Background: While most viral response studies have focused on adaptive immunity, to launch an infection, a virus must breach the epithelial barrier that protects our organs. We found that epithelial monolayers can rapidly eliminate rhinovirus, responsible for most common colds, by extruding cells. Importantly, these extruded virally-infected cells act as viral bombs that can infect fresh epithelia, but do not re-infect previously infected epithelia, suggesting a new type of epithelial-based learned innate immunity. Recent evidence that innate response can effectively protect mice without T- or B-cells, emphasizes the importance of this finding and suggests that we could boost learned innate immunity.
Rationale and aims: Here, we want to learn if epithelia eliminate SARS-CoV2 similarly by extrusion, yielding an infection-resistant monolayer in collaboration with Rui Galao. We have preliminary data suggesting that the original wave 1 SARS-CoV2 virus is eliminated by extrusion. Yet, evidence suggest that SARS-CoV2 variants of concern (VOCs) evolved mechanisms of innate immune evasion. To investigate this hypothesis, the student will be working with the Galao and Rosenblatt labs at KCL and the Crick to:
1) Test if epithelial eliminate various variants of SARS CoV2-infected cells by extrusion
2) Investigate if the remaining monolayer is resistant to further infections
3) If monolayer acquires learned innate immunity, does it apply to all variants?
Approach and objectives:
The student will learn: how to work with viruses safely, how to do extrusion assays in both live and fixed monolayers (Year 1), learn high resolution and live microscopy (all years), and transcriptomic approaches to investigate changes after infection (Year 2). Identify pathways for cells to protect themselves against infections, using knockdowns, inhibitors, and viral bomb assays (Year 3). The student will be expected to be self-motivated in learning techniques, reading literature, and networking to become an engaged and successful scientist.
