*2.3.1 Cytokines and innate immunity*

The contact between fungi and host, result in expression of pattern recognition receptors (PRRs) on host epithelial and immune cells, which recognize the fungi. PPRs are Toll-like receptors (TLRs, including TLR2 and TLR4), C-type Lectin receptors (CLRs, including Dectin-1, Dectin-2 and Mincle). Dectin-1 recognizes β-glucan in fungal cell wall, while Dectin-2 and Mincle recognize mannan of cell wall [32]. *Candida albicans* and Aspergillus fumigatus encounter during fungal keratitis have been reported to be sensed by TLR [33–35]. Activated TLRs in corneal epithelium induce production of CXC chemokines and recruit neutrophils (are more than 90% of the infiltrating cells). Neutrophils are predominant source of mature interleukin-1β (IL-1β) and acidic mammalian chitinase (AMCase) in corneas, which can inhibit the hyphal growth [36, 37]. The increased expression and the activation of PPRs in response to *A. fumigatus* with resultant increased secretion of inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17 and IL-23) in human corneal epithelial cells and neutrophils is reported [38]. Increased production of reactive oxygen species (ROS) in response to increased levels of IL-1β, TLR4, Dectin-1 and LOX-1, facilitates the fungal killing [39, 40].

Leal et al. found that neutrophils produced NADPH oxidase to control the growth of fungi. The antifungal activity of neutrophils depended on CD18, and inhibiting thioredoxin, an antioxidant increased the sensitivity of fungal hyphae to neutrophil-mediated killing in vitro [41]. The expression of PPRs, promote the production of pro-inflammatory cytokines, as well as the recruitment of neutrophils that can also cause serious inflammatory damages to cornea leading to opacification [32, 40, 42]. In fungal keratitis, the levels of pro-inflammatory IL-1β, IL-6, IL-8, IL-17, IL-23 and IFN-γ in aqueous humor were significantly higher in comparison to the non-keratitis control group [38]. A study among a Han Chinese population of patients with FK compared controls found a particular TLR4 allele that was associated with an increased risk of developing FK [43].

Fungi can produce enzymes that degrade physical barriers and facilitate tissue invasion. The mycotoxins produced from Fusarium species can inhibit immunity, break down tissues, and promote the fungal survival in host. Corneal epithelial cells can be destroyed by some cytosolic proteins and peptide toxins produced by fungi [44]. The protease and phospholipase activities detected in *A. flavus and F. solani* isolated from human eyes and their role in causation of ulceration in fungal keratitis, are reported in several studies [45, 46].
