Antifungal Immunological Defenses in Newborns

Abstract

Newborns are prone to fungal infections, largely due to Candida species. The immunological basis for this vulnerability is not yet fully understood. However, useful insights can be gained from the knowledge of the maturation of immune pathways during ontogeny, particularly when placed in context with how rare genetic mutations in humans predispose to fungal diseases. In this article, we review these most current data on immune functions in human newborns, highlighting pathways most relevant to the response to Candida. While discussing these data, we propose a framework of why deficiencies in these pathways make newborns particularly vulnerable to this opportunistic pathogen.

Keywords: Candida; fungus; humans; immunology; infection; neonate; prematurity.

Figure 1

Developmental changes in the immunological response to Candida. Developmental differences in some of the main immunological events involved in the recognition of Candida, between adults (in black) and neonates (in red, cross also indicates a reduction in neonates compared to adults). Candida colonizes the skin or mucosa as yeast but often invades in hyphae form allowing to penetrate through epithelial barriers more efficiently. Upon innate immune detection of Candida through pattern recognition receptors [e.g., toll-like receptors (TLRs); Dectin-1 receptor], microorganisms get opsonized (reduced in preterm neonates), facilitating phagocytosis and resulting in the production of pro-inflammatory cytokines (also reduced in neonates) through Syk and NFκB-mediated intracellular signaling. Internalized Candida antigens are presented (reduced in neonates) to naïve CD4 T cells, resulting in their differentiation into Th1/Th17 effector cells (skewed toward T helper 2 in neonates). Whereas deficiencies in innate functions (e.g., MALT-1/CARD9) can lead to invasive candidemia, selective deficiencies in adaptive functions (e.g., IL-17 responses) most often lead to chronic mucocutaneous infections.