Proteinous Components of Neutrophil Extracellular Traps Are Arrested by the Cell Wall Proteins of Candida albicans during Fungal Infection, and Can Be Used in the Host Invasion

Abstract

One of defense mechanisms of the human immune system to counteract infection by the opportunistic fungal pathogen Candida albicans is the recruitment of neutrophils to the site of invasion, and the subsequent production of neutrophil extracellular traps (NETs) that efficiently capture and kill the invader cells. In the current study, we demonstrate that within these structures composed of chromatin and proteins, the latter play a pivotal role in the entrapment of the fungal pathogen. The proteinous components of NETs, such as the granular enzymes elastase, myeloperoxidase and lactotransferrin, as well as histones and cathelicidin-derived peptide LL-37, are involved in contact with the surface of C. albicans cells. The fungal partners in these interactions are a typical adhesin of the agglutinin-like sequence protein family Als3, and several atypical surface-exposed proteins of cytoplasmic origin, including enolase, triosephosphate isomerase and phosphoglycerate mutase. Importantly, the adhesion of both the elastase itself and the mixture of proteins originating from NETs on the C. albicans cell surface considerably increased the pathogen potency of human epithelial cell destruction compared with fungal cells without human proteins attached. Such an implementation of adsorbed NET-derived proteins by invading C. albicans cells might alter the effectiveness of the fungal pathogen entrapment and affect the further host colonization.

The emerging role of neutrophil extracellular traps in fungal infection

“…Unlike mannans and bglucans, Als3 (a member of the agglutinin-like sequence family) and enolase, which are cell wall surface proteins of C. albicans did not stimulate NETosis (Zawrotniak et al, 2017). However, they can bind to proteins in NETs such as MPO, NE, lactotransferrin (LF), and LL-37 (cathelicidin-derived peptide) (Karkowska-Kuleta et al, 2021).…”

“…Both C. albicans conidia and hyphae can be captured or entwined by chromatins in by NETs and then killed by the granular proteins (Urban et al, 2006;Karkowska-Kuleta et al, 2021), among which calprotectin is essential for the elimination of C. albicans (Urban et al, 2009). Of note, MPO is also a key antifungal factor in NETs.…”

“…Another intriguing study points out a negative aspect of NETs, which is the destruction of human tissue associated with interacting with C. albicans. Protein components of NETs, such as NE, MPO, lactotransferrin, and LL-37 (cathelicidin-derived peptide), binding with C. albicans surface proteins results in surrounding tissue damage and acceleration of fungal invasion (Karkowska-Kuleta et al, 2021). Moreover, NET-dependent tissue damage and fungal invasion can be promoted by Saps, which is secreted by C. albicans.…”

“…When compared with Pb265, virulent strain Pb18 co-cultured with neutrophils has a higher expression of PADG_08528, which is a hypothetical protein in the fungus genome (Desjardins et al, 2011), suggesting that this gene may be related to the production of DNAse-like protein (Zonta et al, 2020). In addition to degrading chromatins, degrading NETs proteins by Saps secreted by C.albicans is another available method (Rapala-Kozik et al, 2015;Gogol et al, 2016;Karkowska-Kuleta et al, 2021). LL-37 and histones are most sensitive components to Saps, especially Saps3 and Saps9, which are most effective in NETs proteins degradation and weakening NETs (Rapala-Kozik et al, 2015;Karkowska-Kuleta et al, 2021).…”

Neutrophil Extracellular Traps in Candida albicans Infection

“…Unexpectedly, C. albicans , in turn, takes advantages of these proteins to enhance its colonization and tissue damages to the host. NET-related proteins such as NE bind to adhesin Als3 of the lectin-like sequence protein family as well as other atypical proteins exposed on the surface of C. albicans cells ( 68 ). C. albicans cells attached by the mixture of NET proteins are significantly more destructive to human epithelial cells than the fungi themselves are.…”