Current Protein and Peptide Science - Volume 21, Issue 3, 2020

The cell wall that surrounds fungal cells is essential for their survival, provides protection against physical and chemical stresses, and plays relevant roles during infection. In general, the fungal cell wall is composed of an outer layer of glycoprotein and an inner skeletal layer of β-glucans or α- glucans and chitin. Chitin synthase genes have been shown to be important for septum formation, cell division and virulence. In the same way, chitin can act as a potent elicitor to activate defense response in several plant species; however, the fungi can convert chitin to chitosan during plant infection to evade plant defense mechanisms. Moreover, α-1,3-Glucan, a non-degradable polysaccharide in plants, represents a key feature in fungal cell walls formed in plants and plays a protective role for this fungus against plant lytic enzymes. A similar case is with β-1,3- and β-1,6-glucan which are essential for infection, structure rigidity and pathogenicity during fungal infection. Cell wall glycoproteins are also vital to fungi. They have been associated with conidial separation, the increase of chitin in conidial cell walls, germination, appressorium formation, as well as osmotic and cell wall stress and virulence; however, the specific roles of glycoproteins in filamentous fungi remain unknown. Fungi that can respond to environmental stimuli distinguish these signals and relay them through intracellular signaling pathways to change the cell wall composition. They play a crucial role in appressorium formation and penetration, and release cell wall degrading enzymes, which determine the outcome of the interaction with the host. In this review, we highlight the interaction of phypatophogen cell wall and signaling pathways with its host and their contribution to fungal pathogenesis.

By being the first point of contact of the fungus with the host, the cell wall plays an important role in the pathogenesis, having many molecules that participate as antigens that are recognized by immune cells, and also that help the fungus to establish infection. The main molecules reported to trigger an immune response are chitin, glucans, oligosaccharides, proteins, melanin, phospholipids, and others, being present in the principal pathogenic fungi with clinical importance worldwide, such as Histoplasma capsulatum, Paracoccidioides brasiliensis, Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Blastomyces dermatitidis, and Sporothrix schenckii. Knowledge and understanding of how the immune system recognizes and responds to fungal antigens are relevant for the future research and development of new diagnostic tools and treatments for the control of mycosis caused by these fungi.

The cell wall (CW) and plasma membrane are fundamental structures that define cell shape and support different cellular functions. In pathogenic fungi, such as Aspegillus fumigatus, they not only play structural roles but are also important for virulence and immune recognition. Both the CW and the plasma membrane remain as attractive drug targets to treat fungal infections, such as the Invasive Pulmonary Aspergillosis (IPA), a disease associated with high morbimortality in immunocompromised individuals. The low efficiency of echinocandins that target the fungal CW biosynthesis, the occurrence of environmental isolates resistant to azoles such as voriconazole and the known drawbacks associated with amphotericin toxicity foster the urgent need for fungal-specific drugable targets and/or more efficient combinatorial therapeutic strategies. Reverse genetic approaches in fungi unveil that perturbations of the CW also render cells with increased susceptibility to membrane disrupting agents and vice-versa. However, how the fungal cells simultaneously cope with perturbation in CW polysaccharides and cell membrane proteins to allow morphogenesis is scarcely known. Here, we focus on current information on how the main signaling pathways that maintain fungal cell wall integrity, such as the Cell Wall Integrity and the High Osmolarity Glycerol pathways, in different species often cross-talk to regulate the synthesis of molecules that comprise the plasma membrane, especially sphingolipids, ergosterol and phospholipids to promote functioning of both structures concomitantly and thus, cell viability. We propose that the conclusions drawn from other organisms are the foundations to point out experimental lines that can be endeavored in A. fumigatus.

Lectins are proteins characterized by their ability to specifically bind different carbohydrate motifs. This feature is associated with their endogenous biological function as well as with multiple applications. Plants are important natural sources of these proteins; however, only a reduced group was shown to display antifungal activity. Although it is hypothesized that the target of lectins is the fungal cell wall, the mechanism through which they exert the antifungal action is poorly understood. This topic is relevant to improve treatment against pathogens of importance for human health. In this context, mechanisms pointing to essential attributes for virulence instead of the viability of the pathogen emerge as a promising approach. This review provides the current knowledge on the action mechanism of plant antifungal lectins and their putative use for the development of novel active principles against fungal infections.

Sporothrix schenckii is one of the etiological agents of sporotrichosis, a fungal infection distributed worldwide. Both, the causative organism and the disease have currently received limited attention by the medical mycology community, most likely because of the low mortality rates associated with it. Nonetheless, morbidity is high in endemic regions and the versatility of S. schenckii to cause zoonosis and sapronosis has attracted attention. Thus far, virulence factors associated with this organism are poorly described. Here, comparing the S. schenckii genome sequence with other medically relevant fungi, genes involved in morphological change, cell wall synthesis, immune evasion, thermotolerance, adhesion, biofilm formation, melanin production, nutrient uptake, response to stress, extracellular vesicle formation, and toxin production are predicted and discussed as putative virulence factors in S. schenckii.

Fungal diseases are severe and have very high morbidity as well as up to 60% mortality for patients diagnosed with invasive fungal infection. In this review, in vitro and in vivo studies provided us with the insight into the role of Candida virulence factors that mediate their success as pathogens, such as: membrane and cell wall (CW) barriers, dimorphism, biofilm formation, signal transduction pathway, proteins related to stress tolerance, hydrolytic enzymes (e.g. proteases, lipases, haemolysins), and toxin production. The review characterized the virulence of clinically important C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei. Due to the white-opaque transition in the mating-type locus MTL-homozygous cells, C. albicans demonstrates an advantage over other less related species of Candida as a human commensal and pathogen. It was reviewed that Candida ergosterol biosynthesis genes play a role in cellular stress and are essential for Candida pathogenesis both in invasive and superficial infections. Hydrolases associated with CW are involved in the host-pathogen interactions. Adhesins are crucial in colonization and biofilm formation, an important virulence factor for candidiasis. Calcineurin is involved in membrane and CW stress as well as virulence. The hyphae-specific toxin, named candidalysin, invades mucosal cells facilitating fungal invasion into deeper tissues. Expression of this protein promotes resistance to neutrophil killing in candidiasis. The virulence factors provide immunostimulatory factors, activating dendric cells and promoting T cell infiltration and activation. Targeting virulence factors, can reduce the risk of resistance development in Candida infections.

The fungal genus Metarhizium has been used as an entomopathogen worldwide for approximately 140 years, and its mechanism of infection and its virulence factors have been studied. The present review is a compilation of virulence factors described in the literature to date and their participation in specific stages of the infection process.