RESUMEN
Chagas disease (CD) is a parasitic disease caused by Trypanosoma cruzi protozoa, presenting with cardiomyopathy, megaesophagus, and/or megacolon. To determine the mechanisms of gastrointestinal (GI) CD tissue tropism, we systematically characterized the spatial localization of infection-induced metabolic and microbiome alterations, in a mouse model of CD. Notably, the impact of the transition between acute and persistent infection differed between tissue sites, with sustained large-scale effects of infection in the esophagus and large intestine, providing a potential mechanism for the tropism of CD within the GI tract. Infection affected acylcarnitine metabolism; carnitine supplementation prevented acute-stage CD mortality without affecting parasite burden by mitigating infection-induced metabolic disturbances and reducing cardiac strain. Overall, results identified a previously-unknown mechanism of disease tolerance in CD, with potential for new therapeutic regimen development. More broadly, results highlight the potential of spatially resolved metabolomics to provide insight into disease pathogenesis and infectious disease drug development.
Asunto(s)
Enfermedad de Chagas , Microbiota , Parásitos , Trypanosoma cruzi , Animales , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/parasitología , Ratones , Tropismo , Trypanosoma cruzi/metabolismoRESUMEN
Five commercially available devices for performing prick skin testing were compared for reproducibility, patient acceptance, occurrence of false-negative skin test results, and size distribution of reactions at the negative control sites. Reproducibility of skin testing with 10 mg/ml histamine base, as expressed by coefficient of variation, was similar. However, a clear range of trauma to the skin was produced by the devices. This trauma was least with the Hollister-Stier and ALK Laboratories lancets, intermediate for the bifurcated needle by either prick or puncture, and greatest for the Multi-Test and DermaPIK devices. The more traumatic devices produced larger mean wheals and more frequent and large reactions at saline control sites, and were less acceptable to subjects. However, except for the Multi-Test device, they less often yielded false-negative responses. It is proposed that for each device a different size of wheal must be produced at the allergen site to have confidence that it exceeds the control site. The wheal size necessary for 99% specificity were as follows: Hollister-Stier lancet, 2 mm; ALK lancet, 3.0 mm; bifurcated needle prick, 4.0 mm; bifurcated needle puncture, 4.5 mm; Multi-Test device, 5.0 mm; and DermaPIK device, 5.5 mm. An additional observation was the presence of a significant gradient of reaction size on the back to both histamine and allergen (p < 0.0001), with the smallest reactions in the upper third and the largest in the lower third of the back.