Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of Monocytes

Abstract

SUMMARY Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of “trained immunity,” we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall β-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the β-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by β-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of “trained immunity” and may be employed for the design of improved vaccination strategies.

'Trained immunity: consequences for lymphoid malignancies

“…5 On reinfection or rechallenge with microbial ligands, prototypical innate immune cells such as monocytes/macrophages exhibit enhanced functionality with the release of pro-inflammatory cytokines and effector functions e.g., phagocytosis ( Figure 1). 16,17 The training of monocytes/macrophages is mediated by the activation of pattern-recognition receptors by microbe-associated molecular patterns (MAMPs) from bacteria and fungi; for example dectin-1 by β-glucan, and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by components of the BCG vaccine. [16][17][18][19] Several mechanisms are involved in the development of innate immune memory, among which epigenetic histone modifications (e.g., histone methylation and acetylation), and autophagy play a central role.…”

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

“…Such training effects were also seen in human monocytes following neonatal BCG vaccination. 37 Similar training effects were observed following stimulation of adult human monocytes in vitro with either C. albicans or β-glucan (a component of fungal cell walls) for 24 h. 38 Upon a second stimulation with C. albicans, bacteria or various PAMP/PRR ligands up to 2 weeks later, pre-stimulated monocytes showed significant increases (of up to 10-fold) in TNF-α and IL-6 production relative to naive monocytes. The magnitude of the training effects was dependent on the doses of both the primary and secondary stimulation.…”

“…Human monocyte training as a result of BCG or Candida/β-glucan exposure results in an increase in H3K4me3, a histone modification associated with the regulation of immune-related genes, at the promoters of target genes, including TNF-α, IL-6 and IL-18. 38 Consequently, blocking histone methylation by inhibition of histone methyltransferases prevented training. Training of monocytes by non-microbial stimuli, such as oxidized low-density lipoprotein, is also dependent on the enrichment of H3K4me3 at the promoters of various immune-related genes.…”

Primed Immune Responses to Gram-negative Peptidoglycans Confer Infection Resistance in Silkworms

“…At the second exposure to the antigen, the antigen-specific memory cells induce the booster reaction in vertebrate immunity (3). Recent reports also showed in a vertebrate the existence of an immune memory that does not depend on T-cells or B-cells but depends on macrophages (27). Although there was no change in the number of silkworm hemocytes present after preinjection of heat-killed Sakai cells (Fig.…”