Heat inactivated mycobacteria, alpha‐Gal and zebrafish: Insights gained from experiences with two promising trained immunity inductors and a validated animal model

Trained immunity (TRAIM) may be defined as a form of memory where innate immune cells such as monocytes, macrophages, dendritic and natural killer (NK) cells undergo an epigenetic reprogramming that enhances their primary defensive capabilities. Cross‐pathogen protective TRAIM can be triggered in different hosts by exposure to live microbes or microbe‐derived products such as heat‐inactivated Mycobacterium bovis or with the glycan α‐Gal to elicit protective responses against several pathogens. We review the TRAIM paradigm using two models representing distinct scales of immune sensitization: the whole bacterial cell and one of its building blocks, the polysaccharides or glycans. Observations point out to macrophage lytic capabilities and cytokine regulation as two key components in non‐specific innate immune responses against infections. The study of the TRAIM response deserves attention to better characterize the evolution of host–pathogen cooperation both for identifying the aetiology of some diseases and for finding new therapeutic strategies. In this field, the zebrafish provides a convenient and complete biological system that could help to deepen in the knowledge of TRAIM‐mediated mechanisms in pathogen–host interactions. BCG vaccine, a live and attenuated strain of Mycobacterium bovis, and fungal β‐glucans, derived from Saccharomyces cerevisiae or Candida albicans, have been traditionally used in experimental studies aiming to induce non‐specific cross‐protection and to assess the mechanism involved in the trained immunity phenomenon. Likewise, the murine model is, by far, the most frequently used in immunological studies. Based on previous literature, in addition to our own experience, we propose two alternative candidates for inducing trained immunity: heat‐inactivated Mycobacterium bovis and α‐Gal, as well a novel animal model, the zebrafish, that would allow conducting leading‐edge studies in the growing field of immunology.