Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.13.3 (histidine kinase)
 2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have observed that human neutrophils (polymorphonuclear leukocytes [PMNs]) have an increased growth-inhibitory and killing effect on a strain of Candida albicans with a deletion of CHK1, a gene encoding a putative histidine kinase. The PMN effect was not due to increased phagocytosis of the null strain. This observation may partially explain the reduced virulence in a hematogenously disseminated murine model of candidiasis.
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PMID:Deletion of the two-component histidine kinase gene (CHK1) of Candida albicans contributes to enhanced growth inhibition and killing by human neutrophils in vitro. 1179 36

We previously demonstrated that genes encoding a putative two-component histidine kinase (CHK1) or a response regulator (CSSK1) are each required for virulence in a murine model of hematogenously disseminated candidiasis and that strains with each gene deleted are also defective in morphogenesis under certain growth conditions. In the present study, the role of these two genes in the adherence to and colonization of reconstituted human esophageal tissue (RHE) is described. We compared strains of Candida albicans with deletions of chk1 (strain CHK21) and cssk1 (strain CSSK21) to wild-type cells (CAF2), as well as strains with CHK1 and CSSK1 reconstituted (strains CHK23 and CSSK23, respectively). Adherence and colonization of RHE were evaluated in periodic acid-Schiff-stained sections, as well as by SEM. We observed that both deletion-containing strains colonized the RHE to a lesser extent than did CAF2 and that the percent germination by both strains was reduced in comparison to that of control strains at 1 h postinfection. Expression of CHK1 or CSSK1 was quantitated by reverse transcription (RT)-PCR from RHE tissues infected with wild-type C. albicans yeast cells. Expression of both CHK1 and CSSK1 increased over the 48-h period following infection of the tissue, although expression of CHK1 was greater than that of CSSK1. By RT-PCR, we have also shown that expression of CHK1 and CSSK1 in the strains with cssk1 and chk1 deleted, respectively, was similar to that of CAF2, indicating that CHK1 and CSSK1 do not regulate each other but probably encode signal proteins of different pathways. Our observations indicate that CHK1 and CSSK1 are each partially required for colonization and conversion to filamentous growth on RHE tissue.
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PMID:Temporal expression of the Candida albicans genes CHK1 and CSSK1, adherence, and morphogenesis in a model of reconstituted human esophageal epithelial candidiasis. 1185 44

Fungal pathogens have evolved diverse strategies to sense host-relevant cues and coordinate cellular responses, which enable virulence and drug resistance. Defining circuitry controlling these traits opens new opportunities for chemical diversity in therapeutics, as the cognate inhibitors are rarely explored by conventional screening approaches. This has great potential to address the pressing need for new therapeutic strategies for invasive fungal infections, which have a staggering impact on human health. To explore this approach, we focused on a leading human fungal pathogen, Candida albicans, and screened 1,280 pharmacologically active compounds to identify those that potentiate the activity of echinocandins, which are front-line therapeutics that target fungal cell wall synthesis. We identified 19 compounds that enhance activity of the echinocandin caspofungin against an echinocandin-resistant clinical isolate, with the broad-spectrum chelator DTPA demonstrating the greatest synergistic activity. We found that DTPA increases susceptibility to echinocandins via chelation of magnesium. Whole genome sequencing of mutants resistant to the combination of DTPA and caspofungin identified mutations in the histidine kinase gene NIK1 that confer resistance to the combination. Functional analyses demonstrated that DTPA activates the mitogen-activated protein kinase Hog1, and that NIK1 mutations block Hog1 activation in response to both caspofungin and DTPA. The combination has therapeutic relevance as DTPA enhanced the efficacy of caspofungin in a mouse model of echinocandin-resistant candidiasis. We found that DTPA not only reduces drug resistance but also modulates morphogenesis, a key virulence trait that is normally regulated by environmental cues. DTPA induced filamentation via depletion of zinc, in a manner that is contingent upon Ras1-PKA signaling, as well as the transcription factors Brg1 and Rob1. Thus, we establish a new mechanism by which metal chelation modulates morphogenetic circuitry and echinocandin resistance, and illuminate a novel facet to metal homeostasis at the host-pathogen interface, with broad therapeutic potential.
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PMID:Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. 2769 31