Understanding mechanisms of pulmonary phenotypes in pneumonia

Summary

Pneumonia is the leading infectious disease killer worldwide, responsible for an estimated 2.5 million deaths a year. Death is driven by the host response to infection, triggering life-threatening organ failure that persists after the precipitating insult has been removed.  Despite the significant burden of global disease, the underlying pathophysiology of severe pneumonia remains poorly understood.  

My group has recently identified mechanistically distinct endotypes in severe pneumonia (termed ‘pneumotypes (Pn)’). These ‘pneumotypes’ are underpinned by changes in cellular frequency and apparent phenotype, but to date have relied on bulk RNA sequencing and conventional cytology for their understanding.

Project aims

The aim of the proposed project is to understand these pneumotypes in more detail, refining the understanding of the underpinning mechanisms and seeking to identify potential therapies.

The project will use a range of clinical samples from patients with pneumonia, using samples of lung and blood immune cells.  

Alongside this peripheral blood cells from healthy donors will be used to establish baseline features, and to allow in-vitro manipulation of cells. These will be analysed using well established techniques in my lab.

The project consists of two parts:

Part 1 - Deep phenotyping of the lungs of patients with severe pneumonia. 

  • Using single-cell profiling (RNA sequencing and high dimensional flow cytometry) to evaluate the cellular identity, subgroups and transcriptional programmes that underpin each of the identified pneumotypes, and to establish the relationship between peripheral blood and pulmonary neutrophil maturity status.  
  • Identification of the frequency of circulating haematopoietic stem cells (HSCs) in the peripheral blood and how this relates to pneumotypes identified in the lungs.

Part 2 - Understanding the role of HSCs in developing and sustaining pneumotypes. 

  • Using enrichment techniques to identify and isolate HSCs from patients with pneumonia compared to control donors without pulmonary inflammation to allow epigenetic phenotyping, anticipating a skewing towards emergency granulopoeisis in the HSCs.
  • Ex-vivo differentiation of neutrophils from circulating HSCs to understand the effects of epigenetic changes on neutrophil function and dysfunction.

Contact details

Dr Andrew Conway Morris - ac926@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

  • PhD