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I am proud to say that our latest manuscript has finally been published in the world-leading journal Nature Immunology!
First authors Marko Šestan and Sanja Mikašinović, together with our collaborators in Croatia and abroad have generated a study in which we explored the impact of infection on blood glucose regulation. In this manuscript we show that viral infection can cause a sugar crash: a drop in blood glucose levels. The purpose of this mechanism is to change systemic metabolism and make cells more responsive to viral infection. Importantly, when this mechanism was blocked in models for type 1 and type 2 diabetes, detection of virus was impaired and viral loads were increased. Šestan and Mikašinović thus uncovered why it is beneficial to feel low on energy when you are sick; it helps you better fight infection.
To give you a brief overview of our study:
What we observed is that in mice (and in a pilot study we found this also in people), when the infection is strong enough, blood sugar levels drop to a minimum baseline. This happens when the virus penetrates deep into the spleen and reaches an immune cell population called γδ (gamma-delta) T cells. These cells function as ‘tripwires’: when they get activated they produce large amounts of the immunological hormone (cytokine) Interferon gamma (IFNγ). IFNγ directly targets pancreatic beta cells to produce more insulin. As you know, the role of insulin is to lower blood sugar levels and this is what happens during infection.
Of course, this is how it happens, but the question was why. What we found is that, when systemic availability of glucose is reduced, cells in the body change how they metabolize glucose to generate energy. Instead of using the relatively inefficient glycolysis, a process producing lactate, they increase respiratory metabolism, which generates more energy per molecule of glucose and no lactate. Lactate is a natural inhibitor of a viral detection system that is present in every cell and results in the production of an alarm signal: the cytokine interferon-beta (IFNβ). IFNβ is crucial for the early anti-viral response. In summary, by lowering systemic glucose upon infection, cells in the body make less lactate, bringing them into a ‘heightened state of awareness’, if you will. This allows them to react stronger to viral infection and produce more IFNβ, thus limiting viral replication.
Finally, why is this important to know? Well, diabetes is an increasingly common disease and is characterized by high blood sugar levels. Also, these people have more frequent and severe infections. We investigated whether high glucose levels in his condition disrupts our anti-viral detection system. Using models for type 1 and type 2 diabetes, we caused hyperglycemia in mice and subsequently infected them with virus. Indeed, we found that these animals had lower IFNβ and higher viral titers.
Read the paper in full here: https://doi.org/10.1038/s41590-024-01848-3
Great work of first author Karlo Mladenić and the rest of the team for publishing a great Review article on the mechanisms of inflammation in fatty liver disease in the European Journal of Immunology.
Great work of first author Karlo Mladenić and the rest of the team for publishing a great Review article on the mechanisms of inflammation in fatty liver disease in the European Journal of Immunology.
Read the article here:
Read the article here:
Find more information on our work here:
Read our latest manuscript on the first steps of hepatic inflammation in context of fatty liver disease in Science Immunology!
Read our latest manuscript on the first steps of hepatic inflammation in context of fatty liver disease in Science Immunology!
Read the article here:
Read the article here:
Assoc.Prof. Felix Wensveen
Specialists on immuno-endocrinology and anti-viral immunology
Specialists on immuno-endocrinology and anti-viral immunology
Since 2006, the focus of my research has been on how lymphocytes deal with cellular stress, such as infections, but also metabolic stress. People can be infected with a shockingly large number of pathogens such as bacteria and viruses. In addition, cells can malfunction due to oncogenic transformation or as a result of the accumulation of metabolites in context of obesity. Somehow, the immune system must be able to identify all these signals as a reason to respond, whilst leaving all the molecular structures healthy tissues intact. Once the threat has been eliminated, the immune system must retain a small but effective, standing army in the form of memory cells, that protect from re-infection with the original pathogen, but also of potential mutants.
All of these examples require complex molecular strategies which we are studying in my group. More recently, we have expanded our research to investigate not only how the immune system directly identifies and eliminates these threats, but also how it modifies systemic metabolism in order to optimally fight incursions. Our work has identified several mechanisms how this system derails in the context of metabolic disease.
Research highlights:
Research highlights:
Mladenić K, Lenartić M, Marinović S, Polić B, Wensveen FM, The “Domino effect” in MASLD: The Inflammatory cascade of steatohepatitis Eur J Immunol. 2024 accepted for publication.
Gašparini D, Wensveen FM, Turk Wensveen T. Inflammageing mediated by cytotoxic lymphocytes is associated with diabetes duration Diabetes Res Clin Pract. 2023 Dec 15:207:111056. doi: 10.1016/j.diabres.2023.111056.
Gašparini D, Zuljani A, Wensveen FM, Turk Wensveen T., A cross-sectional study in type 2 diabetes patients reveals that elevated pulse wave velocity predicts asymptomatic peripheral arterial disease associated with age and diabetes duration. Int J Cardiol Heart Vasc. 2023 Nov 26;49:101308. doi: 10.1016/j.ijcha.2023.101308
Marinović S, Lenartić M, Mladenić K , Šestan, M, Kavazović I, Benić A, Krapić M, Rindlisbacher L, Cokarić Brdovčak M, Sparano C, Litscher G, Turk Wensveen T, Mikolasevic I, Fučkar Čupić D, Bilić-Zulle L, Steinle A, Waisman A, Hayday A, Tugues S, Becher B, Polić B, Wensveen FM, NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis, Sci Immunol. 2023 Sep 29;8(87):eadd1599. doi: 10.1126/sciimmunol.add1599.
Imširović V, Lenartić M, Wensveen FM, Polić B, Jelenčić V. Largely preserved functionality after the combined loss of NKG2D, NCR1 and CD16 demonstrates the remarkable plasticity of NK cell responsiveness. Front Immunol. 2023 Jul 13;14:1191884. doi: 10.3389/fimmu.2023.1191884. eCollection 2023.
Kavazović I, Dimitropoulos C, Gašparini D, Rončević Filipović M, Barković I, Koster J, Lemmermann NA, Babić M, Cekinović Grbeša Đ, Wensveen FM.,, Vaccination provides superior in vivo recall capacity of SARS-CoV-2-specific memory CD8 T cells. Cell Rep. 2023 Apr 4;42(4):112395. doi: 10.1016/j.celrep.2023.112395.
Martens AWJ, Kavazović I, Krapić M, Pack SM, Arens R, Jongejan A, Moerland PD, Eldering E, van der Windt GJW, Wensveen FM, Peters FS, Kater AP. Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors. Leukemia. 2023 Jan 19:1-11. doi: 10.1038/s41375-023-01817-z.
Benić A, Mikašinović S, Wensveen FM, Polić B, Activation of Granulocytes in Response to a High Protein Diet Leads to the Formation of Necrotic Lesions in the Liver. Metabolites, 13 (2023), 2; 153. https://doi.org/10.3390/metabo13020153
Gašparini D, Kavazović I, Barković I, Maričić V, Ivaniš V, Samsa DT, Peršić V, Polić B, Turk Wensveen T, Wensveen FM. Extreme anaerobic exercse causes reduced cytotoxicity and increased cytokine production by peripheral blood lymphocytes. Immunol Lett. 2022 Aug;248:45-55. doi: 10.1016/j.imlet.2022.06.001. Epub 2022 Jun 13.
Kavazović I, Krapić M, Beumer-Chuwonpad A, Polić B, Turk Wensveen T, Lemmermann NA, Van Gisbergen KPJM, Wensveen FM, Hyperglycemia and not hyperinsulinemia mediates diabetes-induced memory CD8 t cell dysfunction, Diabetes. 2022. Apr 1;71(4):706-721. doi: 10.2337/db21-0209.
Krapić M, Kavazović I, Wensveen FM. Immunological Mechanisms of Sickness Behavior in Viral Infection. Viruses. 2021 Nov 8;13(11):2245. doi: 10.3390/v13112245.
Parga-Vidal L, Behr FM, Kragten NAM, Nota B, Wesselink TH, Kavazović I, Covill LE, Schuller MBP, Bryceson YT, Wensveen FM, van Lier RAW, van Dam TJP, Stark R, van Gisbergen KPJM. Hobit identifies tissue-resident memory T cell precursors that are regulated by Eomes. Sci Immunol. 2021 Aug 20;6(62):eabg3533. doi: 10.1126/sciimmunol.abg3533.
Wensveen FM, Šestan M, Turk Wensveen T, Polić B. Blood glucose regulation in context of infection. Vitam Horm. 2021;117:253-318. doi: 10.1016/bs.vh.2021.06.009.
Turk Wensveen T, Gašparini D, Rahelić D, Wensveen FM, Type 2 diabetes and viral infection; cause and effect of disease. Diabetes Res Clin Pract. 2021 Feb;172:108637.
Kavazović I, Han H, Balzaretti G, Slinger E, Lemmermann NAW, Ten Brinke A, Merkler D, Koster J, Bryceson Y, De Vries N, Jonjić S, Klarenbeek PL, Polić B, Eldering E, Wensveen FM, Eomes broadens the scope of CD8 T cell memory by inhibiting apoptosis in cells of low affinity. PLoS Biol. 2020 Mar 17;18(3):e3000648. doi: 10.1371/journal.pbio.3000648.
Turk Wensveen T, Fučkar Ćupić D, Jurišić Eržen D, Polić B, Wensveen FM, Severe lipoatrophy in a patient with diabetes mellitus type 2 in response to glargine and degludec insulin: Possible involvement of CD4 T cell mediated tissue remodelling. Diabetes Care. 2020 Feb;43(2):494-496. doi: 10.2337/dc19-1888.
Šestan M, Marinović S, Kavazović I, Cekinović Đ, Wueest S, Turk Wensveen T, Brizić I, Jonjić S, Konrad D, Wensveen FM, Polić B. Virus-Induced Interferon-γ Causes Insulin Resistance in Skeletal Muscle and Derails Glycemic Control in Obesity. Immunity. 2018 Jul 17;49(1):164-177.e6. doi: 10.1016/j.immuni.2018.05.005.
Wensveen FM, Jelenčić V, Valentić S, Šestan M, Wensveen TT, Theurich S, Glasner A, Mendrila D, Štimac D, Wunderlich FT, Brüning JC, Mandelboim O, Polić B. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol. 2015 Apr;16(4):376-85. doi: 10.1038/ni.3120.
Wensveen FM, Derks IA, van Gisbergen KP, de Bruin AM, Meijers JC, Yigittop H, Nolte MA, Eldering E, van Lier RA. BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation. Blood. 2012 Feb 9;119(6):1440-9. doi: 10.1182/blood-2011-09-378877.
Wensveen FM, van Gisbergen KP, Derks IA, Gerlach C, Schumacher TN, van Lier RA, Eldering E. Apoptosis threshold set by Noxa and Mcl-1 after T cell activation regulates competitive selection of high-affinity clones. Immunity. 2010 Jun 25;32(6):754-65. doi: 10.1016/j.immuni.2010.06.005.
A full list of publications of my group can be found HERE.
Group leader Felix Wensveen won the 2019 award of the Croatian Academy of Sciences and Arts for the best Scientific achievement in the field of Medical Sciences!
Group leader Felix Wensveen won the 2019 award of the Croatian Academy of Sciences and Arts for the best Scientific achievement in the field of Medical Sciences!
http://info.hazu.hr/upload/File/2020/DEPLIJAN-NAGRADE-HAZU-2020-INACICA-03.pdf
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