Sepsis is a systemic inflammatory response to infection while severe sepsis is characterised by organ dysfunction due to dysregulated immune response. Septic shock is the most severe form of sepsis and results in reduced organ perfusion. Severe sepsis is associated with 30% mortality rate while that in septic shock is 30-40%. Globally, there are ~50 million cases of sepsis per year leading to 11 million deaths, making it a significant public health burden. Early diagnosis and prompt treatment are the critical in the management of severe sepsis and septic shock. However, sepsis-specific predictive biomarkers and organ protective therapeutics remain elusive.
In this study, we comprehensively profiled human serum from 31 patients suffering with varying degrees of septic shock stratified by vasoactive infusion score and 10 healthy donors using the OlinkExplore HT panel marking its first application in Australia. This proximity ligation approach allowed for simultaneous quantification of ~5,300 proteins in human serum ranging fg/mL – mg/mL levels, overcoming the inherent sensitivity issues with conventional mass spectrometry-enabled serum proteomics.
Our analysis revealed a distinct proteomic signature differentiating sepsis from healthy serum, highlighting circulating organ stress markers consistent with multi-organ failure, including cardiac, brain, lung, kidney, and muscle atrophy markers. Using our human cardiac organoid model, we then demonstrated cardiac dysfunction is directly induced by the sepsis serum, correlating with the identified cardiac stress markers. To uncover predictive biomarkers for organ-specific and pan-organ failure we performed linear regression correlation analyses identifying secreted factors, such as cytokines, growth factors and metalloproteases associated with organ damage. Ongoing studies will assess the direct effect of these putative drivers on the relevant organs using human organoid models, to validate causal relationship and identify potential therapeutic interventions.