Profiling, prototyping, and perturbing human immune responses

Abstract

Studies in animal models paved the way for the discovery of several basic mechanisms in immunology, but successful translation of these findings into clinical practice has been rare. Recent advances in biological methods and instrumentation allow the analysis and manipulation of limited quantities of human samples, shifting focus away from inbred mice and allowing an alternative research framework to emerge. This approach aims to ‘reverse-engineer’ the human response by finding disease-relevant biological phenomena through deep phenotyping of humans and using insight from patients to rationally design experimental models and perturbations. By devising systems that faithfully recapitulate human disease biology, this paradigm would enable the discovery of new immunological mechanisms in humans and narrow the translational gap between basic biological findings and their clinical application.

In this thesis, we describe the development of technologies that support this paradigm and the application of this research framework in the study of sepsis. We describe two technologies: one which enables cell-type specific transcriptomic profiling of human blood using an integrated fluidic circuit, and another which enables combinatorial chemical perturbation of human immune cells using droplet microfluidics. In addition, we apply this framework to identify immune phenotypes associated with sepsis and severe COVID-19, and develop an experimental system that models sepsis-induced emergency myelopoiesis using human cells.