Abstract
Serial passaging of the human fungal pathogen Candida albicans 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 via 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 C. albicans against a virulent C. albicans strain, suggesting that gut-evolved C. albicans strains induce trained immunity via other pathways. Cytometry by time of flight (CyTOF) analysis of mouse splenocytes revealed that immunization with gut-evolved C. albicans 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 C. albicans. Splenocytes and bone marrow cells of mice immunized with gut-evolved C. albicans 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 C. albicans 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.
Highlights
Immunological memory is classically ascribed to T and B cells, but protection against reinfection has been observed in organisms that lack adaptive immunity, such us invertebrates and plants (Durrant and Dong, 2004) as well as Recombination activating gene 1 (Rag1) knock-out (KO) mice (Quintin et al, 2012)
All six mice that survived the primary immunization with R24 survived the secondary challenge with the lethal dose of SC5314 strain, indicating that Dectin-1 is not involved in the protective mechanism of trained immunity induced by gutevolved C. albicans R24 (Figure 1A)
We repeated a similar experiment in Nod2 KO mice and observed that 70% of the R24 immunized mice survived the lethal challenge with SC5314 C. albicans, indicating that gut-evolved C. albicans is still able to confer a significant protection to host animals even in the absence of this receptor (Figure 1B)
Summary
Immunological memory is classically ascribed to T and B cells, but protection against reinfection has been observed in organisms that lack adaptive immunity, such us invertebrates and plants (Durrant and Dong, 2004) as well as Recombination activating gene 1 (Rag1) knock-out (KO) mice (Quintin et al, 2012) This phenomenon is referred to as ‘trained immunity’, defined as an enhanced state of the innate immune system after primary exposure of a host to certain pathogens or Neutrophils Training by Candida albicans molecules, which results in stronger secondary innate responses and greater protection of the host against reinfections (Netea et al, 2011). Immunization with sublethal doses of the human fungal pathogen Candida albicans or with the fungal cell wall component b-glucan protects mice from secondary infection with a fully virulent strain of C. albicans (Quintin et al, 2012), via a mechanism involving epigenetic and metabolic reprogramming of monocytes and macrophages (Cheng et al, 2014; Saeed et al, 2014)
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