Deletion of the Gene in Blocks Its Escape From Macrophage Clearance.

Macrophages provide the first-line defense against invasive fungal infections and, therefore, escape from macrophage becomes the basis for the establishment of invasive infection. Here, we found that deletion of (Δ/Δ) in resulted in a dramatic decrease from 69.2% (WT) to 1.2% in the escape rate . The effect of on macrophage clearance stands out among the genes currently known to affect clearance. In the normal mice, the Δ/Δ cells were undetectable in major organs 72 h after systemic infection, while WT cells persisted . However, in the macrophage-depleted mice, Δ/Δ could persist for 72 h at an amount comparable to that at 24 h. Regarding the mechanism, WT cells sustained growth and switched to hyphal form, which was more conducive to escape from macrophages, in media that mimic the glucose-deficient environment in macrophages. In contrast, Δ/Δ cells can remained viable but were unable to complete morphogenesis in these media, resulting in them being trapped within macrophages in the yeast form. Meanwhile, Δ/Δ cells were killed by oxidative stress in alternative carbon sources by 2- to 3-fold more than WT cells. Taken together, deletion prevents from escaping macrophage clearance, and therefore has a functional basis as a drug target that interferes with macrophage clearance.