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Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. 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. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection—Chagas heart disease—and concludes with a discussion of key unanswered questions and a view to the future.

Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of individuals infected with the protozoan parasite Trypanosoma cruzi . Since the discovery of T. cruzi by Carlos Chagas >100 years ago, much has been learned about Chagas disease pathogenesis; however, the outcome of T. cruzi infection is highly variable and difficult to predict. Many mechanisms have been proposed to promote tissue inflammation, but the determinants and the relative importance of each have yet to be fully elucidated. The notion that some factor other than the parasite significantly contributes to the development of myocarditis was hypothesized by the first physician-scientists who noted the conspicuous absence of parasites in the hearts of those who succumbed to Chagas disease. One of these factors—autoimmunity—has been extensively studied for more than half a century. Although questions regarding the functional role of autoimmunity in the pathogenesis of Chagas disease remain unanswered, the development of autoimmune responses during infection clearly occurs in some individuals, and the implications that this autoimmunity may be pathogenic are significant. In this review, we summarize what is known about the pathogenesis of Chagas heart disease and conclude with a view of the future of Chagas disease diagnosis, pathogenesis, therapy, and prevention, emphasizing recent advances in these areas that aid in the management of Chagas disease.

Infection with the protozoan parasite Trypanosoma cruzi may lead to a potentially fatal cardiomyopathy known as Chagas heart disease. This disease is characterized by infiltration of the myocardium by mononuclear cells, including CD4+ T cells, together with edema, myofibrillary destruction and fibrosis. A multifaceted systemic immune response develops that ultimately keeps parasitemia and tissue parasitosis low. T helper 1 and other pro-inflammatory T cell responses are effective at keeping levels of T. cruzi low in tissues and blood, but they may also lead to tissue inflammation when present chronically. The mechanism by which the inflammatory response is regulated in T. cruzi infected individuals is complex, and the specific roles that Th17 and T regulatory (Treg) cells may play in that regulation are beginning to be elucidated. In this study, we found that depletion of Treg cells in T. cruzi-infected mice leads to reduced cardiac parasitosis and inflammation, accompanied by an augmented Th1 response early in the course of infection. This is followed by a down-regulation of the Th1 response and increased Th17 response late in infection. The effect of Treg cell depletion on the Th1 and Th17 cells is not observed in mice immunized with T. cruzi in adjuvant. This suggests that Treg cells specifically regulate Th1 and Th17 cell responses during T. cruzi infection, and may also be important for modulating parasite clearance and inflammation in the myocardium of T. cruzi-infected individuals.

Summary Cardiac inflammation that develops during infection with Trypanosoma cruzi may result in part from autoimmunity, which may occur after bystander activation, after parasite-induced cardiomyocyte damage, or molecular mimicry. A/J mice infected with T. cruzi or immunized with heat-killed T. cruzi (HKTC) develop strong autoimmunity accompanied by cardiac damage. To determine whether this cardiac damage occurs via an antibody-dependent mechanism, we analysed T. cruzi-infected and HKTC-immunized mice for the presence of autoantibodies, cardiac antibody deposition, and serum cardiac troponin I as a measure of cardiac damage. We also performed a serum transfer experiment in which sera from T. cruzi-infected and T. cruzi-immunized mice (and controls) were transferred into naive recipients, which were then analysed for the presence of antibodies and serum troponin. Unlike T. cruzi-infected mice, T. cruzi-immunized mice did not show significant antibody deposition in the myocardium. These results indicate that antibody deposition does not precede cardiac damage and inflammation in mice immunized with or infected with T. cruzi. Serum adoptive transfer did not induce cardiac damage in any recipients. Based on these findings, we conclude that the cardiac damage induced by immunization with HKTC is not mediated by antibodies.

The mismatch correction (MMC) system repairs DNA mismatches and single nucleotide insertions or deletions postreplication. To test the functions of MMC in the obligate human pathogen Neisseria gonorrhoeae , homologues of the core MMC genes mutS and mutL were inactivated in strain FA1090. No mutH homologue was found in the FA1090 genome, suggesting that gonococcal MMC is not methyl directed. MMC mutants were compared to a mutant in uvrD , the helicase that functions with MMC in Escherichia coli . Inactivation of MMC or uvrD increased spontaneous resistance to rifampin and nalidixic acid, and MMC/ uvrD double mutants exhibited higher mutation frequencies than any single mutant. Loss of MMC marginally enhanced the transformation efficiency of DNA carrying a single nucleotide mismatch but not that of DNA with a 1-kb insertion. Unlike the exquisite UV sensitivity of the uvrD mutant, inactivating MMC did not affect survival after UV irradiation. MMC and uvrD mutants exhibited increased PilC-dependent pilus phase variation. mutS- deficient gonococci underwent an increased frequency of pilin antigenic variation, whereas uvrD had no effect. Recombination tracts in the mutS pilin variants were longer than in parental gonococci but utilized the same donor pilS loci. These results show that gonococcal MMC repairs mismatches and small insertion/deletions in DNA and also affects the recombination events underlying pilin antigenic variation. The differential effects of MMC and uvrD in gonococci unexpectedly reveal that MMC can function independently of uvrD in this human-specific pathogen.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a major public health burden in Latin America and a potentially serious emerging threat to a number of countries throughout the world. Although public health programs have significantly reduced the prevalence of Chagas disease in Latin America in recent decades, the number of infections in the United States and non-endemic countries in Europe and the Western Pacific Region continues to rise. Moreover, there is still no vaccine or highly effective cure available for the approximately 10 million people currently infected with T. cruzi, a third of which will develop potentially fatal cardiomyopathy and/or severe digestive tract disorders. As Chagas disease becomes an increasingly globalized public health issue in the twenty-first century, continued attentiveness from governmental and health organizations as well as improved diagnostic tools, expanded surveillance and increased research funding will be required to maintain existing public health successes and stymie the spread of the disease to new areas and populations.

Neglected tropical diseases constitute a significant public health burden, affecting over one billion people globally, yet this group of diseases is underrepresented in the appropriation of both monetary and intellectual capital for developing improved therapies and public health campaigns. The topic of neglected tropical diseases has been similarly marginalized in the biology classrooms of our nation’s high schools and colleges, despite offering an opportunity to teach and learn about a diverse area of microbiology with far-reaching public health, social, and economic implications. Discussed herein is an argument for increasing the representation of neglected tropical diseases in microbiology education as a means to generate increased interest in these diseases among the generation of future researchers and policy-makers, and to promote interdisciplinary learning, civic engagement, and critical thinking.

Neglected tropical diseases (NTDs) affect over one billion people globally creating a public health burden that has far reaching implications for the fields of economics, politics, sociology, and science. Educating students and the public about relevant risks, implications, and treatments is a key component of reducing the public health burden associated with NTDs. Furthermore, teaching and learning about NTDs provides myriad opportunities to incorporate interdisciplinary teaching, active learning, and civic engagement into a broad range of courses throughout grade school, high school, college. However, despite the importance of NTD-focused education, few educational programs sufficiently emphasize this topic. Presented here is an overview of NTDs, a brief rationale for broadening inclusion of NTDs in a variety of educational settings, and a series of suggestions for promoting civic engagement with NTD education.

There is an error in the author contributions. KMB should be listed in "wrote the paper" rather than DME. The correct author contributions are: Conceived and designed the experiments: KMB CLE DME. Performed the experiments: KMB JMT MDD. Analyzed the data: KMB. Contributed reagents/materials/analysis tools: KMB. Wrote the paper: KMB. Edited the manuscript: CLE DME.

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.

Chagas heart disease, caused by the protozoan parasite Trypanosoma cruzi, is a potentially fatal cardiomyopathy often associated with cardiac autoimmunity. T. cruzi infection induces the development of autoimmunity to a number of antigens via molecular mimicry and other mechanisms, but the genesis and pathogenic potential of this autoimmune response has not been fully elucidated. To determine whether exposure to T. cruzi antigens alone in the absence of active infection is sufficient to induce autoimmunity, we immunized A/J mice with heat-killed T. cruzi (HKTC) emulsified in complete Freund's adjuvant, and compared the resulting immune response to that induced by infection with live T. cruzi. We found that HKTC immunization is capable of inducing acute cardiac damage, as evidenced by elevated serum cardiac troponin I, and that this damage is associated with the generation of polyantigenic humoral and cell-mediated autoimmunity with similar antigen specificity to that induced by infection with T. cruzi. However, while significant and preferential production of Th1 and Th17-associated cytokines, accompanied by myocarditis, develops in T. cruzi-infected mice, HKTC-immunized mice produce lower levels of these cytokines, do not develop Th1-skewed immunity, and lack tissue inflammation. These results demonstrate that exposure to parasite antigen alone is sufficient to induce autoimmunity and cardiac damage, yet additional immune factors, including a dominant Th1/Th17 immune response, are likely required to induce cardiac inflammation.