Galectin-3 Inhibits Paracoccidioides brasiliensis Growth and Impacts Paracoccidioidomycosis through Multiple Mechanisms

Abstract

The thermodimorphic pathogenic fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii are the etiologic causes of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America. Galectin-3 (Gal-3), an animal β-galactoside-binding protein, modulates important roles during microbial infections, such as triggering a Th2-polarized immune response in PCM. Herein, we demonstrate that Gal-3 also plays other important roles in P. brasiliensis infection. We verified that Gal-3 levels are upregulated in human and mice infections and established that Gal-3 inhibited P. brasiliensis growth by inhibiting budding. Furthermore, Gal-3 affected disruption and internalization of extracellular vesicles (EVs) from P. brasiliensis by macrophages. Our results suggest important protective roles for Gal-3 in P. brasiliensis infection, indicating that increased Gal-3 production during P. brasiliensis infection may affect fungal growth and EV stability, thus promoting beneficial effects that could influence the course of PCM. The finding that Gal-3 has effects against P. brasiliensis together with previously reported effects against Cryptococcus neoformans suggests that molecule has a general antifungal role in innate defenses against fungal pathogens. IMPORTANCE Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis in Latin America. Although the immune mechanisms to control PCM are still not fully understood, several events of the host innate and adaptive immunity are crucial to determine the progress of the infection. Mammalian β-galactoside-binding protein galectin-3 (Gal-3) plays significant roles during microbial infections and has been studied for its immunomodulatory roles, but it can also have direct antimicrobial effects. We asked whether this protein plays a role in Paracoccidioides brasiliensis. We report herein that Gal-3 indeed has direct effects on the fungal pathogen, inhibiting fungal growth and reducing extracellular vesicle stability. Our results suggest a direct role for Gal-3 in P. brasiliensis infection, with beneficial effects for the mammalian host.

Extracellular Vesicles from Aspergillus flavus Induce M1 Polarization In Vitro

“…Considering the description of EV production from fungal species, these structures have been considered to be important carriers of biological compounds and are related to several functions such as pathogenicity, cell communication, and immunogenicity of fungal infections (12). Several studies previously described biologically active EVs produced by the fungal species (T. interdigitale, P. brasiliensis, C. neoformans, C. albicans, M. sympodialis, S. brasiliensis) (21,22,24,(28)(29)(30)(31)(32). Among the Aspergillus spp., EVs from A. fumigatus were able to stimulate TNF-␣ and chemokine (C-C motif) ligand 2 (CCL2) production by macrophages in vitro (26).…”

Extracellular vesicles carry cellulases in the industrial fungus Trichoderma reesei

“…Thus, to understand the biological functions of fungal EVs should reveal important roles of EVs in several biological processes [96]. Galectin-3, a mammalian β-galactoside-binding protein, has been reported playing disruption and internalization of EVs produced from C. neoformans [35] and P. brasiliensis [99] by macrophages. However, additional studies are needed to discern how EVs deliver their cargo, as well as to identify new molecules playing a lytic effect on fungal EVs.…”

Calreticulin and Galectin-3 Opsonise Bacteria for Phagocytosis by Microglia

“…Galectin-3 is also found in human plasma and CSF, and levels increases with disease (39, 40). Galectin-3 levels also increase in mouse and humans during fungal infection and play roles in reducing infection (41). The interaction of galectin-3 with LPS from different species of bacteria enhances the binding and interaction of LPS with neutrophils (33).…”