This exciting and topical iCASE studentship aims to characterise the different contributions of distinct platelet subpopulations identified from septic patients in both hemostasis and the immune response to respiratory infections associated with sepsis, using human data acquired from prior and current clinical studies and through the use of animal models. It is made possible through a stimulating collaboration between King’s College London and Public Health England.
Sepsis is a life-threatening condition of organ dysfunction caused by a dysregulated yet complex host response to infection consisting of an initial hyperinflammatory response to pathogenic infection, and a secondary protracted immunosuppressive phase that can extend for significant periods post recovery. Therefore, any therapeutic interventions in sepsis are both mechanism specific and time-critical. Consequently, a greater understanding of the immune pathology at each of these stages of sepsis is urgently required.
Platelets provide a undefined, yet complex role in in the innate immune responses to infection. Whilst their contributions to infection induced thrombosis is more widely understood, we have shown that platelets are also critical for efficient leukocyte recruitment and activation in infected tissue (Amison et al 2018). Furthermore, research has implicated a protective role of platelets against pathogen induced airway-vascular barrier disruption as well as direct anti-microbial roles of platelets through either pathogen internalisation or by the release of antimicrobial peptides (Youssefian et al. 2002; Shannon et al. 2015). The importance of platelets in the immune response to infections is also replicated clinically where septic patients in the ICU demonstrate a systemic thrombocytopenia that is recognised as a poor prognostic sign, with the level of thrombocytopenia correlating closely to increased organ failure and mortality.
Our collaborators at Public Health England recently identified a pattern of gene expression highlighting platelet involvement in sepsis through a metanalysis of published severe inflammatory response syndrome (SIRS) and sepsis datasets (Tong et al 2020). They subsequently identified potential cellular groups within both neutrophil and platelet populations, with 3 distinct platelet populations detected. The use of animal infection models appropriate for early onset sepsis capable of reproducing the human phenotype will enable the characterisation of these platelet populations across the complete time-course of sepsis associated infections which is difficult to achieve in the clinical setting. To date the functionality of these platelet populations in septic patients and how they may be associated with the immune pathology of sepsis remains unclear. Therefore the analysis of these populations in both clinical patients and animal models provides a unique opportunity to assess the functionality of these platelets and their interactions with immune cells including neutrophils and their association with both disease progression and patient survival to identify immunomodulatory mechanisms suitable for potential for therapeutic intervention.
This 4-year PhD project relies on the experience and techniques made available to the student through the research staff of the Sackler Institute of Pulmonary Pharmacology at King’s College London who have led international research efforts on the non-haemostatic functions of platelets, and of Public Health England (PHE) under the supervision of Dr Richard Amison and Dr Karen Kempsell. In year 1 of the project at KCL, it is anticipated that the student will learn the necessary in vivo skills to develop animal models of pulmonary infection appropriate for sepsis that are required to characterise the full-time course of the infection, whilst also learning the relevant in vitro and ex vivo assays of platelet isolation, phenotype analysis and functional assays. During a placement opportunity with PHE in year 2 the student will gain understanding in the use of data mining to examine gene expression data using parametric statistical and pathway analyses. This will be required for the detailed characterisation of platelet populations in both clinical data and the aforementioned animal models. During years 3 and 4 (both at KCL and PHE) the student will use techniques acquired in the first two years of the project, alongside additional techniques including advanced cell isolation protocols such as immunomagnetic cell separation. This will enable the isolation of individual platelet populations from in vivo studies and subsequent functional analysis allowing the characterisation of their potential immunomodulatory and antimicrobial capabilities. The identification and isolation of distinct platelet populations will be of internationally significant impact, and this data will form the basis of fundamentally new hypotheses with regard to platelet science.