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Complement-Mediated Differential Immune Response of Human Macrophages to Sporothrix Species Through Interaction With
Gabriela W P Neves1, Sarah Sze Wah Wong2, Vishukumar Aimanianda2
1Cell Biology Department, Rio de Janeiro State University, Rio de Janeiro, Brazil.
Abstract:
In this study, the human immune response mechanisms against Sporothrix brasiliensis and Sporothrix schenckii, two causative agents of human and animal sporotrichosis, were investigated. The interaction of S. brasiliensis and S. schenckii with human monocyte-derived macrophages (hMDMs) was shown to be dependent on the thermolabile serum complement protein C3, which facilitated the phagocytosis of Sporothrix yeast cells through opsonization. The peptidorhamnomannan (PRM) component of the cell walls of these two Sporothrix yeasts was found to be one of their surfaces exposed pathogen-associated molecular pattern (PAMP), leading to activation of the complement system and deposition of C3b on the Sporothrix yeast surfaces. PRM also showed direct interaction with CD11b, the specific component of the complement receptor-3 (CR3). Furthermore, the blockade of CR3 specifically impacted the interleukin (IL)-1β secretion by hMDM in response to both S. brasiliensis and S. schenckii, suggesting that the host complement system plays an essential role in the inflammatory immune response against these Sporothrix species. Nevertheless, the structural differences in the PRMs of the two Sporothrix species, as revealed by NMR, were related to the differences observed in the host complement activation pathways. Together, this work reports a new PAMP of the cell surface of pathogenic fungi playing a role through the activation of complement system and via CR3 receptor mediating an inflammatory response to Sporothrix species.
Insights
This study reveals peptidorhamnomannan (PRM) on Sporothrix fungi activates the complement system and CR3 receptor, crucial for immune response against sporotrichosis. Understanding this interaction aids in developing targeted therapies.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Sporothrix brasiliensis and Sporothrix schenckii cause sporotrichosis in humans and animals.
- The human immune response to these fungal pathogens is complex and not fully understood.
Purpose of the Study:
- To investigate the immune mechanisms against Sporothrix brasiliensis and Sporothrix schenckii.
- To identify pathogen-associated molecular patterns (PAMPs) involved in the host-pathogen interaction.
- To elucidate the role of the complement system and complement receptor-3 (CR3) in the immune response.
Main Methods:
- Co-culture of human monocyte-derived macrophages (hMDMs) with Sporothrix yeasts.
- Complement fixation assays to assess C3 deposition.
- Nuclear Magnetic Resonance (NMR) spectroscopy to analyze PRM structure.
- CR3 blockade experiments to evaluate interleukin-1β secretion.
Main Results:
- Phagocytosis of Sporothrix yeasts by hMDMs is mediated by complement protein C3 opsonization.
- Peptidorhamnomannan (PRM) acts as a surface-exposed PAMP, activating the complement system and binding to CR3.
- CR3 blockade inhibits IL-1β secretion by hMDMs, highlighting its role in the inflammatory response.
- Structural differences in PRMs correlate with variations in complement activation pathways.
Conclusions:
- The complement system and CR3 receptor are essential for the inflammatory immune response against Sporothrix species.
- PRM is identified as a novel fungal PAMP involved in complement activation and CR3-mediated immune signaling.
- This research provides insights into host-pathogen interactions in sporotrichosis, potentially informing therapeutic strategies.
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