Complement-Mediated Differential Immune Response of Human Macrophages to Sporothrix Species Through Interaction With Their Cell Wall Peptidorhamnomannans.

Janet A Willment,Gabriela W P Neves,Sarah Sze Wah Wong,Catherine Simenel,Leila M Lopes-Bezerra,J Iñaki Guijarro,Vishukumar Aimanianda,Catriona Walls,Carol A Munro,Gordon D Brown,Neil A R Gow

doi:10.3389/fimmu.2021.749074

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.

Highlights

The fungal genus Sporothrix harbors thermo-dimorphic species that often cause sporotrichosis, a sapronosis and/or an anthropozoonotic disease that can be transmitted from cats to humans [1]
After 1 h interaction with human monocytederived macrophages (hMDMs), flow cytometry analysis showed a significant decrease in the uptake of the two Sporothrix species in the medium containing inactivated human serum (iHS) compared to that containing whole human serum (wHS), suggesting that thermolabile serum factors facilitate the uptake of Sporothrix yeasts by hMDMs
These results confirm that hMDMs recognize S. schenckii and S. brasiliensis yeasts distinctively and that thermolabile serum factors mediate the uptake of both species, albeit at different degrees

Summary

Introduction

The fungal genus Sporothrix harbors thermo-dimorphic species that often cause sporotrichosis, a sapronosis and/or an anthropozoonotic disease that can be transmitted from cats to humans [1]. For more than a century, sporotrichosis was considered a benign subcutaneous mycosis caused only by Sporothrix schenckii. This paradigm has changed due to the discovery of new pathogenic cryptic species, S. schenckii sensu stricto, Sporothrix brasiliensis, and Sporothrix globosa, a pathogenic clade within the Sporothrix genus [2, 3]. S. brasiliensis is the prevalent species related to sporotrichosis in cats (Felis catus domesticus) followed by S. schenckii [9, 10]

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Results

Conclusion