Differential cardiomyocyte transcriptomic remodeling during in vitro Trypanosoma cruzi infection using laboratory strains provides implications on pathogenic host responses.

BACKGROUND: Chagas disease can lead to life-threatening cardiac manifestations. Regional factors, including genetic characteristics of circulating Trypanosoma cruzi (T. cruzi), have attracted attention as likely determinants of Chagas disease phenotypic expression and Chagas cardiomyopathy (CCM) progression. Our objective was to elucidate the differential transcriptomic signatures of cardiomyocytes resulting from infection with genetically discrete T. cruzi strains and explore their relationships with CCM pathogenesis and progression. METHODS: HL-1 rodent cardiomyocytes were infected with T. cruzi trypomastigotes of the Colombian, Y, or Tulahuen strain. RNA was serially isolated post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change ≥ 2 or ≤ 0.5) highlighted over-represented biological pathways. Intracellular levels of reactive oxygen species (ROS) were compared between T. cruzi-infected and non-infected HL-1 cardiomyocytes. RESULTS: We found that oxidative stress-related gene ontology terms (GO terms), 'Hypertrophy model', 'Apoptosis', and 'MAPK signaling' pathways (all with P < 0.01) were upregulated. 'Glutathione and one-carbon metabolism' pathway, and 'Cellular nitrogen compound metabolic process' GO term (all with P < 0.001) were upregulated exclusively in the cardiomyocytes infected with the Colombian/Y strains. Mean intracellular levels of ROS were significantly higher in the T. cruzi-infected cardiomyocytes compared to the non-infected (P < 0.0001). CONCLUSIONS: The upregulation of oxidative stress-related and hypertrophic pathways constitutes the universal hallmarks of the cardiomyocyte response elicited by T. cruzi infection. Nitrogen metabolism upregulation and glutathione metabolism imbalance may implicate a relationship between nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of Chagas cardiomyopathy.

State-dependent interhemispheric inhibition reveals individual differences in motor behavior in chronic stroke.

OBJECTIVE: To investigate state-dependent interhemispheric inhibition (IHI) in chronic stroke survivors compared to neurotypical older adult controls, and test whether abnormal IHI modulation was associated with upper extremity motor behavior. METHODS: Dual-coil transcranial magnetic stimulation (TMS) measured IHI bi-directionally, between non-lesioned and lesioned motor cortex (M1) in two activity states: (1) at rest and (2) during contralateral isometric hand muscle contraction. IHI was tested by delivering a conditioning stimulus 8-msec or 50-msec prior to a test stimulus over contralateral M1. Paretic motor behavior was assessed by clinical measures of impairment, strength, and dexterity, and mirroring activity in the non-paretic hand. RESULTS: Stroke survivors demonstrated reduced IHI at rest, and less IHI modulation (active - rest) compared to controls. Individual differences in IHI modulation were related to motor behavior differences where greater IHI modulation was associated with greater motor impairment and more mirroring. In contrast, there were no relationships between IHI at rest and motor behavior. CONCLUSIONS: Abnormal state-dependent interhemispheric circuit activity may be more sensitive to post-stroke motor deficits than when assessed in a single motor state. SIGNIFICANCE: Characterizing state-dependent changes in neural circuitry may enhance models of stroke recovery and inform rehabilitation interventions.