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

Department of Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.
Cell host & microbe (Impact Factor: 12.33). 08/2012; 12(2):223-32. DOI: 10.1016/j.chom.2012.06.006
Source: PubMed


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.

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    • "Monocytes stimulated with microbial products were demonstrated to acquire a long-lasting proinflammatory phenotype through induction of persistent epigenetic changes [179]. Remarkably, a large number of genes with an altered epigenetic state are involved in atherosclerosis , suggesting the involvement of trained immunity in atherosclerosis [179] [180]. Indeed, also oxLDL (in contrast to LDL) can promote trained immunity in monocytes via inducing persistent H3K4me3 modifications in promoter regions important to foam cell formation and cytokine production. "
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    ABSTRACT: Nowadays, epigenetic mechanisms involving DNA methylation, histone modifications and microRNA regulation emerge as important players in cardiovascular disease (CVD). Epigenetics may provide the missing link between environment, genome and disease phenotype and be responsible for the strong interindividual variation in disease risk factors underlying CVD. Daily diet is known to have a major influence on both the development and the prevention of CVD. Interestingly, the dietary lifestyle of our (grand)parents and of us contributes to CVD risk by metabolic (re)programming of our epigenome in utero, after birth or during life. In contrast to genetic mutations, the plasticity of CVD related epigenetic changes makes them attractive candidates for nutritional prevention or pharmacological intervention. Although a growing number of epidemiologic studies have shown a link between the ingestion of nutritional polyphenols and cardiovascular health benefits, potential involvement of epigenetic mechanisms has been underexplored. In this review, we will give an overview of epigenetic alterations in atherosclerosis, with the focus on DNA and histone modifications by chromatin-modifying proteins. Finally, we illustrate that cocoa flavanols and other classes of dietary molecules may promote cardiovascular health by targeting multiple classes of chromatin writer-reader-eraser proteins related to histone acetylation-methylation and DNA methylation.
    Current topics in medicinal chemistry 08/2015; 15(999). DOI:10.2174/1568026615666150825141720 · 3.40 Impact Factor
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    • "Emerging in vitro studies reveal that innate monocytes may adopt distinct phenotypes by prior conditioning or " training " with varying dosages of innate stimulants (Deng et al., 2013; Netea et al., 2011; Quintin et al., 2012). For example, pre-conditioning with super-low dose LPS " primes " the expression of selected pro-inflammatory mediators such as TNF-α and IL-12, while suppressing the expression of iNOS (Hirohashi and Morrison, 1996). "
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    ABSTRACT: Sepsis mortality varies dramatically in individuals of variable immune conditions, with poorly defined mechanisms. This phenomenon complements the hypothesis that innate immunity may adopt rudimentary memory, as demonstrated in vitro with endotoxin priming and tolerance in cultured monocytes. However, previous in vivo studies only examined the protective effect of endotoxin tolerance in the context of sepsis. In sharp contrast, we report herein that pre-conditioning with super-low or low dose endotoxin lipopolysaccharide (LPS) cause strikingly opposite survival outcomes. Mice pre-conditioned with super-low dose LPS experienced severe tissue damage, inflammation, increased bacterial load in circulation, and elevated mortality when they were subjected to cecal-ligation and puncture (CLP). This is in contrast to the well-reported protective phenomenon with CLP mice pre-conditioned with low dose LPS. Mechanistically, we demonstrated that super-low and low dose LPS differentially modulate the formation of neutrophil extracellular trap (NET) in neutrophils. Instead of increased ERK activation and NET formation in neutrophils pre-conditioned with low dose LPS, we observed significantly reduced ERK activation and compromised NET generation in neutrophils pre-conditioned with super-low dose LPS. Collectively, our findings reveal a mechanism potentially responsible for the dynamic programming of innate immunity in vivo as it relates to sepsis risks.
    03/2015; 3(4). DOI:10.1016/j.ebiom.2015.03.001
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    • "One could speculate on the mechanisms inducing these effects. The process of trained immunity in monocytes is mediated by epigenetic regulation [1] [2], and similar processes have been reported to mediate at least some aspects of NK cell maturation and adaptive change [17]. "
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    ABSTRACT: Adaptive features of innate immunity, also termed 'trained immunity', have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination. BCG vaccination of healthy volunteers increased proinflammatory cytokine production following ex vivo stimulation of NK cells with mycobacteria and other unrelated pathogens up until at least three months after vaccination. In addition, in a murine model of disseminated candidiasis, BCG vaccination led to an increased survival in SCID mice, which was partially dependent on NK cells. These findings suggest that NK cells may contribute to the non-specific (heterologous) beneficial effects of BCG vaccination.
    Clinical Immunology 12/2014; 155(2). DOI:10.1016/j.clim.2014.10.005 · 3.67 Impact Factor
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