New single‑cell technique reveals how tuberculosis‑like bacteria alter human cells

Using the new method, the researchers have shown how bacteria used to model tuberculosis (TB) infection influences the metabolism of the human cell. The findings could help to understand why some human cells are vulnerable to infection while others remain uninfected.

Tuberculosis remains the world’s leading cause of death by a single infectious agent and is caused by the bacterium Mycobacterium tuberculosis. These bacteria primarily reside in immune cells called macrophages, the very cells designed to destroy pathogens. However, not all macrophages become infected. Understanding why some cells never get infected, and why some are more susceptible, could lead to novel therapies to treat tuberculosis.

Seeing each cell’s metabolic ‘fingerprint’

Published in Analytical Chemistry, the study focused on developing methods sensitive enough to measure tiny concentrations of the by-products of metabolism in single human cells. This is done by selecting a single cell under a microscope and analysing it using a technique known as ‘liquid chromatography-mass spectrometry’ (LC-MS). This approach allows researchers to generate a metabolic ‘fingerprint’ – a unique pattern that can describe what processes are going on inside the cell.

Until now, most methods have either looked at bulk mixtures of human cells altogether or sorted cells into groups, which makes it impossible to see how cells affect their neighbours. With this new method, the researchers can use a microscope to selectively pick out and study individual infected and uninfected macrophages, while keeping them in their natural state and preserving knowledge of their location. This allows them to spot differences between these cells that were previously impossible to see.

The technique can also be used to map the location of cells in relation to their neighbours. This could pave the way for studies on how cells communicate with their surroundings and whether infected cells send warning signals to uninfected cells about the infection.

Such insights could help to uncover mechanisms behind infection and antimicrobial resistance and potentially guide the development of new treatments.

The team will now continue the research at the SEISMIC Facility based at King’s College London, which specialises in single cell studies.

This study was supported by the Doctoral College at the University of Surrey, Yokogawa Electric Corporation and grants from the Engineering and Physical Sciences Research Council (EPSRC) and the Biotechnology and Biological Sciences Research Council (BBSRC).