The role of mitogen-activated protein kinase (MPKA) MpkA in regulating gliotoxin production in Aspergillus fumigatus.

Abstract

Aspergillus fumigatus is a filamentous fungus and an important opportunistic pathogen and mammalian allergen. It is responsible for approximately 65% of all invasive fungal infections in humans, and also the main species related to lung infections. The importance of infections by this fungus is reflected by a series of reviews that have been published in recent years on its biology and pathology, in addition to a great effort that has been made to identify the virulence factors of this pathogen. Among these factors, secondary metabolites stand out, once they are secreted during infection, generally considered to be the front line virulence factors, and cause suppression of the host's immune functions. Gliotoxin (GT) is the main, most abundant and most potent secondary metabolite produced by A. fumigatus. It exhibits a diverse range of biological effects, including a potent intracellular redox activity, which leads to an imbalance in homeostasis and severe oxidative stress in human cells. The regulation of its biosynthesis is a hierarchical, multifactorial process, which is highly integrated in the metabolism of A. fumigatus, and some studies point to the involvement of the G protein-coupled receptor (GPCR, GprK) and the pathways of MAP kinases, more specifically for the mitogen-activated protein kinase (MPKA) MpkA. Our research group has generated extremely relevant data in the areas of A. fumigatus biology, mainly in the understanding of MAP kinase-mediated cell signaling of the pathogen. In addition, recently, we identified 16 new transcription factors with possible involvement in gliotoxin biosynthesis, since the null mutants for these genes showed sensitivity to gliotoxin. In addition, some of them obtained altered production of gliotoxin and bisdethiobis(methylthio)GT , suggesting an important role of these FTs in the biosynthesis of GT and also in the mechanism of self-protection of GT in A. fumigatus. In this context, exploring a putative mechanism for regulating GT production via GprK-MpkA-FTs, checking a probable connection between GprK and MpkA, and verifying a possible involvement of MpkA in the expression of the identified FTs and their role in the GT biosynthesis and self-protection will be of great importance for a deeper understanding of the establishment of the virulence and infection program in A. fumigatus.