Seminar

The Mac and the Furious: Phagocytes Coping with Good, Bad and Ugly Memories

Juan Anguita, PhD

Macrophages constitute the first line of defense of the immune system against infections. Since their identification by Metchnikoff as cells capable of ingesting microorganisms, their functional characterization has continuously evolved; yet much is still unknown about key aspects of their biology and how they are regulated. The discovery of Toll-like receptors in the mid to late 1990’s provided the first clue to a certain degree of specificity. This has been complemented along the years with the discovery of new recognition pathways that are able to identify infectious agents (pathogen-associated molecular patterns, PAMPs) and initiate specific responses. Further along, researchers identified the capacity of macrophages to differentiate into distinct effector cells based on the stimulus applied to them. From the initial dichotomy M1/M2, macrophage research evolved to the idea that rather than the final phenotype of the macrophage, the stimulus is the determinant factor; therefore, there may be as many phenotypes as there is variety of stimuli. Recently, the existence of long-term consequences of the stimulation of macrophages with certain simple (e.g. beta glucans) or complex (e.g. BCG, the mycobacterial vaccine strain) stimuli has been recognized, which has been termed ‘innate immune memory’. This concept originally evolved from observations in BCG-vaccinated individuals in which a level of protection against disparate pathogens was identified. Responses identified as memory have been divided into innate immune training and tolerance; the difference being the nature of the secondary response (heightened versus reduced). Although the mechanisms underlying the development of innate immune memory are not completely known, both variations in metabolism (Warburg effect) mediated by the AKT/mTOR/HIF axis, and epigenetic changes are known to occur. Our laboratory is interested in the following questions: Does innate immune memory control the interaction between live microorganisms and host cells?; Is innate immune memory relevant during persistent infections, reinfection (and vaccine development) and homeostasis?; Are molecular changes associated with innate immune memory universally conserved?; Can we manipulate ongoing innate immune memory responses as therapeutic strategies against infection? Data obtained with the pathogens, Borrelia burgdorferi and SARS-CoV-2, as well as the symbiont, Lactobacillus plantarum, will be discussed.