The overarching goal of the Jost lab is to define the molecular mechanisms of host-microbiome communication using a combination of systematic CRISPR technologies, physiological cell models such as organoids, and an interdisciplinary set of targeted approaches.
Microbiome biology is fascinating. Sweeping efforts over the past decades have provided a catalog of the microbes in the human microbiome – we know who’s there – and revealed a staggering extent of communication between these microbes and the human host: these microbes are essential for immune system development, impact how much we eat and how many calories we extract, and change our behavior. This communication is a fundamental aspect of human biology and dysregulation can trigger diseases in every organ.
At the same time, we do not understand many of the mechanisms underlying this communication: which microbes cause these phenomena? What molecules do they produce to do so and which receptors do these molecules bind? How does such binding change immune responses or the rate of fat burning or the activities of neurons? And what happens when communication goes awry? The Jost lab will address these questions using state-of-the-art CRISPR technologies such as CRISPR screens and perturb-seq in cell lines, primary cell models, and organoids. Using these technologies, we can interrogate, rapidly and at large scale, how deletion, overexpression, or mutation of genes in both microbes and human cells changes a given microbiome-driven phenotype. Such systematic and reciprocal genetic approaches are ideally suited to connect specific species and molecules to host pathways – to define the language of communication.
We can probe, for example, how recognition of chemical structures on the surfaces of microbes by immune receptors allows immune cells to mount specific responses to individual microbes, how human cells parse the complex molecular repertoire of the microbiome, which likely falls outside the scope of classical “one molecule-one receptor” models of signal transduction, and how gut microbes affect systemic processes by interfacing with endocrine cells in the gut epithelium. The resulting mechanistic insight will be essential for the development of therapeutics targeted at microbiome-associated diseases and more broadly, given how fundamentally the microbiome affects human physiology, such investigations are bound to uncover exciting basic biology.
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