The LAMMER Kinase, LkhA, Affects Aspergillus fumigatus Pathogenicity by Modulating Reproduction and Biosynthesis of Cell Wall PAMPs

Abstract

The LAMMER kinase in eukaryotes is a well-conserved dual-specificity kinase. <i>Aspergillus</i> species cause a wide spectrum of diseases called aspergillosis in humans, depending on the underlying immune status of the host, such as allergy, aspergilloma, and invasive aspergillosis. <i>Aspergillus fumigatus</i> is the most common opportunistic fungal pathogen that causes invasive aspergillosis. Although LAMMER kinase has various functions in morphology, development, and cell cycle regulation in yeast and filamentous fungi, its function in <i>A. fumigatus</i> is not known. We performed molecular studies on the function of the <i>A. fumigatus</i> LAMMER kinase, <i>Af</i>LkhA, and reported its involvement in multiple cellular processes, including development and virulence. Deletion of <i>AflkhA</i> resulted in defects in colonial growth, production of conidia, and sexual development. Transcription and genetic analyses indicated that <i>Af</i>LkhA modulates the expression of key developmental regulatory genes. The <i>AflkhA</i>-deletion strain showed increased production of gliotoxins and protease activity. When conidia were challenged with alveolar macrophages, enodocytosis of conidia by macrophages was increased in the <i>AflkhA</i>-deletion strain, resulting from changes in expression of the cell wall genes and thus content of cell wall pathogen-associated molecular patterns, including β-1,3-glucan and GM. While T cell-deficient zebrafish larvae were significantly susceptible to wild-type <i>A. fumigatus</i> infection, <i>AflkhA</i>-deletion conidia infection reduced host mortality. <i>A. fumigatus Af</i>LkhA is required for the establishment of virulence factors, including conidial production, mycotoxin synthesis, protease activity, and interaction with macrophages, which ultimately affect pathogenicity at the organismal level.