Immunometabolic changes of β-glucan-trained immunity induction and inhibition on neonatal calf immune innate cells

Neonatal calf mortality from infectious diseases contributes considerably to economic losses for the cattle industry, notwithstanding the wide availability of vaccines and antibiotics (Vlasova and Saif, 2021). The increasing antibiotic-resistant pathogens, low efficiency of some vaccines, climate change, and intensifying agriculture have given rise to new pathogens that may lead to emerging diseases, and the re-emergence of infections already controlled in animals (Thomas et al., 2022, Vaz-Rodrigues et al., 2022). Altogether, the above considerations make deeper studies compulsory to better understand the immune mechanism function of the calves to design prophylactic and therapeutic strategies againts current and future diseases.

Similar to other animals, bovine innate immunity is the first line of defense against invading pathogens. Although the memory feature is classically attributed to the adaptive immune system, recent evidences have indicated that cells of the innate immune system can enable an immunological memory program known as “trained immunity” (Netea et al., 2020). Monocytes, macrophages, natural killer (NK) cells, neutrophils, and group 2 innate lymphoid cells (ILC2s) can be “trained” upon exposure to an initial stimulus and after being re-exposed to a secondary heterologous or homologous stimulus (Martinez-Gonzalez et al., 2016, Smith et al., 2017, Hammer and Romagnani, 2017, Moorlag et al., 2020). Several stimuli including Bacillus Calmette-Guérin (BCG) vaccine and β-glucans have been able to induce trained immunity through a cell reprogrammation (Arts et al., 2016; Waikhom et al., 2022). Reprogramming innate immune trained cells consists of remarkable changes in cellular metabolism and epigenetic rewiring, which in turn leads to augmented immunological processes. In this sense, the epigenetic changes modulate chromatin unfolding and expose the regulatory elements (promoters and enhancers) of immune-related genes, increasing the accessibility of the transcription factors (Fanucchi et al., 2021). This epigenetic rewiring is accompanied by metabolic shifts. An example is the switch from oxidative phosphorylation to aerobic glycolysis mediated through the activation of the dectin-1–Akt–mTOR–HIF-1α pathway in trained cells (Cheng et al., 2014). In addition, other changes have been evidenced in the metabolic pathways involved in the trained immunity induction, such as tricarboxylic acid (TCA) cycle, glutaminolysis, and cholesterol synthesis (Arts et al., 2016, Bekkering et al., 2018, Pan et al., 2020).

In spite of the protective benefits of trained immunity against reinfections, the pro-inflammatory phenotype generated can be prejudicial when activation is uncontrolled (Hu et al., 2022). This persistent innate immune response provided by trained immunity causes chronic inflammatory diseases (Włodarczyk et al., 2019). In this scenario, the suppression by molecular inhibitors of signaling pathways and processes involved in trained immunity can reduce excessive immune training (Mourits et la, 2018). An example is the MCC950 specific inhibitor of the NLRP3 inflammasome, whose activation results in an inflammatory response involving IL-1β production (Coll et al., 2015).

Yeast β-glucans are known inductors of trained immunity; β-glucans from Candida albicans and Saccharomyces cerevisiae have led to in vitro reprogramming of innate immune cells of humans, mice, goat kids, and dogs (Quintin et al., 2012; Angulo et al., 2020a; Paris et al., 2020; Su et al., 2021; Geller et al., 2022). Remarkably, trained immunity induction by glucans in terrestrial animals has only been evaluated in goat kids by the oral administration of Debaryomyces hansenii strain CBS8339-β-glucans (Angulo et al., 2020a). D. hansenii CBS8339 isolated from the gut of rainbow trout (Salmo gairdneri) by Andlid et al. (1995) has demonstrated excellent probiotic traits in mammalian, fish, and crustacean species (Angulo et al., 2020b); and its β-glucans induced trained immunity in goat kids through the enhancement of respiratory burst activity, IL-1β, IL-6, and TNFα production in plasma, and transcription of the macrophage surface markers CD11b and CD11c (Angulo et al., 2020a). Therefore, this study has aimed to analyze the metabolic changes involved in trained immunity induction (by D. hansenii β-glucans) and inhibition (by MCC950) in neonatal calf monocytes, as well as, the protective immunological training effects on newborn calves by oral D. hansenii β-glucan administration against an ex vivo infection with Escherichia coli.

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