Aspergillus fumigatus is a saprotrophic fungus widespread in the environment and the most common opportunistic aerial fungal pathogen, causing allergic and chronic lung pathologies including the fatal invasive aspergillosis in immunocompromised patients. To date, the options against A. fumigatus infections are limited. Moreover, there is an increased A. fumigatus resistance to antifungals due to antifungal prophylaxis, therapeutic regimens, and abusive usage of fungicide in agriculture.
New therapeutic strategies, which aim to limit and fight the infection without inducing resistance, are needed. Epigenetic modifications regulate the fungal phenotype and therefore also the formation of the biofilm and the production of virulence factors. A. fumigatus can evade and adapt to the host by forming biofilm and producing molecules as melanin. Biofilm is resistant to antifungals. Melanin, a pigment present on the wall of conidia, makes the conidia resistant to extreme environmental conditions, and host phagocytosis.
The goal of this research is to identify epigenetic modulators that can alter the expression of virulence factors, that increase the diffusion and cause disease in humans, without killing the fungus in order not to alter the host environment balance and not to cause resistance. This study will be to evaluate the anti-virulence activity of different synthetic epigenetic modulators such as UMONJY inhibitor (IOX-1), bromodomain and extra terminal inhibitor (JQ-1), DNA methyltransferase-1 inhibitor (MC3343), enhancer of zeste homolog 2 inhibitor (tazemetostat), histone deacetylase inhibitors (SAHA, MC 1855, MC 2189, MC 1568, MC1716, MC 1714), acetyltransferase inhibitors (anacardic acid, MC 2580). In particular, their activity will be evaluated on the production of melanin, on biofilm formation in vitro. Moreover, larvae of Galleria mellonella will be used as an in vivo model to study the activity of epigenetic modulators on the virulence of A. fumigatus.
To date, antifungal therapy against A. fumigatus involves the inhibition of the growth or killing of the fungus.
An innovative strategy could be to inhibit Aspergillus virulence factors linked to the diffusion, resistance, and formation of the biofilm. The study of the activity of epigenetic modulators against A. fumigatus could lead to the identification of the new targets and new therapeutic strategies that do not lead to the elimination of the fungus but only to the reduction of virulence factors. Moreover, these studies could give new information about epigenetic mechanisms in Aspergillus. About epigenetic mechanisms, most of the studies have focused on mammalian systems and only a few mechanisms on fungal epigenetics have been studied. Furthermore, the study focused almost entirely on yeasts. Fungi kingdom has over 1 million species. Therefore, research into this realm has barely scratched the surface (Madhani. Unbelievable but True: Epigenetics and Chromatin in Fungi. Trends in Genetics. 2020).
The results obtained could pave the way towards the study of a new therapeutic strategy. This approach would allow to reduce the diseases caused by A. fumigatus and would not alter the beneficial role that Aspergillus has in the various environmental niches. Collectively, these findings suggest that epigenetic modulation of virulence factors may be a promising approach for the development of new agents to prevent or treat A. fumigatus infection.