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Reduced PICD in Monocytes Mounts Altered Neonate Immune Response to Candida albicans
Stephan Dreschers1, Peter Saupp1, Mathias Hornef2
1Department of Neonatology, University Children's Hospital, Aachen, Germany.
Background:
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 initializes apoptosis in monocytes (phagocytosis induced cell death, PICD). PICD is reduced in neonatal cord blood monocytes (CBMO).
Hypothesis:
Phagocytosis 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.
Methods:
The 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).
Results:
Phagocytic 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).
Conclusion:
Our data suggest direct involvement of TLR2-signalling in C. albicans-induced PICD in monocytes and an alteration of this pathway in CBMO.
Insights
Neonatal monocytes show reduced phagocytosis-induced cell death (PICD) in response to Candida albicans due to impaired Toll-like receptor 2 (TLR2) signaling. This finding is crucial for understanding invasive fungal infections in extremely low birthweight infants.
Area of Science:
- Immunology
- Cell Biology
- Neonatal Medicine
Background:
- Invasive fungal infections caused by Candida albicans are common and dangerous in extremely low birthweight infants.
- Phagocytosis of Candida albicans triggers apoptosis in monocytes, a process known as phagocytosis-induced cell death (PICD).
- Neonatal cord blood monocytes (CBMO) exhibit reduced PICD compared to adult peripheral blood monocytes (PBMO).
Purpose of the Study:
- To investigate the differences in phagocytosis-induced cell death (PICD) between neonatal cord blood monocytes (CBMO) and adult peripheral blood monocytes (PBMO) when exposed to Candida albicans.
- To explore the role of Toll-like receptor (TLR)-mediated immune responses in Candida albicans-induced PICD in different monocyte populations.
Main Methods:
- Flow cytometry (FACS) was used to analyze monocyte phagocytosis of Candida albicans, TLR expression, and apoptosis.
- TLR signaling pathways were activated using agonists (LPS, Pam3Cys, FSL-1, Zymosan) and inhibited using neutralizing TLR2 antibodies and a MYD88 inhibitor.
Main Results:
- Phagocytic indices were comparable between adult peripheral blood monocytes (PBMO) and neonatal cord blood monocytes (CBMO).
- Stimulation with agonists and Candida albicans led to increased TLR2 expression, p38 MAP kinase phosphorylation, and TNF-α production, which were significantly lower in CBMO compared to PBMO.
- TLR2 signaling initiated caspase-3-dependent PICD, which was significantly reduced in CBMO versus PBMO.
Conclusions:
- Toll-like receptor 2 (TLR2) signaling plays a direct role in Candida albicans-induced phagocytosis-induced cell death (PICD) in monocytes.
- The TLR2 signaling pathway involved in PICD is altered in neonatal cord blood monocytes (CBMO), contributing to their reduced apoptotic response.
