Complex Roles of Annexin A2 in Host Blood-Brain Barrier Invasion by Cryptococcus neoformans
Wei Fang1,2, Zhen-Zong Fa2, Qun Xie3
1PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.
Introduction:
Fungal transversal across the brain microvascular endothelial cells (BMECs) is the essential step for the development of cryptococcal meningoencephalitis. Annexin A2 (AnxA2) is an important signaling protein involved in several intracellular processes such as membrane trafficking, endocytosis, and exocytosis.
Aim:
To investigate the roles and mechanism of AnxA2 during cryptococcal transversal of BMECs.
Results:
Cryptococcus neoformans infection initiated upregulation of AnxA2 in mouse BMECs. Blockade with anti-AnxA2 antibody led to a reduction in fungal transcytosis activity but no change in its adhesion efficiency. Intriguingly, AnxA2 depletion caused a significant increase in fungal association activity but had no effect on their transcytosis. AnxA2 suppression resulted in marked reduction in its partner protein S100A10, and S100A10 suppression in BMECs significantly reduced the cryptococcal transcytosis efficiency. Furthermore, AnxA2 dephosphorylation at Tyr23 and dephosphorylation of downstream cofilin were required for cryptococcal transversal of BMECs, both of which might be primarily involved in the association of C. neoformans with host cells.
Conclusions:
Our work indicated that AnxA2 played complex roles in traversal of C. neoformans across host BMECs, which might be dependent on downstream cofilin to inhibit fungal adhesion but rely on its partner S100A10 to promote cryptococcal transcytosis.
Insights
Annexin A2 (AnxA2) has dual roles in fungal brain infections. It promotes fungal cell traversal via S100A10 but inhibits fungal adhesion through cofilin, impacting cryptococcal meningoencephalitis development.
Area of Science:
- Neuroscience
- Infectious Diseases
- Cell Biology
Background:
- Fungal traversal of brain microvascular endothelial cells (BMECs) is critical for cryptococcal meningoencephalitis.
- Annexin A2 (AnxA2) is a signaling protein involved in membrane trafficking and endocytosis.
Purpose of the Study:
- To elucidate the mechanism of AnxA2 in cryptococcal traversal of BMECs.
- To investigate the distinct roles of AnxA2 in fungal adhesion and transcytosis.
Main Methods:
- Upregulation of AnxA2 in mouse BMECs upon Cryptococcus neoformans infection.
- Utilized anti-AnxA2 antibody blockade and AnxA2/S100A10 gene suppression.
- Analyzed fungal adhesion, association, and transcytosis efficiency.
- Investigated AnxA2 phosphorylation and downstream cofilin activity.
Main Results:
- AnxA2 blockade reduced fungal transcytosis but not adhesion.
- AnxA2 depletion increased fungal association but did not affect transcytosis.
- AnxA2 suppression reduced its partner S100A10, impairing fungal transcytosis.
- AnxA2 dephosphorylation at Tyr23 and cofilin dephosphorylation were crucial for fungal association.
Conclusions:
- AnxA2 exhibits complex roles in C. neoformans traversal across BMECs.
- AnxA2 promotes transcytosis via S100A10 and inhibits adhesion possibly via cofilin.
- Understanding AnxA2's dual function is key for targeting cryptococcal meningoencephalitis.
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