Biology subjects

Dolezal, T.

Publications and source records attributed to Dolezal, T..

4 recordsLinked to original sources

bioRxiv2024

SAM transmethylation pathway and adenosine recycling to ATP are essential for systemic regulation and immune response

During parasitoid wasp infection, activated immune cells of Drosophila melanogaster larvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. Here, we show that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delay Drosophila larval development and ensure sufficient nutrient supply to the immune system. We further show that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients.

cell biology↗

bioRxiv2023

JAK/STAT mediated insulin resistance in muscles is essential for effective immune response

The metabolically demanding nature of immune response requires nutrients to be preferentially directed towards the immune system at the expense of peripheral tissues. We study the mechanisms by which this metabolic reprograming occurs using the parasitoid infection of Drosophila larvae. To overcome such an immune challenge hemocytes differentiate into lamellocytes, which encapsulate and melanize the parasitoid egg. Hemocytes acquire the energy for this process by expressing JAK/STAT ligands upd2 and upd3, which activates JAK/STAT signaling in muscles and redirects carbohydrates away from muscles in favor of immune cells. Absence of upd/JAK/STAT signaling leads to an impaired immune response and increased mortality. We demonstrate how JAK/STAT signaling in muscles leads to suppression of insulin signaling through activation of ImpL2, the inhibitor of Drosophila insulin like peptides. We reveal the crucial function of muscles during immune response and show the benefits of insulin resistance as an adaptive mechanism that is necessary for survival.

immunology↗

bioRxiv2023

Metabolism of glucose and trehalose by cyclic pentose phosphate pathway is essential for effective immune response in Drosophila

Activation of immune cells requires the remodeling of cell metabolism in order to support immune function. We study these metabolic changes through the infection of Drosophila larvae by parasitoid wasp. Neutralization of the parasitoid egg involves the differentiation of lamellocytes, which encapsulate the egg. A melanization cascade is initiated, producing toxic molecules to destroy the egg; meanwhile the capsule created also protects the host from the toxic reaction. We combine transcriptomics and metabolomics, including 13C-labeled glucose and trehalose tracing, as well as genetic manipulation of sugar metabolism to study changes in metabolism, specifically in Drosophila hemocytes. We found that hemocytes increase the expression of several carbohydrate transporters, and accordingly uptake of sugar during infection. These carbohydrates are metabolized by increased glycolysis, associated with lactate production, and cyclic pentose phosphate pathway (PPP), in which glucose-6-phosphate is re-oxidized to maximize NADPH production. Oxidative PPP is required for lamellocyte differentiation and resistance, as is systemic trehalose metabolism. In addition, fully differentiated lamellocytes use a cytoplasmic form of trehalase to cleave trehalose to glucose, within the cell, to fuel cyclic PPP. Intracellular trehalose metabolism is not required for resistance, but may be associated with host protection from its own toxic response. Thus, our results suggest that sugar metabolism within immune cells, and specifically in cyclic PPP, may be important for not only fighting infection, but also for protecting the host from its own immune response and ensuring sufficient fitness of the survivor.

immunology↗

bioRxiv2020

Macrophage-derived insulin/IGF antagonist ImpL2 regulates systemic metabolism for mounting an effective acute immune response in Drosophila

In response to invading pathogens, macrophages metabolically polarize towards Hif1-induced aerobic glycolysis, requiring increased supply of nutrients. Here, we show that in order to obtain sufficient resources, Drosophila macrophages release the insulin/IGF antagonist ImpL2, whose expression is regulated by Hif1. ImpL2 remotely induces the release of lipids and carbohydrates from adipose tissue by reducing insulin signaling, followed by increased nutrient accumulation in activated immune cells. ImpL2 thus translates the metabolic requirements of immune cells into a systemic metabolic switch. Although these ImpL2 effects are essential during the acute immune response to streptococcal infection, they become maladaptive upon chronic infection by an intracellular pathogen. The relevance of our model to mammalian immunometabolism is demonstrated by the increased expression of the ImpL2 homolog IGFBP7 in human macrophages exposed to Streptococcus.

immunology↗