KSRP deficiency attenuates the course of pulmonary aspergil-losis, associated with elevated pathogen-killing activity of in-nate myeloid immune cells

The mRNA-binding protein KSRP (KH-type splicing regulatory protein) is known to modulate immune cell functions post-transcriptionally e.g. by reducing the mRNA stability of cytokines. It is known that KSRP binds AU-rich motifs (ARE) within the 3´-untranslated region of mRNA spe-cies, which in many cases encode dynamically regulated proteins like cytokines. Innate myeloid immune cells, such as polymorphonuclear neutrophils (PMN) or macrophages (MAC) eliminate pathogens by multiple mechanisms, including phagocytosis, as well as secretion of chemo- and cytokines. Here, we investigated the role of KSRP on the phenotype and functions of both innate immune cell types in mouse model of invasive pulmonary aspergillosis (IPA). Here, KSRP-/- mice showed lower levels of Aspergillus fumigatus conidia (AFC) and an increase in the frequencies of PMN and MAC in the lungs. Our results showed that PMN and MAC from KSRP-/- mice exhibited enhanced phagocytic uptake of AFC, accompanied by increased ROS production in PMN upon stimulation. As a comparison of RNA sequencing data revealed that 64 genes related to inflam-matory and immune responses were shared between PMN and MAC. The majority of genes up-regulated in PMN were involved in metabolic processes, cell cycle and DNA repair. In agreement, KSRP-deficient PMN displayed reduced levels of apoptosis. In conclusion, our results indicate that KSRP serves as a critical negative regulator of PMN and MAC anti-pathogen activity. Polymorphonuclear neutrophils (PMN) were purified from bone marrow of WT and KSRP-/- mice and were either treated with 1 µg/µl LPS for 6 h or left untreated. 1x10^6 cells of each samples were lysed and total RNA was purified for sequencing.