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Published on: May 19, 2020
The Impact of Paracoccidioides spp Infection on Central Nervous System Cell Junctional Complexes
Sérgio Monteiro de Almeida1,2, Amanda Kulik3, Mineia Alessandra Scaranello Malaquias4
1Medical Pathology Department, School of Medicine, Universidade Federal do Paraná, Curitiba, Paraná, Brazil. sergio.ma@ufpr.br.
Abstract:
Paracoccidioidomycosis (PCM), a systemic mycosis caused by the fungus Paracoccidioides spp. is the most prevalent fungal infection among immunocompetent patients in Latin America. The estimated frequency of central nervous system (CNS) involvement among the human immunodeficiency virus (HIV)/PCM-positive population is 2.5%. We aimed to address the impact of neuroparacoccidioidomycosis (NPCM) and HIV/NPCM co-infection on the tight junctions (TJ) and adherens junction (AJ) proteins of the CNS. Four CNS formalin-fixed paraffin-embedded (FFPE) tissue specimens were studied: NPCM, NPCM/HIV co-infection, HIV-positive without opportunistic CNS infection, and normal brain autopsy (negative control). Immunohistochemistry was used to analyze the endothelial cells and astrocytes expressions of TJ markers: claudins (CLDN)-1, -3, -5 and occludin; AJ markers: β-catenin and E-cadherin; and pericyte marker: alpha-smooth muscle actin. FFPE CNS tissue specimens were analyzed using the immunoperoxidase assay. CLDN-5 expression in the capillaries of the HIV/NPCM coinfected tissues (mixed clinical form of PCM) was lower than that in the capillaries of the HIV or NPCM monoinfected (chronic clinical form of PCM) tissues. A marked decrease in CLDN-5 expression and a compensatory increase in CLDN-1 expression in the NPCM/HIV co-infection tissue samples was observed. The authors suggest that Paracoccidioides spp. crosses the blood-brain barrier through paracellular pathway, owing to the alteration in the CLDN expression, or inside the macrophages (Trojan horse).
Insights
Neuroparacoccidioidomycosis (NPCM) with HIV co-infection alters blood-brain barrier proteins. Claudin-5 decreased, while Claudin-1 increased, suggesting fungal entry via paracellular routes or macrophages.
Area of Science:
- Neuroscience
- Mycology
- Immunology
Background:
- Paracoccidioidomycosis (PCM) is a prevalent fungal infection in Latin America.
- Central nervous system (CNS) involvement occurs in 2.5% of HIV-positive individuals with PCM.
- Understanding the impact of neuroparacoccidioidomycosis (NPCM) and HIV co-infection on CNS barriers is crucial.
Purpose of the Study:
- To investigate the effects of NPCM and HIV/NPCM co-infection on tight junction (TJ) and adherens junction (AJ) proteins in the CNS.
- To analyze the expression of specific TJ, AJ, and pericyte markers in affected CNS tissues.
Main Methods:
- Analysis of four formalin-fixed paraffin-embedded (FFPE) CNS tissue specimens: NPCM, NPCM/HIV co-infection, HIV-positive, and normal autopsy.
- Immunohistochemistry and immunoperoxidase assay to evaluate endothelial and astrocyte expression of CLDNs, occludin, β-catenin, E-cadherin, and alpha-smooth muscle actin.
- Comparison of protein expression patterns across different clinical conditions.
Main Results:
- Reduced Claudin-5 (CLDN-5) expression in capillaries of HIV/NPCM co-infected tissues compared to NPCM or HIV monoinfected tissues.
- Significant decrease in CLDN-5 and compensatory increase in Claudin-1 (CLDN-1) expression observed in NPCM/HIV co-infection samples.
- Alterations in TJ protein expression suggest potential disruption of the blood-brain barrier.
Conclusions:
- Paracoccidioides spp. may breach the blood-brain barrier via paracellular pathways due to altered Claudin expression.
- Fungal dissemination into the CNS could also occur through infected macrophages (Trojan horse mechanism).
- These findings highlight the impact of fungal infections and HIV co-infection on CNS barrier integrity.
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