A novel natural inhibitor from Candida albicans hyphae causing dissociation of the neutrophil respiratory burst response to chemotactic peptides from other post-activation events.
Previous work established that Candida albicans hyphae release several inhibitors of human neutrophil function. We now report that the crude hyphal inhibitory product (CHIP) inhibits superoxide anion (O2-) production stimulated by FMLP in a dose-related manner with an EC50 of approximately 2 micrograms/ml. CHIP also inhibited O2- production stimulated by A23187 and by opsonized zymosan, although this effect could be overcome by increasing the concentration of agonist. No inhibition of the PMA-stimulated burst was seen at any concentration of PMA tested, indicating that CHIP neither affected polymorphonuclear neutrophil viability nor quenched superoxide anion detection. A saturating dose of inhibitor had no effect on chemotaxis stimulated either by 0.1 to 100 nM FMLP or by zymosan-activated serum. Peak inositol trisphosphate levels stimulated by FMLP were not inhibited by a dose of CHIP producing maximum inhibition of FMLP-induced superoxide production. Peak changes in cytosolic free calcium levels (as measured by indo-1 fluorescence) stimulated by 50 nM or greater FMLP were unaffected by CHIP, although for subsaturating doses of FMLP a more rapid decline from peak calcium levels was seen in CHIP-exposed cells. Taken together, these data suggest that the common fungal pathogen C. albicans releases a substance that selectively impairs the neutrophil respiratory burst. It appears to do so without inhibiting the fully assembled NADPH oxidase and with minimal or no effect on events tightly coupled to FMLP-R/G protein activation, suggesting that these events may be uncoupled from activation of the burst. In addition, the absence of effect of CHIP on chemotaxis despite profound inhibition of the respiratory burst suggests these neutrophil functions may be mediated by divergent transduction pathways.
Smail
E H
EH
Department of Medicine, Boston University School of Medicine, MA 02118.
Melnick
D A
DA
Ruggeri
R
R
Diamond
R D
RD
D002118:Calcium / Q000378:metabolism; D002176:Candida albicans / Q000032:analysis / Q000502:physiology*; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D005656:Fungal Proteins / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8; D008564:Membrane Potentials / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors*
D002630:Chemotactic Factors; D005656:Fungal Proteins; D016209:Interleukin-8; D010716:Phosphatidylinositols; D013481:Superoxides; D002118:Calcium