and reciprocally promote their virulence factor secretion and pro-inflammatory effects.

BACKGROUND

Co-infections of and can significantly increase morbidity and mortality. However, the effect of co-existence on virulence factor secretion and pro-inflammatory effects remain elusive.

METHODS

We systematically investigated the virulence factors released by and under different culturing conditions using proteomics. We characterized their pro-inflammatory effects in macrophages with transcriptomics and gene set enrichment analysis.

RESULTS AND DISCUSSION

We showed that co-culturing of and promoted the secretion of 7 cytolytic, 11 proteolytic, and 3 lipolytic extracellular virulence factors (ECVFs) and impacted non-ECVFs, owing to Als1/Als3-mediated interactions, the presence of , or its pH maintenance. Co-culturing promotes hypha formation and β-glucan masking, suggesting that co-culturing enhances both invasion and immune evasion. Moreover, the secretome of co-culture increased pro-inflammatory pathways including promoting TNF-, NFKB-, and Toll-like receptor signaling pathways, as well as cytokine-cytokine receptor interactions in macrophages. Our findings support that and reciprocally promote their virulence potential and pro-inflammatory effects, which may provide mechanistic insights into the increased morbidity and mortality during their co-infection .