Attributable Mortality of Nosocomial Candidemia, Revisited

Guðlaugsson, Ólafur; Gillespie, Shane; Lee, Kathleen; Berg, Jeff Vande; Hu, Jing; Messer, S. A.; Herwaldt, Loreen A.; Pfaller, Michael A.; Diekema, Daniel J.

doi:10.1086/378745

Cited by 1,038 publications

(725 citation statements)

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“…Pneumocystosis, endemic fungal infections, and cryptococcosis were rarely encountered in the HSCT population. Consistent with prior reports [4][5][6][7], mortality was high and one-year survival was low for HSCT patients with IFI. Fusarium infections and IA were associated with the lowest one year survival (6% and 25%, respectively); however, survival among patients with zygomycosis (28%) and IC (34%) was not substantially better.…”

Section: Epidemiology Of Invasive Fungal Infectionssupporting

confidence: 91%

Fungal Infections in Transplant and Oncology Patients

Person

Kontoyiannis

Alexander

2011

Hematology/Oncology Clinics of North America

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Section: Epidemiology Of Invasive Fungal Infectionssupporting

confidence: 91%

Fungal Infections in Transplant and Oncology Patients

Person

Kontoyiannis

Alexander

2011

Hematology/Oncology Clinics of North America

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“…However, under conditions of primary or secondary immunodeficiency, this yeast can cause opportunistic infections such as mucosal inflammation and systemic sepsis [1]. The mortality rate associated with invasive candidiasis Correspondence: Dr. Anna Vecchiarelli e-mail: vecchiar@unipg.it has been reported to be as high as 40-50% [2]. Candida species are the fourth most common pathogens isolated from nosocomial bloodstream infections in the USA and Europe [3].…”

mentioning

confidence: 99%

Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

et al. 2013

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In a recent report, we demonstrated that distinct members of the secreted aspartic protease (Sap) family of Candida albicans are able to induce secretion of proinflammatory cytokines by human monocytes, independently of their proteolytic activity and specific pH optima. In particular, C. albicans Sap2 and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Here, we demonstrate that Sap2 and Sap6 proteins trigger IL-1β and IL-18 production through inflammasome activation. This occurs via NLRP3 and caspase-1 activation, which cleaves pro-IL-1β into secreted bioactive IL-1β, a cytokine that was induced by Saps in monocytes, in monocyte-derived macrophages and in dendritic cells. Downregulation of NLRP3 by RNA interference strongly reduced the secretion of bioactive IL-1β. Inflammasome activation required Sap internalization via a clathrin-dependent mechanism, intracellular induction of K + efflux, and ROS production. Inflammasome activation of monocytes induced by Sap2 and Sap6 differed from that induced by LPS-ATP in several aspects. Our data reveal novel immunoregulatory mechanisms of C. albicans and suggest that Saps contribute to the pathogenesis of candidiasis by fostering rather than evading host immunity.Keywords: Aspartic proteases r C. albicans r IL-1β r Inflammasome r Virulence factor IntroductionCandida albicans is a commensal fungus that colonizes human mucosal surfaces such as the vaginal and gastrointestinal tracts without causing harm. However, under conditions of primary or secondary immunodeficiency, this yeast can cause opportunistic infections such as mucosal inflammation and systemic sepsis [1]. The mortality rate associated with invasive candidiasis Correspondence: Dr. Anna Vecchiarelli e-mail: vecchiar@unipg.it has been reported to be as high as 40-50% [2]. Candida species are the fourth most common pathogens isolated from nosocomial bloodstream infections in the USA and Europe [3]. Although the immune status of the host plays a key role in the prevention or pathogenesis of C. albicans infections, a number of virulence attributes of C. albicans, such as factors that mediate adhesion, enzyme secretion, or hyphal formation, contribute to the disease process [4]. Particularly, the secretion of aspartic proteases (Saps), * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 680Donatella Pietrella et al. Eur. J. Immunol. 2013. 43: 679-692 which are encoded by a gene family with ten members, has long been recognized as a virulence-associated trait of this pathogenic yeast [5].We recently reported that various members of the Sap family, including Sap1, Sap2, Sap3, and Sap6, have different abilities to induce secretion of pro-inflammatory cytokines by human monocytes via Akt/NF-κB activation. Sap1, Sap2, and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Importantly, Sapinduced cytokine production was independent of the proteolytic activity and of the optimal pH for the individual Sap activities [6]. These data suggest ...

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“…Candidaemia is generally difficult to diagnose and treat and mortality rates remain at approximately 50%, with great costs to the healthcare system (Gudlaugsson et al 2003, Colombo et al 2008, Arnold et al 2010.…”

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confidence: 99%