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Published on: July 14, 2020
Involvement of human CD44 during Cryptococcus neoformans infection of brain microvascular endothelial cells
Ambrose Jong1, Chun-Hua Wu, Gregory M Shackleford
1Division of Hematology-Oncology, The Saban Research Institute, Childrens Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. ajong@chla.usc.edu
Abstract:
Pathogenic yeast Cryptococcus neoformans causes devastating cryptococcal meningoencephalitis. Our previous studies demonstrated that C. neoformans hyaluronic acid was required for invasion into human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier. In this report, we demonstrate that C. neoformans hyaluronic acid interacts with CD44 on HBMEC. Our results suggest that HBMEC CD44 is a primary receptor during C. neoformans infection, based on the following observations. First, anti-CD44 neutralizing antibody treatment was able to significantly reduce C. neoformans association with HBMEC. Second, C. neoformans association was considerably impaired using either CD44-knock-down HBMEC or C. neoformans hyaluronic acid-deficient strains. Third, overexpression of CD44 in HBMEC increased their association activity towards C. neoformans. Fourth, confocal microscopic images showed that CD44 was enriched at and around the C. neoformans association sites. Fifth, upon C. neoformans and HBMEC engagement, a subpopulation of CD44 and actin translocated to the host membrane rafts. Our results highlight the interactions between C. neoformans hyaluronic acid and host CD44 and the dynamic results of these interactions, which may represent events during the adhesion and entry of C. neoformans at HBMEC membrane rafts.
Insights
Cryptococcus neoformans uses its hyaluronic acid to bind to CD44 receptors on human brain cells. This interaction is crucial for yeast invasion across the blood-brain barrier.
Area of Science:
- Mycology
- Immunology
- Cell Biology
Background:
- Cryptococcus neoformans is a pathogenic yeast responsible for severe meningoencephalitis.
- The yeast's hyaluronic acid is essential for its invasion of human brain microvascular endothelial cells (HBMEC), which form the blood-brain barrier.
Purpose of the Study:
- To investigate the interaction between Cryptococcus neoformans hyaluronic acid and host cell receptors.
- To determine the role of CD44 on HBMEC in the context of C. neoformans infection.
Main Methods:
- Utilized anti-CD44 neutralizing antibodies to assess C. neoformans association with HBMEC.
- Employed CD44-knock-down HBMEC and C. neoformans hyaluronic acid-deficient strains.
- Investigated the effect of CD44 overexpression in HBMEC on yeast association.
- Employed confocal microscopy to visualize CD44 localization during yeast-cell interaction.
- Analyzed the translocation of CD44 and actin to host membrane rafts.
Main Results:
- Anti-CD44 antibody treatment significantly reduced C. neoformans association with HBMEC.
- Impaired association was observed with CD44-knock-down HBMEC and hyaluronic acid-deficient C. neoformans.
- Overexpression of CD44 enhanced HBMEC's association with C. neoformans.
- CD44 localized to sites of C. neoformans association on HBMEC.
- CD44 and actin translocated to host membrane rafts upon yeast-cell engagement.
Conclusions:
- HBMEC CD44 acts as a primary receptor for Cryptococcus neoformans.
- The interaction between C. neoformans hyaluronic acid and CD44 is critical for yeast adhesion and potential entry into brain endothelial cells.
- These interactions, involving membrane raft dynamics, are key events in the pathogenesis of cryptococcal meningoencephalitis.
