Deletion of the Candida albicans histidine kinase gene CHK1 improves recognition by phagocytes through an increased exposure of cell wall β-1,3-glucans

Abstract

The pathogenic fungus Candida albicans is able to cover its most potent proinflammatory cell wall molecules, the b-glucans, underneath a dense mannan layer, so that the pathogen becomes partly invisible for immune cells such as phagocytes. As the C. albicans histidine kinases Chk1p, Cos1p and CaSln1p had been reported to be involved in virulence and cell wall biosynthesis, we investigated whether deletion of the respective genes influences the activity of phagocytes against C. albicans. We found that among all histidine kinase genes, CHK1 plays a prominent role in phagocyte activation. Uptake of the deletion mutant Dchk1 as well as the acidification of Dchk1-carrying phagosomes was significantly increased compared with the parental strain. These improved activities could be correlated with an enhanced accessibility of the mutant b-1,3-glucans for immunolabelling. In addition, any inhibition of b-1,3-glucan-mediated phagocytosis resulted in a reduced uptake of Dchk1, while ingestion of the parental strain was hardly affected. Moreover, deletion of CHK1 caused an enhanced release of interleukins 6 and 10, indicating a stronger activation of the b-1,3-glucan receptor dectin-1. In conclusion, the Chk1p protein is likely to be involved in masking b-1,3-glucans from immune recognition. As there are no homologues of fungal histidine kinases in mammals, Chk1p has to be considered as a promising target for new antifungal agents.

Stage Specific Assessment of Candida albicans Phagocytosis by Macrophages Identifies Cell Wall Composition and Morphogenesis as Key Determinants

“…This translated into much higher overall uptake compared to the phosphomannan deficient mmn 4Δ mutant and is in keeping with our previous published results [10]. It is conceivable that enhanced macrophage migration in response to the absence of O -linked ( mnt1 Δ mnt2 Δ) or N -linked mannans ( mns1 Δ) is a consequence of unmasking underlying β-glucans [28], [29] or electrostatic signals as a consequence of alterations in surface charge following loss of phosphomannan ( mnn4 Δ) [30], [31]. Observation of individual macrophage migration patterns indicated that macrophage movement was slow and random initially, but became directional towards a specific C. albicans cell, associated with a marked increase in macrophage velocity.…”

Cell Wall Changes in Amphotericin B-Resistant Strains from Candida tropicalis and Relationship with the Immune Responses Elicited by the Host

“…These polysaccharides induce protective responses during infection (61,62). Most of the biological studies on the effects of glucans have focused on ␤-1,3-glucans (28,(63)(64)(65)(66)(67). In agreement with these data, the increase of ␤-1,3-glucans in AmB-resistant strains correlates with the enhanced response of PBMCs exposed to these isolates.…”

Chromosome 5 Monosomy of Candida albicans Controls Susceptibility to Various Toxic Agents, Including Major Antifungals

“…Importantly, all of the control strains analyzed, Sor5, m2, m5, m6, m7, m8, m15, and m16, retained a level of zymolyase resistance similar to that of the parental strain. Zymolyase resistance has been suggested to result from changes in the structure of the glucan network (38,39) or from masking, leading to less zymolase-mediated cleavage of 1,3-␤-glucan due to changes in the external mannoprotein layer (40,41). Ch5 copy number controls the level of 1,3-␤-glucan and chitin of the cell wall and the cellular level of ergosterol.…”