Investigating distinct platelet populations and their function in immunopathology and hemostasis associated with sepsis.

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Platelets are critical in innate immunity and possess complex roles in responses to infections. Firstly, plateletsare critical for efficient leukocyte recruitment and activation in infected tissue (Clark et al. 2007; Amison et al2018), and augment antimicrobial activity of other immune cells (Tang et al. 2002). Secondly, platelets appearto possess a protective role against pathogen induced airway-vascular barrier disruption. Finally, plateletpathogeninteraction studies have suggested a direct anti-microbial role of platelets through either pathogeninternalisation or release of antimicrobial peptides e.g. cleaved peptides of PF-4, in addition to their role ininfection induced thrombosis (Youssefian et al. 2002; Shannon et al. 2015). Clinically, septic patients in theICU demonstrate thrombocytopenia that is recognised as a poor prognostic sign, with the level ofthrombocytopenia closely related to increased organ failure and mortality, potentially via sepsis inducedcoagulopathy (Venkata et al. 2013). In a recent UKRI funded project, metanalysis of published severeinflammatory response syndrome (SIRS) and sepsis datasets identified a pattern of gene expressionhighlighting platelet involvement in sepsis but not SIRS. Further validation work identified potential cellularsubgroups within both neutrophil and platelet populations, with 3 distinct platelet groups identified.Considering the multifaceted role of platelets in infections associated with sepsis, identification of specificbiomarkers such as CD41 & CD61 alongside MYL9 & CD274 provides potential insight as to the function ofthese different populations and their interactions with neutrophils potentially associated with diseaseprogression and patient survival (Tong et al. 2020).As these clinical studies only commenced upon ICU admission, it is important to identify and characterisethese distinct populations over the full time-course of sepsis associated infections difficult to achieve in clinicalstudies. Therefore, using animal infection models appropriate for early onset sepsis that reproduce both bloodmarkers of human sepsis and treatment efficacy, a complete time-course of both low and high grade infectionscan be modelled. Expertise from PHE will enable the PhD student to identify the distinct platelet populationspreviously identified in human patients that either survive or succumb to disease. Subsequent isolation andfunctional characterisation of these platelet populations will investigate their individual, specific roles withinthe immune response and hemostasis associated with sepsis. This requires an interdisciplinary approach,where the student will learn techniques in pharmacology/physiology (in vitro/ vivo assays) and Bioinformatics(parametric statistical and pathway analysis of RNA microarray data).