Induction of ERK-kinase signalling triggers morphotype-specific killing of Candida albicans filaments by human neutrophils

Abstract

SummaryCandida albicans is among the most important fungal pathogens in humans. Morphological plasticity has been linked to its pathogenic potential as filamentous forms are associated with tissue invasion and infection. Here we show that human neutrophils discriminate between yeasts and filaments of C. albicans. Whereas filaments induced targeted motility, resulting in the establishment of close contact between neutrophils and fungal cells, yeast forms were largely ignored during coincubation. In transwell assays, C. albicans filaments induced significantly higher migratory activity in neutrophils than yeasts. Neutrophil motility based on actin rearrangement was essential for killing of C. albicans filaments but not involved in killing of yeast forms. Using inhibitors for MAP-kinase cascades, it was shown that recognition of C. albicans filaments by neutrophils is mediated via the MEK/ERK cascade and independent of JNK or p38 activation. Inhibition of the ERK signalling pathway abolished neutrophil migration induced by C. albicans filaments and selectively impaired the ability to kill this morphotype. These data show that invasive filamentous forms of C. albicans trigger a morphotype-specific activation of neutrophils, which is strongly dependent on neutrophil motility. Therefore, human neutrophils are capable of sensing C. albicans invasion and initiating an appropriate early immune response.

Candida albicansdimorphism as a therapeutic target

“…For example, dendritic cells phagocytose both yeast and hyphae but kill yeast cells more efficiently [60]. In contrast, neutrophils are more attracted to hyphae but kill yeast and hyphae at the same rate [61,62]. Similarly, macrophages were shown to phagocytose a higher proportion of inactivated hyphae than yeast [63].…”

“…Attraction Weak Strong [61] Phagocytosis Low High [61] Killing of C. albicans Efficient Efficient [61,62] IL-8 production Moderate High [61] Macrophages/monocytes…”

Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

“…The ability to switch between yeast and hyphal growth is one of the key virulence attributes of C. albicans: this causes the blockade of TLR recognition by Ag modification during the germination of yeasts into hyphae [59]. It is clear that yeast and hyphae induce different responses [60] by exposing different cell wall Ags [61] to protective immunity.…”

A Second Stimulus Required for Enhanced Antifungal Activity of Human Neutrophils in Blood Is Provided by Anaphylatoxin C5a

“…Among those, neutrophilic granulocytes (polymorphonuclear neutrophilic granulocytes [PMN]) have been found to play a central role in the defense against invasive candidiasis and neutropenia is an independent risk factor (2). Isolated human neutrophils respond to C. albicans in a morphotype-specific manner: only filamentous forms, which have been associated with tissue invasion and destruction, trigger an activation program that leads to targeted motility, degranulation, formation of reactive oxygen intermediates (ROI), and secretion of the chemotactic factor IL-8 (3). Rapid engulfment of filamentous C. albicans by activated neutrophils results in efficient killing of the pathogen.…”