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

Platelets are critical in innate immunity and possess complex roles in responses to infections. Firstly, platelets
are critical for efficient leukocyte recruitment and activation in infected tissue (Clark et al. 2007; Amison et al
2018), and augment antimicrobial activity of other immune cells (Tang et al. 2002). Secondly, platelets appear
to possess a protective role against pathogen induced airway-vascular barrier disruption. Finally, plateletpathogen
interaction studies have suggested a direct anti-microbial role of platelets through either pathogen
internalisation or release of antimicrobial peptides e.g. cleaved peptides of PF-4, in addition to their role in
infection induced thrombosis (Youssefian et al. 2002; Shannon et al. 2015). Clinically, septic patients in the
ICU demonstrate thrombocytopenia that is recognised as a poor prognostic sign, with the level of
thrombocytopenia closely related to increased organ failure and mortality, potentially via sepsis induced
coagulopathy (Venkata et al. 2013). In a recent UKRI funded project, metanalysis of published severe
inflammatory response syndrome (SIRS) and sepsis datasets identified a pattern of gene expression
highlighting platelet involvement in sepsis but not SIRS. Further validation work identified potential cellular
subgroups 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 specific
biomarkers such as CD41 & CD61 alongside MYL9 & CD274 provides potential insight as to the function of
these different populations and their interactions with neutrophils potentially associated with disease
progression and patient survival (Tong et al. 2020).
As these clinical studies only commenced upon ICU admission, it is important to identify and characterise
these distinct populations over the full time-course of sepsis associated infections difficult to achieve in clinical
studies. Therefore, using animal infection models appropriate for early onset sepsis that reproduce both blood
markers of human sepsis and treatment efficacy, a complete time-course of both low and high grade infections
can be modelled. Expertise from PHE will enable the PhD student to identify the distinct platelet populations
previously identified in human patients that either survive or succumb to disease. Subsequent isolation and
functional characterisation of these platelet populations will investigate their individual, specific roles within
the 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).