Retrovirus-derivedRTL9plays an important role in innate antifungal immunity in the eutherian brain

Retrotransposon Gag-like (RTL) genes plays a variety of essential/important roles in the eutherian placenta and brain. It has recently been demonstrated that RTL5 and RTL6 (aka sushi-ichi retrotransposon homolog 8 ( SIRH8 ) and SIRH3 ) are microglial genes that play important roles in the brain’s innate immunity against viruses and bacteria by their removal of double-stranded RNA and lipopolysaccharide, respectively. Here we demonstrate that RTL9 (aka SIRH10 ) also plays an important role, degrading fungal zymosan in the brain. The RTL9 protein is localized in the microglial lysosomes where incorporated zymosan is digested. Interestingly, in Rtl9 knockout mice expressing RTL9ΔC protein lacking the C-terminus retroviral GAG-like region, the zymosan degrading activity was lost, demonstrating that RTL9 is essentially engaged in this reaction, presumably via its GAG-like region. Together with our previous study, this result highlights the importance of three retrovirus-derived microglial RTL genes as eutherian-specific constituents of the current brain innate immune system, RTL9 , RTL5 and RTL6 responding to fungi, viruses and bacteria, respectively. Author Summary We have recently demonstrated that RTL5 and RTL6 are microglial genes that play important roles in the brain’s innate immunity against viruses and bacteria. In this report, we demonstrate that RTL9 is functional in innate antifungal immunity in the brain because Rtl9 KO mice lose zymosan degradation activity. Fungi are one of the most dangerous infectious pathogens, along with viruses, bacteria and protozoa. Phagocytic cells, such as microglia/macrophages, are essential for mounting a defense against fungal infection. As defects in these cells reduce host resistance to fungal infection, RTL9 is an antifungal therapy target as a newly identified member of innate antifungal immunity in eutherians.