AUTHOR=Reales-Calderon Jose Antonio , Tso Gloria H. W. , Tan Alrina S. M. , Hor Pei Xiang , Böhme Julia , Teng Karen W. W. , Newell Evan W. , Singhal Amit , Pavelka Norman 

TITLE=Gut-Evolved Candida albicans Induces Metabolic Changes in Neutrophils

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.743735

DOI=10.3389/fcimb.2021.743735

ISSN=2235-2988

ABSTRACT=<p>Serial passaging of the human fungal pathogen <italic>Candida albicans</italic> in the gastrointestinal tract of antibiotics-treated mice selects for virulence-attenuated strains. These gut-evolved strains protect the host from infection by a wide range of pathogens <italic>via</italic> trained immunity. Here, we further investigated the molecular and cellular mechanisms underlying this innate immune memory. Both Dectin-1 (the main receptor for β-glucan; a well-described immune training molecule in the fungal cell wall) and Nod2 (a receptor described to mediate BCG-induced trained immunity), were redundant for the protection induced by gut-evolved <italic>C. albicans</italic> against a virulent <italic>C. albicans</italic> strain, suggesting that gut-evolved <italic>C. albicans</italic> strains induce trained immunity <italic>via</italic> other pathways. Cytometry by time of flight (CyTOF) analysis of mouse splenocytes revealed that immunization with gut-evolved <italic>C. albicans</italic> resulted in an expansion of neutrophils and a reduction in natural killer (NK) cells, but no significant numeric changes in monocytes, macrophages or dendritic cell populations. Systemic depletion of phagocytes or neutrophils, but not of macrophages or NK cells, reduced protection mediated by gut-evolved <italic>C. albicans</italic>. Splenocytes and bone marrow cells of mice immunized with gut-evolved <italic>C. albicans</italic> demonstrated metabolic changes. In particular, splenic neutrophils displayed significantly elevated glycolytic and respiratory activity in comparison to those from mock-immunized mice. Although further investigation is required for fully deciphering the trained immunity mechanism induced by gut-evolved <italic>C. albicans</italic> strains, this data is consistent with the existence of several mechanisms of trained immunity, triggered by different training stimuli and involving different immune molecules and cell types.</p>