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Title: Glycolysis, monocarboxylate transport, and purinergic signaling are key events in Eimeria bovis-induced NETosis
Authors: Conejeros, Iván
López-Osorio, Sara
Zhou, Ershun
Velásquez, Zahady D.
Del Río Gismero, María Cristina 
Agustín Burgos, Rafael
Alarcón, Pablo
Chaparro-Gutiérrez, Jenny Jovana
Hermosilla, Carlos
Taubert, Anja
UNESCO Clasification: 32 Ciencias médicas
3207 Patología
320710 Inmunopatología
3109 Ciencias veterinarias
Keywords: Eimeria bovis
NET formation
Cattle, et al
Issue Date: 2022
Journal: Frontiers in Immunology 
Abstract: The protozoan parasite Eimeria bovis is the causative agent of bovine coccidiosis, an enteric disease of global importance that significantly affects cattle productivity. Previous studies showed that bovine NETosis—an important early host innate effector mechanism of polymorphonuclear neutrophil (PMN)—is elicited by E. bovis stages. So far, the metabolic requirements of E. bovis-triggered NET formation are unknown. We here studied early glycolytic and mitochondrial responses of PMN as well as the role of pH, distinct metabolic pathways, P2 receptor-mediated purinergic signaling, and monocarboxylate transporters 1 and 2 (MCT1, MCT2) in E. bovis sporozoite-induced NET formation. Seahorse-based experiments revealed a rapid induction of both neutrophil oxygen consumption rate (OCR) and early glycolytic responses, thereby reflecting immediate PMN activation and metabolic changes upon confrontation with sporozoites. The impact of these metabolic changes on NET formation was studied via chemical inhibition experiments targeting glycolysis and energy generation by the use of 2-fluor-2-deoxy-D-glucose (FDG), 6-diazo-5-oxo-L-norleucin (DON), sodium dichloroacetate (DCA), oxythiamine (OT), sodium oxamate (OXA), and oligomycin A (OmA) to block glycolysis, glutaminolysis, pyruvate dehydrogenase kinase, pyruvate dehydrogenase, lactate dehydrogenase, and mitochondrial ATP-synthase, respectively. Overall, sporozoite-induced NET formation was significantly diminished via PMN pretreatments with OmA and OXA, thereby indicating a key role of ATP- and lactate-mediated metabolic pathways. Consequently, we additionally studied the effects of extracellular pH, MCT1, MCT2, and purinergic receptor inhibitors (AR-C141900, AR-C155858, theobromine, and NF449, respectively). Pretreatment with the latter inhibitors led to blockage of sporozoite-triggered DNA release from exposed bovine PMN. This report provides first evidence on the pivotal role of carbohydrate-related metabolic pathways and purinergic receptors being involved in E. bovis sporozoite-induced NETosis.
ISSN: 1664-3224
DOI: 10.3389/fimmu.2022.842482
Source: Frontiers in Immunology [1664-3224], v. 13: 842482 (Agosto 2022)
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