Updates in Paracoccidioides Biology and Genetic Advances in Fungus Manipulation

Abstract

The dimorphic fungi of the Paracoccidioides genus are the causative agents of paracoccidioidomycosis (PCM). This disease is endemic in Latin America and primarily affects workers in rural areas. PCM is considered a neglected disease, despite being a disabling disease that has a notable impact on the public health system. Paracoccidioides spp. are thermally dimorphic fungi that present infective mycelia at 25 °C and differentiate into pathogenic yeast forms at 37 °C. This transition involves a series of morphological, structural, and metabolic changes which are essential for their survival inside hosts. As a pathogen, the fungus is subjected to several varieties of stress conditions, including the host immune response, which involves the production of reactive nitrogen and oxygen species, thermal stress due to temperature changes during the transition, pH alterations within phagolysosomes, and hypoxia inside granulomas. Over the years, studies focusing on understanding the establishment and development of PCM have been conducted with several limitations due to the low effectiveness of strategies for the genetic manipulation of Paracoccidioides spp. This review describes the most relevant biological features of Paracoccidioides spp., including aspects of the phylogeny, ecology, stress response, infection, and evasion mechanisms of the fungus. We also discuss the genetic aspects and difficulties of fungal manipulation, and, finally, describe the advances in molecular biology that may be employed in molecular research on this fungus in the future.

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall

“…are glucan molecules. As already mentioned, the predominance of β-glucan during the mycelial phase is reverted to α-glucan in the yeast phase [2]. This mechanism is seen as one strategy to evade the immune system.…”

“…Chitin molecules are also recognized by the immune system via TLR-2, inducing the production of cytokines and the recruitment of phagocytic cells by the recognition by Dectin-1 [77]. The outermost region of the P. brasiliensis cell wall comprises a thick layer of mannan [2]. This layer is believed to protect fungal cells from immunological recognition, hiding the main immunogenic molecules [78].…”

“…Paracoccidioidomycosis (PCM) is a systemic granulomatous human disease endemic in Latin America. It is caused by Paracoccidioides spp., a thermally-dimorphic fungus that presents as an infective mycelium in the environment, and it switches to a pathogenic yeast form in the mammalian host [1,2]. Its clinical manifestations occur in two distinct forms, acute or subacute and chronic [3], affecting mainly the lungs, but it is capable of spreading to other tissues [4,5].…”

Proteomic Response of Paracoccidioides brasiliensis Exposed to the Antifungal 4-Methoxynaphthalene-N-acylhydrazone Reveals Alteration in Metabolism

“…Conditions that offer nitrogen limitation to pathogens, a very common environmental stress, affect the virulence and antifungal susceptibility [ 41 ]. P. brasiliensis cells infect macrophages where carbon and nitrogen limitation are prevalent [ 42 ]. Interestingly, nitrogen availability influences the drug sensibility of pathogenic fungi, such as Cryptococcus neoformans , which showed high survivability and higher tolerance to amphotericin B on nitrogen cultures, as a way of adapting to this stress condition.…”

Extracellular Vesicles From Paracoccidioides brasiliensis Can Induce the Expression of Fungal Virulence Traits In Vitro and Enhance Infection in Mice

“…Paracoccidioides spp. still lack an efficient molecular strategy for targeted gene inactivation (Chaves et al, 2021) and studies on the biological role of individual genes are based on Agrobacterium tumefaciens-mediated transformation in conjunction with the antisense RNA technology to obtain mutants with low expression of the target genes (Sturme et al, 2011;Menino et al, 2012). Virulent P. brasiliensis samples kept in the laboratory through continuous subculturing in culture media tend to become attenuated in animal models, but are able to revert to their original pathogenic capacity upon one or more passages in mice and fungal recovery from infected organs (San-Blas et al, 1977;San-Blas et al, 1984;Zacharias et al, 1986;Castaneda et al, 1987;Brummer et al, 1990;Kashino et al, 1990).…”