Chromatin Chaperones in the Regulation of Fungal Virulence

Fungal infections are considered hidden killers of mankind, since more than 1.4 million individuals die from systemic fungal infections every year. The ageing population constitutes a major and ever-growing cohort at risk. Their dramatically increased susceptibility to fungal infections is a direct consequence of age-related decreasing immune-competence. The opportunistic Candida species (C. albicans, glabrata, auris) are the most prevalent human fungal pathogens. Candida pathogenicity is established by fungal gene regulators, but also by the quality of host immune surveillance and defense. In addition to gene regulators, histone-containing chromatin into which all genes are packaged, critically determine the outcome of fungal infections. Host immune surveillance can trigger epigenetic adaptations of fungal chromatin to engage gene regulators and chromatin modifications in altered chromatin states. This orchestrates adaptive fungal responses, which may promote pathogen fitness in the host, immune evasion, and even clinical drug resistance. Of note, genesis of adaptive chromatin states requires chaperones such as the so-called HIR complex. HIR also controls the activity and assembly of histone-containing nucleosomes, which are the smallest units of chromatin. Thus, HIR alters chromatin states by engaging histone-modifying enzymes such as lysine-deacetylases (KDACs)or lysine- acetyltransferases (KATs) that chemically modify nucleosomes. However, the molecular mechanisms of how HIR engages KDACs/KATs and gene regulators in the control of chromatin dynamics that affects fungal virulence, remains an enigma. Moreover, a comprehensive approach to address how the HIR chaperone operates under immune defense has not been conducted. Hence, the central hypothesis is that the fungal HIR complex can respond to host immune surveillance to modulate gene regulatory networks that determine fungal pathogenicity. Therefore, the project will address three major aims, and (i) determine the role of the HIR complex in fungal virulence and host inflammation in animal models, (ii) use next generation sequencing and proteomics to identify HIR-specific genetic regulatory networks and the mechanisms HIR uses to control fungal virulence, (iii) use mass spectrometry to identify regulatory factors as parts of the functional HIR chaperone complex. The results from this FWF project are expected to unravel mechanisms how genetic regulatory elements of fungal pathogens can be altered by the HIR chaperone in response to host immune defence so as to control fungal pathogenicity and immune evasion. 1

Fungal infections are considered hidden killers of mankind, since more 3-4 million individuals die from systemic fungal infections every year. The ageing population constitutes a major and ever-growing cohort at risk. Their dramatically increased susceptibility to fungal infections is a direct consequence of age-related decreasing immune-competence. The opportunistic fungal species such C. albicans, C. glabrata and especially C. auris are the most prevalent human fungal pathogens. Candida pathogenicity and virulence as well as antifungal drug resistance is established by regulators, but also by the quality of host immune defense. In addition to transcriptional regulators, the histone-containing chromatin into which all DNA is tightly packaged, critically determine the outcome of fungal infections. Host immune surveillance can trigger epigenetic adaptations of fungal chromatin to engage regulators and chromatin modifications to yield altered chromatin states that are linked to virulence as well as drug resistance. This orchestrates the adaptive fungal responses, which can promote pathogen fitness in the host, immune evasion, and even clinical drug resistance. Of note, adaptive chromatin states require chaperones such as the so-called HIR complex. HIR acts in concert with transcription to controls the activity and assembly of nucleosomes. Thus, HIR alters chromatin states by engaging histone-modifying enzymes such as lysine-deacetylases (KDACs) or lysine-acetyltransferases (KATs) that chemically modify nucleosomes. However, the molecular mechanisms of how HIR engages KDACs/KATs and gene regulators in the control of chromatin dynamics that affects fungal virulence, remains an enigma. Moreover, a comprehensive study to address how the HIR chaperone operates under immune defense has not been conducted. Hence, the central hypothesis is that the fungal HIR complex can respond to host immune surveillance to modulate gene regulatory networks that determine fungal pathogenicity as well as antifungal resistance. Therefore, the project will address three major aims, and (i) determine the role of the HIR complex in fungal virulence and host inflammation in animal models, (ii) use next generation sequencing and proteomics to identify HIR-specific genetic regulatory networks and the mechanisms HIR uses to control fungal virulence, (iii) use mass spectrometry to identify regulatory factors as parts of the functional HIR chaperone complex. The results from this FWF project are expected to unravel mechanisms how genetic regulatory elements of fungal pathogens can be altered by the HIR chaperone in response to host immune defence so as to control fungal pathogenicity and immune evasion. We do expect that the result will allow for improved therapeutic optiosn for the treatment of invasive infections by fungal pathogens.