Paracoccidioides Spp.: Virulence Factors and Immune-Evasion Strategies

Abstract

Paracoccidioides spp. are dimorphic fungal pathogens responsible for one of the most relevant systemic mycoses in Latin America, paracoccidioidomycosis (PCM). Their exact ecological niche remains unknown; however, they have been isolated from soil samples and armadillos (Dasypus novemcinctus), which have been proposed as animal reservoir for these fungi. Human infection occurs by inhalation of conidia or mycelia fragments and is mostly associated with immunocompetent hosts inhabiting and/or working in endemic rural areas. In this review focusing on the pathogen perspective, we will discuss some of the microbial attributes and molecular mechanisms that enable Paracoccidioides spp. to tolerate, adapt, and ultimately avoid the host immune response, establishing infection.

Figure 1

Silencing of PbAMY1 reduces α-(1,3)-glucan of P. brasiliensis yeast cell. (a) Semiqualitative estimation of α-(1,3)-glucan on Paracoccidioides yeast cells by immunofluorescence. Pseudocolor mask for saturation (ImageJ). (b) Quantification of α-(1,3)-glucan in Paracoccidioides yeast cells by anthrone assay. ^∗∗∗∗P < 0.00001, Welch's test.

Figure 2

Diagram of proposed Paracoccidioides spp. immune-evasion mechanisms. (a) Shielding of stimulatory PAMPs. The cell wall beta-glucan present in the fungus saprophytic forms (conidia and mycelia) is recognized by the macrophage Dectin-1 receptor; however, pathogenic yeast cell α-(1,3)-glucan masks β-(1,3)-glucan, avoiding its recognition. (b) Intracellular survival. Paracoccidiodes spp. use several strategies to overcome the host harsh environment, among them are the following: (1) promoting invasion to the pulmonary epithelial cells by altering their cytoskeleton structure, a process assisted by gp43; (2) avoiding phagocytosis by displaying an enlarged multibudding morphology, boosted by Cdc42 expression, which physically impairs engulfment by macrophages; and (3) adapting to the host environment. The phagocytosed fungus shifts its metabolism to tolerate macrophage stress conditions and even modulate host apoptosis enabling fungal killing. (c) Altering T-cell repertoire. During acute fungal infections, yeast cells invade the thymus altering its epithelial cells' spatial arrangement crucial for T-cell differentiation and pathogen-specific immune response.