The science of virology traditionally relies on the isolation and purification of particles, but cell-to-cell transmission of viruses can be crucial for pathogenesis. For example, the entire lymphatic phase of measles virus (MeV) infection depends on intercellular transmission. Our central hypothesis is that MeV spread within epithelia, and from epithelia to neurons, occurs mainly through infected cells that express nectins, rather than through viral particles. In aim 1 we will characterize the mechanisms of rapid MeV spread between airway epithelial cells. The hypothesis is that MeV co-opts cytoskeletal structures anchored to the cytoplasmic tail of its epithelial receptor nectin-4 (N4) to spread rapidly. In aims 2 and 3 we focus on a novel nectin-dependent process that may explain how, without needing a neural receptor, MeV infections reach neurons, an event that can prime the rare but always-lethal disease subacute sclerosing panencephalitis (SSPE). We discovered that cytoplasmic materials and MeV ribonucleocapsids are transferred from cells expressing N4 to cells expressing nectin-1, including neurons. In aim 2 we will characterize the cell biology of this novel process that we named nectin-elicited cytoplasm transfer (NECT). The hypothesis is that NECT cargo, including viral ribonucleocapsids, has to exit the endocytic pathway of acceptor cells to become functional. In aim 3 we present evidence that infected N4-expressing epithelial cells can transfer MeV to neurons, while viral particles cannot. The hypothesis is that NECT, rather than a receptor, accounts for MeV delivery to neurons. We also use the primary neuron culture system to characterize the genetic basis for MeV spread, modeling the next phase of SSPE.
|Effective start/end date||9/1/20 → 8/31/22|
- National Institute of Allergy and Infectious Diseases: $490,546.00
- National Institute of Allergy and Infectious Diseases: $520,046.00
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