Reduced PICD in Monocytes Mounts Altered Neonate Immune Response to Candida albicans.

Stephan Dreschers,Christopher Platen,Peter Saupp,Thorsten W Orlikowsky,Mathias Hornef,Joachim Morschhäuser,Andrea Prehn,Gernot Zissel

doi:10.1371/journal.pone.0166648

Stephan Dreschers, Christopher Platen + Show 6 more

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https://doi.org/10.1371/journal.pone.0166648

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Journal: PloS one	Publication Date: Nov 21, 2016
Citations: 12	License type: CC BY 4.0

Affiliation: Universitätsklinikum Aachen, University of Würzburg

Abstract

BackgroundInvasive fungal infections with Candida albicans (C. albicans) occur frequently in extremely low birthweight (ELBW) infants and are associated with poor outcome. Phagocytosis of C.albicans initializes apoptosis in monocytes (phagocytosis induced cell death, PICD). PICD is reduced in neonatal cord blood monocytes (CBMO).HypothesisPhagocytosis of C. albicans causes PICD which differs between neonatal monocytes (CBMO) and adult peripheral blood monocytes (PBMO) due to lower stimulation of TLR-mediated immune responses.MethodsThe ability to phagocytose C. albicans, expression of TLRs, the induction of apoptosis (assessment of sub-G1 and nick-strand breaks) were analyzed by FACS. TLR signalling was induced by agonists such as lipopolysaccharide (LPS), Pam3Cys, FSL-1 and Zymosan and blocked (neutralizing TLR2 antibodies and MYD88 inhibitor).ResultsPhagocytic indices of PBMO and CBMO were similar. Following stimulation with agonists and C. albicans induced up-regulation of TLR2 and consecutive phosphorylation of MAP kinase P38 and expression of TNF-α, which were stronger on PBMO compared to CBMO (p < 0.005). Downstream, TLR2 signalling initiated caspase-3-dependent PICD which was found reduced in CBMO (p < 0.05 vs PBMO).ConclusionOur data suggest direct involvement of TLR2-signalling in C. albicans-induced PICD in monocytes and an alteration of this pathway in CBMO.

Highlights

C. albicans is part of the normal microbiota, it may emerge as opportunistic pathogen in the event of innate or acquired immunodeficiency
Following stimulation with agonists and C. albicans induced up-regulation of TLR2 and consecutive phosphorylation of mitogen activated protein (MAP) kinase P38 and expression of TNF-α, which were stronger on peripheral blood monocytes (PBMO) compared to cord blood monocytes (CBMO) (p < 0.005)
Downstream, TLR2 signalling initiated caspase-3-dependent phagocytosis induced cell death (PICD) which was found reduced in CBMO (p < 0.05 vs PBMO)

Summary

Introduction

C. albicans is part of the normal microbiota, it may emerge as opportunistic pathogen in the event of innate or acquired immunodeficiency. C. albicans and other Candida species are common pathogens in preterm infants. Very low birthweight (VLBW) and extremely low birthweight (ELBW) infants are extremely vulnerable to invasive Candida infection (ICI) with adverse neurodevelopmental outcome and high mortality. Preterm infants exhibit a particular sensitivity to fungal infections. These opportunistic pathogens take advantage of the immature neonatal immune system and the need for prolonged antibiotic treatment that facilitates fungal growth, replication and dissemination [3]. Invasive fungal infections with Candida albicans (C. albicans) occur frequently in extremely low birthweight (ELBW) infants and are associated with poor outcome. Phagocytosis of C. albicans causes PICD which differs between neonatal monocytes (CBMO) and adult peripheral blood monocytes (PBMO) due to lower stimulation of TLRmediated immune responses

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Conclusion