LAUSR

Significance Due to increased exposure to various infectious diseases, including COVID-19, there is an urgent need for novel drugs that reduce mortality from severe infectious diseases. Although current drugs can suppress pathogen reproduction, immune cell activation, and inflammatory cytokine functions, these cannot effectively reduce mortality from severe infectious diseases. In this study, we focused on the endothelial cell-specific protein Roundabout4 (Robo4) that ameliorates vascular permeability in inflammation. We demonstrated that Robo4 upregulation suppresses vascular permeability and mortality in severe infectious diseases. Moreover, we also demonstrated that small molecules which enhance Robo4 expression suppress vascular permeability and mortality. Our study thus characterizes a novel therapeutic strategy against severe infectious disease that targets vascular permeability.