Valenzuela-Perez, L. | Search bioRxiv

bioRxiv2023

Temperature influences the excretion time and parasitic load of Trypanosoma cruzi in the Triatoma infestans vector

Trypanosoma cruzi is a protozoan parasite transmitted by triatomine insect vectors, which expel their infectious dejections when they feed, causing Chagas disease in humans. The transmission and incidence of this vector-borne disease depend on the vital traits of its vectors, including Triatoma infestans, the main vector in Southern South America. Being an ectothermic species, its metabolism and its vital traits respond to temperature fluctuations. Here, we evaluated if changes in the average and variability of temperature expected with climate change modify: (i) the extrinsic incubation period (EIP) of T. cruzi within the vector T. infestans, (ii) its parasitic load, and (iii) the probability that its dejections were T. cruzi-positive. We acclimated triatomines infected with Dm28c T. cruzi strain to two constant and two variable temperature treatments and measured T. cruzi in their dejections by qPCR over a 42-day period. We observed that individuals in warm-temperature treatments showed lower EIP and higher parasitic load than cold-temperature treatments. Also, temperature variability can increase the parasitic load peak in cold-temperature treatments. Consequently, in a climate change scenario, there might be an increase in the vector capacity of T. infestans and probably a change in the risk of vectorial transmission of T. cruzi.

ecology↗

bioRxiv2023

Interleukin-21 Drives a Hypermetabolic State and CD4+ T Cell-associated Pathogenicity in Chronic Intestinal Inflammation

BACKGROUND & AIMSIncapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease (IBD); however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODSUsing human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing Seahorse XF analyzer. We utilized Crohns disease single-cell RNA sequencing dataset to infer therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically-modified Tregs in CD4+ T cell-induced murine colitis models. RESULTSMitochondria-endoplasmic reticulum (ER) appositions, known to mediate pyruvate entry into mitochondria via VDAC1, are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate (MePyr) supplementation. Notably, IL-21 diminished mitochondria-ER appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 {beta} (GSK3{beta}), a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. MePyr and GSK3{beta} pharmacologic inhibitor (LY2090314) reversed IL-21-induced metabolic rewiring and inflammatory state. Moreover, IL-21-induced metabolic genes in Tregs in vitro were enriched in human Crohns disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONSIL-21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL-21-induced metabolism in Tregs may mitigate CD4+ T cell-driven chronic intestinal inflammation.

immunology↗