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

Abstract

AbstractRetrotransposon Gag-like (RTL) genes plays a variety of essential/important roles in the eutherian placenta and brain. It has recently been demonstrated thatRTL5andRTL6(akasushi-ichi retrotransposon homolog 8(SIRH8) andSIRH3) 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 thatRTL9(akaSIRH10) 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, inRtl9knockout 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,RTL5andRTL6responding to fungi, viruses and bacteria, respectively.Author SummaryWe have recently demonstrated thatRTL5andRTL6are microglial genes that play important roles in the brain’s innate immunity against viruses and bacteria. In this report, we demonstrate thatRTL9is functional in innate antifungal immunity in the brain becauseRtl9KO 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,RTL9is an antifungal therapy target as a newly identified member of innate antifungal immunity in eutherians.