Roles of Three Histidine Kinase Genes in Hyphal Development and Virulence of the Pathogenic Fungus Candida albicans

Abstract

The pathogenic fungus Candida albicans harbors three histidine kinase genes called CaSLN1, CaNIK1, and CaHK1. The disruption of any one of these three genes impaired the hyphal formation and attenuated the virulence of C. albicans in a mouse systemic candidiasis model. The effects of the disruption on hyphal formation and virulence were most severe in the cahk1Δ null mutants. Although the double disruption of CaSLN1 and CaNIK1 was impossible, further deletion of CaSLN1 or CaNIK1 in thecahk1Δ null mutants partially restored the serum-induced hypha-forming ability and virulence. When incubated with radiolabelled ATP, the recombinant CaSln1 and CaNik1 proteins, which contained their own kinase and response regulator domains, were autophosphorylated, whereas CaHk1p was not. These results imply that in C. albicans, CaSLN1 and CaNIK1 function upstream of CaHK1 but are in distinct signal transmission pathways.

Virulence genes in the pathogenic yeast Candida albicans

“…Interestingly, hk1v/hk1v mutants are only avirulent in the mouse systemic model, and not in the rat vaginitis model [148]. Deletion of SLN1 or NIK1, two other two-component systems found in C. albicans [149,150], in the hk1v/hk1v background recovers the ability to produce hyphae and increases virulence (although virulence is always lower than in the wild-type cell) [151]. Recent data about a two-component phosphorelay gene called SSK1 [152] suggest that CaSSK1 could be acting downstream of HK1 because the ssk1v/ssk1v mutant £occulates in the same way as hk1v mutants.…”

The role of the histidine kinase [) gene in the regulation of cell wall mannan and glucan biosynthesis

“…While homologs of a Hog pathway (similar to the one described above) as well as other HKs have been identi¢ed in C. albicans, these proteins seem to have a minimal function in osmosensing ; rather, strains deleted in these genes are defective in morphogenesis under some conditions and are delayed in a switch phenotype [6,8,13,17,18]. Importantly, deletion mutants are less virulent than parental strains in a hematogenously disseminated murine candidiasis model [11,13,15,18]. We have identi¢ed both a hybrid HK (CHK1) and an RR (CSSK1) gene.…”

The two‐component response regulator Skn7 belongs to a network of transcription factors regulating morphogenesis in Candida albicans and independently limits morphogenesis‐induced ROS accumulation

“…This suggests that Tpk1 might be one of the protein kinases responsible for activation of Skn7 under solid filamentation-inducing conditions and possibly, oxidative stress as inactivation of TPK1 leads to oxidative stress sensitivity (Giacometti et al, 2009). Similarly, chk1 KO mutants exhibit some peroxide sensitivity (Li et al, 2004) as well as a hyphal growth defect on serum agar (Yamada-Okabe et al, 1999), suggesting that Chk1 could also participate in Skn7 regulation under these specific conditions. Skn7 function in oxidative stress tolerance appears highly conserved as SKN7 null mutants in almost all fungal species tested show sensitivity to externally applied oxidative stress (Charizanis et al, 1999;Lee et al, 1999;Singh et al, 2004;Wormley et al, 2005;Ruprich-Robert et al, 2008;Saijo et al, 2010;Zhang et al, 2016).…”