Transferrin Receptor Protein 1 Is an Entry Factor for Rabies Virus

Rabies virus (RABV) is a prototypical neurotropic virus that causes rabies in human and animals with an almost 100% mortality rate. Once RABV enters the central nervous system, no treatment is proven to prevent death. RABV glycoprotein (G) interacts with cell surface receptors and then enters cells via clathrin-mediated endocytosis (CME); however, the key host factors involved remain largely unknown. Here, we identified transferrin receptor 1 (TfR1), a classic receptor that undergoes CME, as an entry factor for RABV. TfR1 interacts with RABV G and is involved in the endocytosis of RABV. An antibody against TfR1 or the TfR1 ectodomain soluble protein significantly blocked RABV infection in HEK293 cells, N2a cells, and mouse primary neuronal cells. We further found that the endocytosis of TfR1 is coupled with the endocytosis of RABV and that TfR1 and RABV are transported to early and late endosomes. Our results suggest that RABV hijacks the transport pathway of TfR1 for entry, thereby deepening our understanding of the entry mechanism of RABV. IMPORTANCE For most viruses, cell entry involves engagement with many distinct plasma membrane components, each of which is essential. After binding to its specific receptor(s), rabies virus (RABV) enters host cells through the process of clathrin-mediated endocytosis. However, whether the receptor-dependent clathrin-mediated endocytosis of RABV requires other plasma membrane components remain largely unknown. Here, we demonstrate that transferrin receptor 1 (TfR1) is a functional entry factor for RABV infection. The endocytosis of RABV is coupled with the endocytosis of TfR1. Our results indicate that RABV hijacks the transport pathway of TfR1 for entry, which deepens our understanding of the entry mechanism of RABV.