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Peptides from Paracoccidioides brasiliensis GP43 inhibit macrophage functions and inflammatory response
Adriana Y C Konno1, Juliana T Maricato, Fabiana T C Konno
1Universidade Federal de São Paulo - UNIFESP, Department of Microbiology, Immunology and Parasitology, Discipline of Immunology, São Paulo, Brazil.
Abstract:
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis (Pb), a thermal dimorphic fungus. Its major antigen is a 43-kDa glycoprotein. Gp43 embodies different functions: it participates in evasion mechanisms during the installation of primary infection, stimulates granuloma-like formation in vitro and presents T-cell epitopes that induce protective response against the fungus. Here, we investigated epitopes from gp43 inhibitory of both, macrophage functions and inflammatory reaction. Different gp43 peptides, spanning the entire sequence of the molecule, were added to cultures of bone marrow-derived macrophages. After challenge with zymosan or Pb cells, phagocytic indexes were measured. Peptides expressed on the molecule surface were determined by graphic analysis using the Protean module; DNAstar Inc. Two peptides which decreased phagocytic index and were expressed at the surface of the molecule, P4 and P23, were selected for further studies. It was shown that both inhibited the release of NO by zymosan stimulated macrophages while enhanced release of H(2)O(2). The release of TNF-alpha in culture supernatants from in vitro phagocytic tests showed different response depending of P4 concentration (data not shown). In vivo assays with Mycobacterium bovis - bacillus Calmette-Guérin (BCG) or Pb cells demonstrated that these peptides presented non-specific and specific anti-inflammatory properties.
Insights
Two peptides from the major antigen gp43 of Paracoccidioides brasiliensis were found to inhibit macrophage functions and reduce inflammation. These findings offer potential therapeutic targets for paracoccidioidomycosis (PCM).
Area of Science:
- Mycology
- Immunology
- Infectious Diseases
Background:
- Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by the fungus Paracoccidioides brasiliensis (Pb).
- The major antigen gp43, a 43-kDa glycoprotein, plays a role in fungal evasion, granuloma formation, and immune response.
- Understanding gp43 epitopes is crucial for developing targeted therapies against PCM.
Purpose of the Study:
- To investigate specific epitopes within gp43 that can inhibit macrophage functions and inflammatory responses.
- To identify potential therapeutic peptides for managing Paracoccidioides brasiliensis infections.
Main Methods:
- Synthesis and testing of various gp43 peptides on bone marrow-derived macrophages.
- Assessment of phagocytic activity after challenge with zymosan or Pb cells.
- Analysis of nitric oxide (NO), hydrogen peroxide (H2O2), and TNF-alpha release.
- In vivo evaluation of anti-inflammatory properties using Mycobacterium bovis bacillus Calmette-Guérin (BCG) and Pb cells.
Main Results:
- Two surface-expressed peptides, P4 and P23, significantly decreased macrophage phagocytic index.
- Both P4 and P23 inhibited NO release while enhancing H2O2 release from stimulated macrophages.
- In vivo studies confirmed that these peptides possess both non-specific and specific anti-inflammatory properties.
Conclusions:
- Specific gp43-derived peptides (P4 and P23) modulate macrophage function and exhibit anti-inflammatory effects.
- These peptides represent promising candidates for novel therapeutic strategies against paracoccidioidomycosis.
- Further research into these epitopes could lead to new treatments for fungal infections.
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