Trypanosoma cruzi genetic diversity: Something new for something known about Chagas disease manifestations, serodiagnosis and drug sensitivity.

Chronic Trypanosoma cruzi infections lead to cardiomyopathy in 20-30% of cases. A causal link between cardiac infection and pathology has been difficult to establish because of a lack of robust methods to detect scarce, focally distributed parasites within tissues. We developed a highly sensitive bioluminescence imaging system based on T. cruzi expressing a novel luciferase that emits tissue-penetrating orange-red light. This enabled long-term serial evaluation of parasite burdens in individual mice with an in vivo limit of detection of significantly less than 1000 parasites. Parasite distributions during chronic infections were highly focal and spatiotemporally dynamic, but did not localize to the heart. End-point ex vivo bioluminescence imaging allowed tissue-specific quantification of parasite loads with minimal sampling bias. During chronic infections, the gastro-intestinal tract, specifically the colon and stomach, was the only site where T. cruzi infection was consistently observed. Quantitative PCR-inferred parasite loads correlated with ex vivo bioluminescence and confirmed the gut as the parasite reservoir. Chronically infected mice developed myocarditis and cardiac fibrosis, despite the absence of locally persistent parasites. These data identify the gut as a permissive niche for long-term T. cruzi infection and show that canonical features of Chagas disease can occur without continual myocardium-specific infection.

/pdf/bioluminescence-imaging-of-chronic-trypanosoma-cruzi-4bt21nfsvc.pdf

Bioluminescence imaging of chronic Trypanosoma cruzi infections reveals tissue‐specific parasite dynamics and heart disease in the absence of locally persistent infection

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.

/pdf/pathology-and-pathogenesis-of-chagas-heart-disease-108n73heyy.pdf

Pathology and Pathogenesis of Chagas Heart Disease

Intracellular colonization and persistent infection by the kinetoplastid protozoan parasite, Trypanosoma cruzi, underlie the pathogenesis of human Chagas disease. To obtain global insights into the T. cruzi infective process, transcriptome dynamics were simultaneously captured in the parasite and host cells in an infection time course of human fibroblasts. Extensive remodeling of the T. cruzi transcriptome was observed during the early establishment of intracellular infection, coincident with a major developmental transition in the parasite. Contrasting this early response, few additional changes in steady state mRNA levels were detected once mature T. cruzi amastigotes were formed. Our findings suggest that transcriptome remodeling is required to establish a modified template to guide developmental transitions in the parasite, whereas homeostatic functions are regulated independently of transcriptomic changes, similar to that reported in related trypanosomatids. Despite complex mechanisms for regulation of phenotypic expression in T. cruzi, transcriptomic signatures derived from distinct developmental stages mirror known or projected characteristics of T. cruzi biology. Focusing on energy metabolism, we were able to validate predictions forecast in the mRNA expression profiles. We demonstrate measurable differences in the bioenergetic properties of the different mammalian-infective stages of T. cruzi and present additional findings that underscore the importance of mitochondrial electron transport in T. cruzi amastigote growth and survival. Consequences of T. cruzi colonization for the host include dynamic expression of immune response genes and cell cycle regulators with upregulation of host cholesterol and lipid synthesis pathways, which may serve to fuel intracellular T. cruzi growth. Thus, in addition to the biological inferences gained from gene ontology and functional enrichment analysis of differentially expressed genes in parasite and host, our comprehensive, high resolution transcriptomic dataset provides a substantially more detailed interpretation of T. cruzi infection biology and offers a basis for future drug and vaccine discovery efforts.

Transcriptome Remodeling in Trypanosoma cruzi and Human Cells during Intracellular Infection

African trypanosomes are devastating human and animal pathogens. Trypanosoma brucei rhodesiense and T. b. gambiense subspecies cause the fatal human disease known as African sleeping sickness. It is estimated that several hundred thousand new infections occur annually and the disease is fatal if untreated. T. brucei is transmitted by the tsetse fly and alternates between bloodstream-form and insect-form life cycle stages that are adapted to survive in the mammalian host and the insect vector, respectively. The importance of the flagellum for parasite motility and attachment to the tsetse fly salivary gland epithelium has been appreciated for many years. Recent studies have revealed both conserved and novel features of T. brucei flagellum structure and composition, as well as surprising new functions that are outlined here. These discoveries are important from the standpoint of understanding trypanosome biology and identifying novel drug targets, as well as for advancing our understanding of fundamental as...

/pdf/the-trypanosoma-brucei-flagellum-moving-parasites-in-new-4lpmv29eag.pdf

The Trypanosoma brucei flagellum: moving parasites in new directions.

Bioluminescent imaging of Trypanosoma cruzi infection

A flagellum-specific calcium sensor.

Defying Environmental Deregulation: As Protections Erode, Health Care Must Lead Sustainably.

We present a case of a 48-year-old patient with multiple penetrating stab wounds of the heart after a suicide attempt with a nail gun. The patient was admitted in stable condition. A chest radiograph (Figure 1A) and computed tomography scan (Figures 1B, 1C [Ao, aorta; LA, left atrium]) revealed 21 nails penetrating the heart and major vascular structures. The patient underwent emergent cardiac operation with cardiopulmonary bypass support initiated before chest opening. The nails from the heart were carefully removed, including the surrounding thrombus (Figure 1D). The postoperative course was complicated by a mild ischemic stroke. The patient was discharged from the hospital without any neurologic deficits. Surgical management of stab wounds of the heart is a lifesaving procedure that can be performed safely with cardiopulmonary bypass support,1Fang X. Yu C. He F. The self-inflicted multiple organs injury with nail gun.Heart Surg Forum. 2021; 24: E1049-E1051Crossref PubMed Scopus (1) Google Scholar which promotes safety and potentially reduces the risk of a significant stroke. However, the number of penetrating nails in our case draws attention to periprocedural stroke as an important complication of foreign material extraction from the heart and great vessels. 

http://www.annalsthoracicsurgeryshortrep.org/article/S277299312300181X/pdf

Surgical Treatment of Multiple Nail Gun Chest Wounds

Postoperative Respiratory Failure After Elective Abdominal Surgery: A Case-Control Study.

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