tracts of Chagas patients. In this, the destruction of the autonomic nervous system innervation of the colon leads to a loss of the normal smooth muscle tone of the wall and subsequent gradual dilation. […] Neurons were strongly reduced all over the digestive tract; megacolon appeared only when there was a reduction of over 80% of the number of neurons; these pathologies appeared as a result of the disruption of the neurally integrated control of peristalsis (muscular annular contraction) in those parts where a strong force is necessary to impel the luminal bolus of feces; idiopathic megacolon and Chagas megacolon appear to have the same cause, namely the degeneration of the myenteric plexus. […] Why T. cruzi causes the destruction, however, remains to be determined. There is evidence for the presence of specific neurotoxins as well as a disorderly immune system reaction.

• #2 Chagas disease: role of parasite genetic variation in pathogenesis | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/chagas-disease-role-of-parasite-genetic-variation-in-pathogenesis/B6A19E307C042589BB61581528423177

  Chagas disease, caused by the parasite protozoan Trypanosoma cruzi, is characterised by a variable clinical course, from symptomless cases to severe chronic disease with cardiac and/or gastrointestinal involvement. […] This variability has been attributed both to differences in the host response and to genomic heterogeneity of the parasite. […] This article reviews the evidence in favour of an important role of the genetic constitution of T. cruzi in determining the clinical characteristics of Chagas disease and discusses the basis of the Clonal-Histotropic Model for the pathogenesis of this disease.

• #2 The End Justifies the Means: Chagas Disease from a Perspective of the Host–Trypanosoma cruzi Interaction

  https://www.mdpi.com/2075-1729/14/4/488

  The development of cardiomyopathy is related to several pathophysiological processes like the passage of parasites through tissues that leads to a cyclical and slow reaction, resulting in a continuous inflammatory reaction that promotes the death of myocardial cells and their replacement by fibrous tissue over the years. […] However, it has already been seen that myocarditis can develop even in the complete absence of cardiac parasitism. […] Thus, it is believed that other mechanisms contribute to the induction of chagasic cardiomyopathy, such as cardiac autonomic dysfunction, microvascular disorders and immune-mediated injury. […] The studies performed to date revealed that the plasticity of T. cruzi’s genome to generate multiple variants of proteins (like TSs, mucins, and MASPs) through gene duplication, recombination, and mutation, are a source for great antigenic diversity, increasing the parasite fitness and survival by promoting the evasion of the mammalian host immune system.

• #2 Heme crystallization in a Chagas disease vector acts as a redox-protective mechanism to allow insect reproduction and parasite infection | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006661

  Thus, targeting heme crystallization in insect vectors represents an innovative way for Chagas disease control, by reducing simultaneously triatomine reproduction and T. cruzi transmission. […] Although the regulation of heme homeostasis is critical for both triatomine vectors and T. cruzi parasites, the physiological significance of Hz for these organisms remains unknown. […] We hypothesized that pharmacological blockage of Hz formation in the triatomine insect Rhodnius prolixus might dysregulate the heme/redox homeostasis and disrupt vector/parasite physiology ultimately, with potential effects in CD transmission. […] Taken together, these results indicate that heme crystallization represents the prime redox regulator for triatomine vectors, highlighting the dual role of Hz as a protective mechanism to allow insect reproduction, and T. cruzi infection, opening new possibilities for effective CD control.

• #2 Achievements and challenges in controlling Chagas disease

  https://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S1665-11462011000200006

  Overall, current evidence does not indicate that autoimmune processes are the primary mediator of chronic tissue damage, but immunological mechanisms likely do play a role in the pathogenesis of chronic chagasic cardiopathy. […] The high prevalence of parasites in the blood and tissue of chronic chagasic patients, the association of T. cruzi antigens with cardiac inflammation, and correlation of parasite presence with disease severity points to a primary role of the parasite in the pathogenesis of chronic Chagas cardiomyopathy. Importantly, a recent study showed etiological treatment of chronic and indeterminate phase patients improved clinical cardiac outcomes, reinforcing the centrality of parasite persistence in chronic disease. […] Several unified theories have been proposed; adequacy of immune response to the parasite may determine degree of parasite persistence and subsequent inflammatory response or parasite presence may act as a trigger for autoimmune activation.

• #3 Pathogenesis of Chagas disease: time to move on

  https://www.imrpress.com/journal/FBE/4/5/10.2741/e495

  Trypanosoma cruzi is the etiologic agent of Chagas disease. The contributions of parasite and immune system for disease pathogenesis remain unresolved and controversial. […] This viewpoint was adopted by cash-strapped health systems in the developing economies where the disease is endemic and has been repeatedly challenged by researchers and clinicians in recent years and there is now a considerable body of evidence and broad consensus that parasite persistence is requisite for pathogenesis and that antiparasitic immunity can be protective against T. cruzi pathogenesis without eliciting autoimmune pathology. Thus, treatment of chronically infected patients is likely to yield positive outcomes and efforts to understand immunity and vaccine development should be recognized as a priority area of research for Chagas disease.

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