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Involvement of CD146 in the Cryptococcus neoformans adhesion and infection of brain endothelial cells
Wei Liu1, Junhong Chen1, Ting Wang1
1Department of Immunology, National Vaccine Innovation Platform, NHC Key Laboratory of Antibody Technique, Jiangsu Key Laboratory of Pathogen Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
Abstract:
Cryptococcal meningitis is a common and refractory central nervous system (CNS) infection with high mortality and disability. For Cryptococcus neoformans (C. neoformans) to penetrate the CNS, it first adheres to and breaches the blood‒brain barrier (BBB). Here, we explored the roles of CD146, an adhesion molecule expressed on the surface of brain microvascular endothelial cells (BMECs), in cryptococcal vascular adhesion and BBB invasion. Following cryptococcal infection, we observed a reduction in CD146 expression in BMECs, which was at least partially mediated by metalloproteinase-9. Once overexpressed on BMECs, CD146 increased C. neoformans adhesion; in contrast, CD146 knockout decreased the attachment of fungi to endothelial cells in vitro. Unexpectedly, CD146 knockout failed to reduce fungal infection in the brain following intravascular instillation of C. neoformans. However, the anti-CD146 antibody AA98 significantly increased the fungemia (spleen CFU), suggesting that CD146 may be involved in the early adhesion and invasion of Cryptococcus into cerebral vessels. AA98, however, failed to extend the survival of C. neoformans infected mice. These results suggest that CD146 may play dispensable roles in the C. neoformans brain infection.
Insights
CD146, a brain endothelial cell adhesion molecule, influences Cryptococcus neoformans binding but does not significantly impact brain infection or survival in mice, suggesting dispensable roles in CNS invasion.
Area of Science:
- Neuroscience
- Infectious Diseases
- Immunology
Background:
- Cryptococcal meningitis is a severe central nervous system (CNS) infection caused by Cryptococcus neoformans.
- Fungal entry into the CNS requires breaching the blood-brain barrier (BBB), involving adhesion to brain microvascular endothelial cells (BMECs).
- CD146 is an adhesion molecule expressed on BMECs, potentially mediating fungal interactions with the BBB.
Purpose of the Study:
- To investigate the role of CD146 in Cryptococcus neoformans adhesion to and invasion of the BBB.
- To determine the impact of CD146 modulation on fungal CNS infection and host survival.
Main Methods:
- Examined CD146 expression in BMECs following C. neoformans infection.
- Utilized CD146 overexpression and knockout models in vitro to assess fungal adhesion.
- Administered anti-CD146 antibody (AA98) in vivo to evaluate effects on fungemia and survival in infected mice.
Main Results:
- C. neoformans infection reduced CD146 expression on BMECs, partly via metalloproteinase-9.
- Overexpressed CD146 enhanced fungal adhesion to BMECs in vitro, while CD146 knockout reduced it.
- CD146 knockout did not decrease fungal brain infection, but anti-CD146 antibody increased fungemia and did not improve survival.
Conclusions:
- CD146 is involved in the initial adhesion of C. neoformans to cerebral vessels.
- Despite influencing early adhesion, CD146 appears to play dispensable roles in established C. neoformans brain infection and overall host survival.
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