RESEARCH INTERESTS

Metabolic regulation during immune response (read more in our review or check our poster)

We employ three different types of infection in our experimental models – ① parasitoid wasp Leptopilina boulardi infection of Drosophila larvae, ② extracellular bacteria Streptococcus pneumonia infection of Drosophila adult fly causing an acute infection and ③ intracellular Listeria monocytogenes infection of adult fly causing a chronic infection. We analyze tissue-specific gene expressions and signaling, metabolites, effects on development and behavior throughout the infection and test impacts of various genetic manipulations on systemic physiology.

We have recently found that a systemic metabolic switch, which changes flow of energy from development towards immunity during immune response, is mediated by extracellular adenosine (e-Ado):

e-Ado is released from immune cells, which are activated to proliferate and differentiate into specialized immune cells - lamellocytes - upon the parasitoid wasp attack. Lamellocytes production requires energy, which is obtained by slowing down the host development. The switch from development to immune response requires e-Ado as a mediator. By releasing e-Ado, immune cells are able to usurp energy from the rest of the organism. This experimentally demonstrates a selfish (or privileged) behavior of immune system, which is hierarchically above all the other organs in the organism during immune challenge; theoretical concept of selfish immune system in humans was recently proposed by Dr. Reiner Straub.

Extracellular adenosine (e-Ado) is an important regulatory molecule with a low physiological concentration that can rapidly increase during tissue damage, inflammation, ischemia or hypoxia. During hypoxia or cellular metabolic stress, adenosine can be transported by nucleoside transporters to extracellular space from cells where its concentration raises up due to excessive breakdown of ATP. e-Ado then informs the surrounding tissues about the metabolic state of the cells/tissues via adenosine receptors. This can lead to various responses as vasodilation, increase of blood flow and therefore substrate delivery or it can stimulate glycogenolysis, providing energy substrates from stores to overcome stress. Increased e-Ado may also lead to a suppression of metabolic processes in certain tissues to conserve overall energy.

Additional information about e-Ado and details of our previous studies of e-Ado role in flies can be found in Tomas Dolezal's habilitation thesis.

Is it possible that adenosine plays similar role during immune response in humans? You can read editorial Adenosine: a selfish-immunity signal? on this topic.

Immune cells can suppress their own privilege behavior

The privilege of the immune system is vital in acute threats to the organism, but sooner or later it is necessary to dampen this behavior again so that privilege does not become selfish (as is the case with immunity that has been activated for too long) and the organism is not exhausted. How this is ensured showed our next model of activation of the immune response, namely bacterial infection of adult flies. We inject a precisely defined amount of bacteria (e.g. streptococcus or listeria) into the fly body. In studying these reactions, we found that the immune cells themselves again produce an enzyme at a later stage of the immune reaction, which reduces the amount of adenosine and thus suppresses its effects on the energy metabolism of the fly. When we genetically suppressed the functioning of this enzyme, it might help the fruit fly to fight streptococcus in the short term, but at the expense of greater depletion of energy reserves. In the longer term, however, it was rather harmful to flies, and in chronic listeria infection, it led to a shorter life and, on the contrary, benefited bacteria that probably got more nutrients at the expense of the host.

The results of this work were published in PLoS Pathogens:

Publications:

• Doležal T. (2023) How to eliminate pathogen without killing oneself? Immunometabolism of encapsulation and melanization in Drosophila. Frontiers in Immunology. DOI: 10.3389/fimmu.2023.1330312
• McMullen E, Strych L, Chodáková L, Krebs A, Dolezal T. (2023) JAK/STAT mediated insulin resistance in muscles is essential for effective immune response. Preprint available: https://doi.org/10.1101/2023.10.04.560867 
• Kazek M, Chodáková , Lehr K, Strych L, Nedbalová P, McMullen E, Bajgar A, Šimek P, Moos M, Doležal T. (2023) Metabolism of glucose and trehalose by cyclic pentose phosphate pathway is essential for effective immune response in Drosophila. Preprint available: https://doi.org/10.1101/2023.08.17.553657
• Krejčová G, Morgantini C, Zemanová H, Lauschke, VM, Kovářová J, Kubásek J, Nedbalová P, Kamps‐Hughes N, Moos M, Aouadi M, Doležal, T and Bajgar A. (2023) Macrophage‐derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection. The EMBO Journal. https://doi.org/10.15252/embj.2023114086
• Bajgar A,  Krejčová G, Doležal T (2021) Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research. Front Cell Dev Biol, 15 February 2021 | https://doi.org/10.3389/fcell.2021.629238 (IF=5.2)
• Doležal T, Nedbalová P, Krejčová G, Kazek M, Lehr K, Chodáková L, Strych L, Dolejšková T, Bajgar A (2020) Privileged immune cell upon activation – how it changes its own metabolism and metabolism of the whole organism.  figshare POSTER DOI: 10.6084/m9.figshare.12144831.v1
• Krejcova G, Danielova A, Nedbalova P, Kazek M, Strych L, Chawla G, Tennessen JM, Lieskovská J, Jindra M, Dolezal T, Bajgar A (2019) Drosophila macrophages switch to aerobic glycolysis to mount effective antibacterial defense. eLife 14;8. pii: e50414. doi: 10.7554/eLife.50414. (IF=7.5)
• Bajgar A, Salon I, Krejcová G, Dolezal T, Jindra M, Stepanek F (2019) Yeast glucan particles enable intracellular protein delivery in Drosophila without compromising the immune system. Biomater Sci 30.   doi: 10.1039/c9bm00539k.   (IF=5.2)
• Dolezal T, Krejcova G, Bajgar A, Nedbalova P, Strasser P (2019) Molecular regulations of metabolism during immune response in insects. Insect Biochem Mol Biol 109:31-42.   doi: 10.1016/j.ibmb.2019.04.005  . (IF=3.9)
• Morgantini C, Jager J, Li X, Levi L, Azzimato V, Sulen A, Barreby E, Xu C, Tencerova M, Näslund E, Kumar C, Verdeguer F, Straniero S, Hultenby K, Björkström NK, Ellis E, Rydén M, Kutter C, Hurrell T, Lauschke VM, Boucher J, Tomčala A, Krejčová G, Bajgar A, Aouadi M (2019) Liver macrophages regulate systemic metabolism through non-inflammatory factors. Nat Metab 1, 445–459 doi:10.1038/s42255-019-0044-9
• Mihajlovic Z, Tanasic D, Bajgar A, Perez-Gomez R, Steffal P, Krejci A (2019) Lime is a new protein linking immunity and metabolism in Drosophila. Dev Biol. 452(2):83-94. doi: 10.1016/j.ydbio.2019.05.005. (IF 2.9)
• Bajgar A, Dolezal T (2018) Extracellular adenosine modulates host-pathogen interactions through regulation of systemic metabolism during immune response in Drosophila. PLoS Pathog 14(4): e1007022 (IF=6.6)
• Dolezal T (2015) - Adenosine: a selfish-immunity signal? Oncotarget - Immunology and Microbiology Section 6 (32), 32307-32308 (IF=6.3)
• Bajgar A, Kucerova K, Jonatova L, Tomcala A, Schneedorferova I, Okrouhlik J, Dolezal T (2015) Extracellular Adenosine Mediates a Systemic Metabolic Switch during Immune Response. PLoS Biol 13(4): e1002135 (IF=11.8)
• Novakova M and Dolezal T (2011). Expression of Drosophila adenosine deaminase in immune cells during inflammatory response. PLoS ONE 6(3): e17741 (IF=3.2)
• Fenckova M, Hobizalova R, Fric Z, Dolezal T (2011). Functional characterization of ecto-5’-nucleotidases and apyrases in Drosophila melanogaster. Insect Biochem Mol Biol 41(12): 956-967 (IF=3.4)
• Zuberova M, Fenckova M, Simek P, Janeckova L, Dolezal T (2010). Increased extracellular adenosine in adenosine deaminase deficient flies activates a release of energy stores leading to wasting and death. Dis Model Mech 3(11-12): 773-84 (IF=4.9)
• Dolezal T, Kucerova K, Neuhold J, Bryant PJ (2010). Casein kinase I epsilon somatic mutations found in breast cancer cause overgrowth in Drosophila. Int J Dev Biol 54: 1419 – 1424 (IF=2.8)
• Foldynova-Trantirkova S, Sekyrova P, Tmejova K, Brumovska E, Bernatik O, Blankenfeldt W, Krejci P, Kozubik A, Dolezal T, Trantirek L, Bryja V. (2010). Breast cancer specific mutations in CK1epsilon inhibit Wnt/beta-catenin and activate Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration. Breast Cancer Res 12(3): R30 (IF=5.5)