TY - JOUR
T1 - Role of calprotectin in withholding zinc and copper from Candida albicans
AU - Besold, Angelique N.
AU - Gilston, Benjamin A.
AU - Radin, Jana N.
AU - Ramsoomair, Christian
AU - Culbertson, Edward M.
AU - Li, Cissy X.
AU - Cormack, Brendan P.
AU - Chazin, Walter J.
AU - Kehl-Fie, Thomas E.
AU - Culotta, Valeria C.
N1 - Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the hostpathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.
AB - The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the hostpathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.
KW - Calprotectin
KW - Candida albicans
KW - Copper
KW - Nutritional immunity
KW - Zinc
UR - http://www.scopus.com/inward/record.url?scp=85040975444&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040975444&partnerID=8YFLogxK
U2 - 10.1128/IAI.00779-17
DO - 10.1128/IAI.00779-17
M3 - Article
C2 - 29133349
AN - SCOPUS:85040975444
SN - 0019-9567
VL - 86
JO - Infection and immunity
JF - Infection and immunity
IS - 2
M1 - e00779-17
ER -