<b>The immunomodulatory effects of sodium new houttuyfonate on different states of macrophage against </b><b><i>Aspergillus fumigatus</i></b><b> infection via distinct mechanism in invasive pulmonary aspergillosis</b>

Invasive pulmonary aspergillosis (IPA) is usually caused by <i>Aspergillus fumigatus</i> infection and associated with high morbidity and mortality in immunocompromised patients. Sodium new houttuyfonate (SNH) has antifungal and immunomodulatory properties, but the therapeutic effect against IPA remains unknown. In this study, intraperitoneal injection of SNH had a therapeutic effect in mice with IPA, as determined by histopathological analysis and measurements of fungal loads. Further investigation confirmed that the therapeutic effect of SNH was closely related to recruitment of neutrophils and T cells to the infection site in IPA mice. Moreover, SNH at 8 μg/mL significantly enhanced the ability of mouse alveolar macrophages (MH-S cells) to phagocytize and kill <i>A. fumigatus</i> conidia. In addition, transcriptomics, real-time quantitative polymerase chain reaction, and molecular docking analyses confirmed that membrane receptor toll like receptor 2 (TLR2) regulated the expression of genes associated with inflammation and chemokine production in MH-S cells. Moreover, SNH increased antifungal activity of MH-S cells to <i>A. fumigatus</i> via the TLR2/TRAF6/IRF5 and TLR2/TRAF6/ERK axes, respectively. MicroRNA sequencing and miRNA_mRNA interaction analyses found that SNH inhibited expression of miR-328-5p and miR-6975-3p in MH-S cells, which negatively regulated TLR2 expression and the phagocytosis and killing functions of MH-S cells. Taken together, these findings clarify the potential immunomodulatory mechanism of SNH for treatment of IPA, suggesting that SNH is effective against<i> A. fumigatus</i> infection.