Interplay between Candida albicans and the Antimicrobial Peptide Armory

Abstract

Antimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungus Candida albicans colonizes different host niches as part of the normal human microbiota. Proliferation of C. albicans is regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host, C. albicans has developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms prevent C. albicans from the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack and C. albicans resistance mechanisms and current developments in the use of AMPs as antifungal agents.

Candida Survival Strategies

“…In addition to exerting direct antifungal activity by pore formation or interference with cellular ATP metabolism, several AMPs also act as chemoattractants promoting the influx of phagocytic immune cells and T cells, thereby modulating the immune response (Swidergall & Ernst, 2014). Several human AMPs, the cathelicidin LL-37, histatin 5, and b-defensins can kill C. albicans in vitro (Chang et al, 2012;den Hertog et al, 2005;Vylkova, Nayyar, Li, & Edgerton, 2007).…”

“…Given the ubiquitous presence of AMPs on mucosal surfaces, it is not surprising that many bacteria have developed AMP resistance mechanisms, likely as a consequence of coevolution with the host (Peschel & Sahl, 2006). The necessity to tolerate basal levels of AMPs on mucosal surfaces during colonization probably also led to the development of AMP resistance mechanisms in C. albicans (recently reviewed in Swidergall & Ernst, 2014): C. albicans inactivates AMPs through proteolytic cleavage by Sap9 and Sap10 (Meiller et al, 2009). Saps might also be involved in the generation of the secreted glycodomain of Msb2, that inactivates a wide range of AMPs extracellularly (Puri, Kumar, Chadha, Tati, Conti, Hube, et al, 2012;Swidergall, Ernst, & Ernst, 2013;Szafranski-Schneider et al, 2012).…”

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

“…Two such examples involve the Cek1 MAPK pathway: (i) C. albicans secreted aspartyl proteases (Saps) with a role in activation of the pathway (58) potentially degrade Hst 5 (59) and (ii) the interaction of the shed domain of Cek1 head sensor Msb2 with Hst 5 potentially offers protection against Hst 5 (60), although it still remains elusive whether the exact concentrations of shed Msb2 in vivo can functionally inhibit Hst 5 activity in the oral cavity. The roles of shed Msb2 and Saps in Hst 5 activity are discussed in detail in the accompanying minireview (by Marc Swidergall and Joachim F. Ernst [61]). …”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…78,79 The antimicrobial peptides can recruit immune cells to sites of infection/proliferation and additionally can bind to PRRs and influences responses. 80 The other is to secrete a profile of pro-inflammatory cytokines and chemokines, which facilitates epithelial cells to cooperate with other types of cells at mucosal surface, including dendritic cells and neutrophils. 81 C. albicans stimulates epithelial cells to produce IL-1a/b, IL-6, G-CSF, GM-CSF, TNF-a, and IL-8, while IL-12, IFN-g, IL-4, and IL-13 are not included.…”