Although copper is required for many eukaryotic functions including enzymatic activity, its role in fungal drug resistance is not direct. In fungi, the conversion of

Melanin inuences the host’s immunological response by reducing the susceptibil­ity of the pathogen and increases the virulence of fungi (Nosanchuk etal. 2015). Melanin is a dark brown pigment produced by some fungal species through the oxidative polymerization of phenolic substances such as glutaminyl-3,4­dihydroxybenzene (GDHB), catechol, 1,8-dihydroxynaphthalene (DHN), and 3,4-dihydroxyphenylalanine (DOPA) (Eisenman et al. 2009). This pigment is known as ‘fungal armour’ because it protects the fungus from harmful conditions by scavenging oxidants produced in response to stress. Other biological effects of mel­anin include thermoregulation, radio- and photoprotection, antibacterial activity, phagocytosis, cytotoxicity, antiviral activity, anti-inammation, and immunomodu­lation (Fig.7.5) (Pombeiro-Sponchiado etal. 2017). One of the most intensively researched melanization pathogens is C. neoformans. C. neoformans differs from other pathogenic fungi in that it uses only the L-DOPA pathway and does not require foreign phenolic substrates to produce melanin. Melanin is responsible for 14% of total pathogenicity. This makes it the second most important virulence component of C. neoformans after the polysaccharide capsule. In C. neoformans, melanization takes place in special vesicles known as melanosomes (Eisenman etal. 2009). The virulence and survival of C. neoformans in macrophages are associated with a lac­case that has been shown to synthesize melanin. Since laccase production is con­trolled by the LAC1 and LAC2 genes, the ability of C. neoformans to survive in macrophages decreases when both genes are removed (Missall etal. 2005). During co-incubation with macrophages, melanin increases the survival of C. neoformans. Studies show that melanized C. neoformans cells in the lung and brain of mice have a greater fungal burden than non-melanized cells. Compared to non-melanized cells, melanized cells can survive longer in phagolysosomes (Baker and Casadevall

Heat shock proteins (HSPs) are proteins that exhibit upregulation in response to stress induction and temperature change and those that show a high sequence simi­larity to recognized categories of HSPs (Chatterjee and Tatu 2017). During infec­tion, human fungal pathogens are subjected to several conditions, including exposure to the host’s body temperature and immune system. Hsp90 and Hsp70 strongly favour the morphological alterations necessary for virulence, resistance to antifun­gal drugs, and thermotolerance (Fig. 7.2) (Horianopoulos and Kronstad 2021). Hsp90in C. albicans is crucial for temperature-dependent morphological changes at 37°C and for the organism to tolerate echinocandins. Transcriptional repression of Hsp90 leads to an impaired yeast-to-hyphae transition in C. albicans and deletion of HSP90 (Δhsp90) also leads to reduced virulence (Shapiro etal. 2009). Hsp90 similarly plays an important role in cell wall integrity in A. fumigatus by interacting with the kinases MpkA and PkcA as well as RlmA.Inhibition of Hsp90 impairs cell integrity and renders A. fumigatus thermosensitive (Rocha etal. 2021). Chemical inhibition of Hsp90in C. neoformans revealed its importance for capsule develop­ment, thermotolerance at 37 and 39°C, tolerance to antifungal drugs, and virulence in a Caenorhabditis elegans model (Chatterjee and Tatu 2017).

Fig. 7.5 Pathogenic role of melanization on fungal cells