Heat Shock Protein 60, Insights to Its Importance in Histoplasma capsulatum: From Biofilm Formation to Host-Interaction

Abstract

Heat shock proteins (Hsps) are among the most widely distributed and evolutionary conserved proteins, acting as essential regulators of diverse constitutive metabolic processes. The Hsp60 of the dimorphic fungal Histoplasma capsulatum is the major surface adhesin to mammalian macrophages and studies of antibody-mediated protection against H. capsulatum have provided insight into the complexity involving Hsp60. However, nothing is known about the role of Hsp60 regarding biofilms, a mechanism of virulence exhibited by H. capsulatum. Considering this, the present study aimed to investigate the influence of the Hsp60 on biofilm features of H. capsulatum. Also, the non-conventional model Galleria mellonella was used to verify the effect of this protein during in vivo interaction. The use of invertebrate models such as G. mellonella is highly proposed for the evaluation of pathogenesis, immune response, virulence mechanisms, and antimicrobial compounds. For that purpose, we used a monoclonal antibody (7B6) against Hsp60 and characterized the biofilm of two H. capsulatum strains by metabolic activity, biomass content, and images from scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). We also evaluated the survival rate of G. mellonella infected with both strains under blockage of Hsp60. The results showed that mAb 7B6 was effective to reduce the metabolic activity and biomass of both H. capsulatum strains. Furthermore, the biofilms of cells treated with the antibody were thinner as well as presented a lower amount of cells and extracellular polymeric matrix compared to its non-treated controls. The blockage of Hsp60 before fungal infection of G. mellonella larvae also resulted in a significant increase of the larvae survival compared to controls. Our results highlight for the first time the importance of the Hsp60 protein to the establishment of the H. capsulatum biofilms and the G. mellonella larvae infection. Interestingly, the results with Hsp60 mAb 7B6 in this invertebrate model suggest a pattern of fungus-host interaction different from those previously found in a murine model, which can be due to the different features between insect and mammalian immune cells such as the absence of Fc receptors in hemocytes. However further studies are needed to support this hypothesis

Pulmonary Histoplasmosis: A Clinical Update

“…The heat shock protein 60 (Hsp60) of H. capsulatum is the major surface adhesin to macrophages and binds to complement receptor 3 (CR3) [ 12 ]. Dectin-1 recognizes 1-3 β glucan which is a major polysaccharide in the cell wall of most fungal pathogens.…”

Insights on Covid‐19 with superimposed pulmonary histoplasmosis: The possible nexus

“…21 HSP60 of H. capsulatum protects against antibody response and improves biofilm formation. 21 HSP60 acts as a ligand for macrophage receptors during fungal infection, though this interaction induces a mild host immune response. 22 In this state, H. capsulatum replicates and survives within the host cells.…”

“…HSP60 of H. capsulatum protects against antibody response and improves biofilm formation. 21 Heine, HSP60, which is essential for macrophage activation and release of proinflammatory cytokines, is activated during H. capsulatum infection causes intense inflammatory disorders. Remarkably, H. capsulatum infection can induce the expression and release of proinflammatory cytokines, chiefly IL-6 and IL-8, in lung epithelial cells through the induction expression of integrin and its membrane interaction.…”

“…Though, the Th2 immune response drives the allergic response to H. capsulatum via the production of IL‐5 and the recruitment of eosinophils 20 . Moreover, heat shock protein 60 (HSP60), which regulates intracellular protein folding, is regarded as an important surface molecule that mediates phagocytosis of H. capsulatum by the activated macrophages 21 . HSP60 of H. capsulatum protects against antibody response and improves biofilm formation 21 .…”

“…Moreover, heat shock protein 60 (HSP60), which regulates intracellular protein folding, is regarded as an important surface molecule that mediates phagocytosis of H. capsulatum by the activated macrophages 21 . HSP60 of H. capsulatum protects against antibody response and improves biofilm formation 21 . HSP60 acts as a ligand for macrophage receptors during fungal infection, though this interaction induces a mild host immune response 22 .…”