An integrated immune -omic approach to unravel the sepsis response

Thesis

Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection. There is major unmet clinical need given the burden of all cause sepsis accounting for 20% of global deaths, in addition to the COVID-19 pandemic where SARS-CoV-2 can lead to viral sepsis. Multiple dynamic host pathophysiological mechanisms exist but are aggregated under a single umbrella syndrome description, leading to substantial patient heterogeneity. This thesis examines the sepsis response through a lens of immune multi-omics, focusing on single-cell transcriptomics with additional proteomic profiling.

Data are presented for novel sepsis patient cohorts recruited under different clinical emphases, including patients with COVID-19 (n=78), influenza (n=12), and all-cause sepsis (n=63), and reanalysis of existing cohorts (n=667). The host response to severe infection is explored via bulk and single-cell transcriptomics (scRNA-seq), and proteomics either simultaneous to scRNA-seq i.e. single-cell multi-omics, or in isolation with CyTOF. Comparisons are made between severe infection/sepsis comparator groups, within groups across transcriptomic subphenotypes, and with healthy and post-cardiac surgery control patients.

The host transcriptomic response showed substantial commonality between COVID-19 viral sepsis and all-cause sepsis although immunoglobulin pathways and the interferon response were elevated in COVID-19. The sepsis response signature (SRS) transcriptomic subphenotyping proved consistent in both cohorts, suggesting its utility as a unifying framework to view the host respnose to severe infection. At single-cell resolution, transcriptomics and cell surface proteomics of peripheral blood mononuclear cells revealed common and distinct aspects of the response to severe infection across cell types such as classical monocytes and CD4+ T cells, with a specific COVID-19 signature uncovered in the form of AP-1 pathway elevation. The basis of SRS was then dissected, revealing that SRS derived mostly from neutrophils with a minor contribution from PBMCs. Sepsis neutrophils displayed immunosuppressive properties, in particular SRS1 neutrophils, suggesting a potential role in sepsis pathogenesis.

Collectively, the work presented in this thesis advances our understanding of the host response to severe infection in terms of the cellular and molecular bases of the sepsis response. This biological understanding highlights potential therapeutic opportunities as we move toward a personalized infectious disease medicine in sepsis and beyond.

Authors: Kwok, AJ

• DOI: 10.5287/ora-n19bkqrn4
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English