Grant: CIHR Fellowship

Single cell organisms are capable of resisting infection from pathogens using biological pathways that are contained entirely within the cell itself. Human cells are also capable of similar single-cell responses. However, the majority of research to date has focused on how the traditional human immune system as a whole prevents infection. Indeed, the cellular defense pathways operating in non-immune human cells of vital organ tissue, which make up the vast majority of the cell population of the body remain largely unknown. Here, I propose to conduct a loss-of-function screen for new pathways that control infection against microbial pathogens in cell-lines derived from human organ tissue. Specifically, I will focus on deciphering how human cells from the liver, small intestine, and brain are able to protect themselves from infection by the major global pathogens that cause malaria, typhoid, and toxoplasmosis respectively. Importantly, it is known that stimulation of these cell-types with cytokines, small proteins secreted by other infected cells, induce the expression of hundreds of new genes that are important for controlling infection. Therefore, I will knockout each of these cytokine-inducible genes in liver, gut, and brain cells using well-established technologies. The importance of each gene in resisting infection by the target pathogen will be evaluated by automated microscopy. I will then conduct more detailed analysis on the mechanism of action of each gene in in primary human or mouse cells. From a medical standpoint, such pathways represent an attractive target in the design of new antibiotics that mimic host effector functions rather than inhibiting microbial processes.