Biology subjects

Sousa, A. G.

Publications and source records attributed to Sousa, A. G..

2 recordsLinked to original sources

bioRxiv2021

A HYPOMETABOLIC DEFENSE STRATEGY AGAINST PLASMODIUM INFECTION

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal presentation of Plasmodium falciparum infection of humans. Here we report that mice reduce blood glucose levels in response to Plasmodium infection via a coordinated response whereby labile heme, an alarmin produced via hemolysis, induces anorexia and represses hepatic glucose production (HGP). While protective against unfettered immune-mediated inflammation, organ damage and anemia, when sustained over time heme-driven repression of HGP can progress towards hypoglycemia, compromising host energy expenditure and thermoregulation. This hypometabolic state arrests the development of asexual stages of Plasmodium spp., which undergo pyknosis and develop mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program reducing its virulence and inducing sexual differentiation towards the production of transmissible gametocytes. We infer that malaria-associated hypoglycemia represents a trade-off of an evolutionarily conserved defense strategy restricting Plasmodium spp. from accessing host-derived glucose and balancing parasite virulence and transmission.

immunology↗

bioRxiv2020

Self-renewal capacity of double negative 3 (DN3) early thymocytes preserves thymus autonomous function but compromises the β-selection checkpoint

T lymphocyte differentiation in the thymus relies on high cellular turnover, and cell competition enforces thymocyte replenishment. If deprived of competent progenitors, the thymus can maintain thymopoiesis autonomously for several weeks but this bears a high risk of leukemia. Here we show that double negative 3 early (DN3e) thymocytes can acquire stem cell like properties, which enables them to maintain thymopoiesis. Specifically, DN3e proved to be long-lived, they proliferated and differentiated in vivo, were necessary for autonomous thymopoiesis, and included DNA-label-retaining cells. Single cell RNAseq revealed a transcriptional program of thymopoiesis similar in autonomy and the controls. Nevertheless, a new population was identified in thymus autonomy that was enriched for an aberrant Notch target gene signature and bypassed the {beta}-selection checkpoint. In sum, DN3e have the potential to self-renew and differentiate in vivo if cell competition is compromised but this enables the accumulation of atypical cells, probably leading to leukemia.

immunology↗