Interrogating innate immunity pathways with massively parallel screens of pathogenic effectors

There are over 2,000 viruses, bacteria, and parasites that are pathogenic to humans. Although these pathogens are incredibly diverse, they have one thing in common: they all have to deal with the human host that is trying to prevent infection, attenuate symptoms, and get rid of the pathogen. Pathogens fight back by encoding proteins that interfere with these defenses and promote their own survival. For example, viruses encode non-structural proteins that promote viral survival and replication inside human cells, whereas many bacteria and parasites use elaborate secretion machines to introduce effector proteins into the host cell. We understand relatively well how some viruses (such as SARS-CoV-2 or HIV) and bacteria (such as E. coli or Salmonella) target the host cell, but most pathogenic proteins remain completely uncharacterized. In this project, we will take a systematic approach to study how pathogenic effector proteins modulate host cell functions. Instead of focusing on a single pathogen or protein and studying it using many different methods, we will characterize thousands of pathogenic effector proteins at the same time, using few (but scalable) methods. By individually expressing them in human cells, we will study how they interfere with key immune response pathways and how they hijack the human host cell for their own purposes. This approach enables us to study individual proteins from hundreds of different pathogenic viral, bacterial, and parasitic species at the same time. This work will reveal novel mechanisms by which pathogens wreak havoc in human cells, pinpoint human proteins that are common targets of pathogens, and potentially identify novel drug targets.