**6. Innate Defense Mechanisms against** *Candida* **and Surgery**

Innate immunity is critical for the survival of neonates, who encounter for the first time a lot of new micro-organisms, such as *C. albicans*, which is the most common fungal pathogen found in NICUs. A wide range of genetic and epigenetic factors may influence neonatal innate immunity [60]. Dysregulation of neonatal innate immune responses increase their susceptibility to severe infections [61].

Polysaccharide structures of *C. albicans* cell wall, such as β-glucans and mannans, constitute the main pathogen-associated molecular patterns (PAMPs) involved in *Candida*– host immune system interaction [62]. In the absence of a specific antibody-mediated opsonization, that cannot be mounted by neonates, PAMPs are identified by patternrecognition receptors (PRRs) expressed on immune cells' surfaces, as macrophage mannose receptors (MMR) and toll-like receptors (TLRs) [63]. Neonatal macrophages are capable to phagocytize *Candida* spp. using MMR, but cannot be entirely stimulated by interferon-γ (IFN-γ), considering the lack of a normal regulation of IFN-γ receptor in neonates [64].

An intact epithelium and endothelium represent important mechanical barriers against fungal invasion [62]. The formation of fungal hyphae contributes to epithelial damage and immune activation through Candidalysin, a recently discovered peptide toxin, encoded by the *ECE1* gene [65].

The intestinal mucosal barrier plays a key role in the protection against an invasion of fungal pathogens. In fact, gut cells behave not only as a physical barrier but have also an active role producing mucus and anti-microbial peptides such as β-defensins [66,67]. However, in the case of impaired barriers, *Candida*, which is usually found in the gut, may invade the intestinal epithelial barrier and translocate into the bloodstream, especially in case of abdominal surgery [67].

Furthermore, mucosal colonization by *Candida* spp. (and *C. albicans* in particular) is a major risk factor for potential life-threatening candidemia [68]. The presence of *C. albicans* stimulates the mitogen-activated protein kinase (MAPK) pathway and c-Fos activation, likely with a threshold level to activate immune response. The threshold could be pivotal in triggering an inflammatory response from a simple colonization [67].
