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Visual illustration of inside of lungs infected with COVID.

A Nature Communications study led by Professor Ling-Pei Ho’s group in the MRC Translational Immune Discovery Unit (TIDU) provides new insights into how immune cells interact in the lungs of patients with severe COVID-19. 

In a damaged lung with a massive cell infiltrate, as seen with severe COVID-19 infection, it can be difficult to figure out which cells are involved in causing lung injury. Understanding this provides a first step to identifying the cells or pathways that can be targeted therapeutically. 

In this paper, the authors used a 35-antibody panel to provide a detailed immune landscape of lung biopsies from patients with fatal COVID-19 infection. Using a bespoke suite of mathematical tools, the authors uncovered a specific association between a highly inflammatory cluster of immature neutrophils, CD8 T-cells and regenerating lung stem cells in the most damaged areas of the lungs.

Neutrophils and T-cells are both types of immune cells. Neutrophils are part of the innate immune system and are one of the first responders in the immune response. T cells, on the other hand, are part of the adaptive immune system, providing a more specific response to infection than the neutrophils.

Circulating immature neutrophils are unusual but are known to be increased in the blood of patients with severe COVID-19. This study provides the first evidence of their presence in the lungs of those with severe COVID-19 and of their specific interaction with CD8 T-cells and lung stem cells. It highlights a potential role for immature neutrophils in lung injury and the possibility that this interferes with the ability of the lung to regenerate after severe viral infections. 

The study was a collaboration between immunobiologists in Oxford and the MRC TIDU, computer scientists at MRC WIMM Centre for Computational Biology and mathematicians at the Mathematical Institute. It demonstrates how mathematics combined with immunobiology and clinical understanding can be used to discover interactions and cellular networks which are otherwise impossible to see.

The authors provide an open-source computational pipeline called Spatial Omics Oxford Pipeline (SpOOx) and an enhanced version of a visual-analytical tool, Multi-Dimensional Viewer (MDV) software first developed at the WIMM, as a resource for spatial analysis. A brief overview is found in the video below:

Lead author Professor Ling-Pei Ho, co-lead of the NIHR Oxford Biomedical Research Centre (BRC) Respiratory Theme, said:

“This paper has been a testament to team science. It was an exciting time to see cellular patterns revealed by mathematical applications, which fitted biologically. Our next task is to tackle the functional side of this observation – how do immature neutrophil and CD8 T cells interact and what do they do to stem cells? We will expand these studies to other severe viral infections like influenza and severe lung diseases like idiopathic pulmonary fibrosis.”

Dr Praveen Weeratunga, one of the first authors, from MRC TIDU, said:

“This paper has the potential to have a wide reach. The  mathematical tools combined with precise and detailed identification of immune cells provides an unbiased method to uncover cellular connections in lung disease.”

Prof Helen Byrne from the Mathematical Institute and Ludwig Institute for Cancer Research said: 

"This work really highlights the benefits of multidisciplinary science: we came together as a new team, learned to speak each other’s languages and generated insight into lung disease that wouldn’t have been possible otherwise."

This work was funded by the MRC TIDU, CAMS Oxford Institute, Oxford Medical Science Division COVID funds, and NIHR Oxford BRC.

Read the full paper here.