Biomarkers in severe Staphylococcal infection

Abstract

Infections caused by Staphylococcus aureus (S. aureus) are often aggressive and can become life-threatening if not detected promptly. In critical care settings, timely diagnosis is essential; however, the biomarkers currently used in routine practice are often non-specific and insufficient for distinguishing S. aureus infection from other inflammatory conditions. This underscores the need for more specific and sensitive indicators that reflect the host’s immune response towards the infection, providing insights into the severity. My work focuses on investigating these indicators at a gene level and examining how their expression correlates with the severity of S. aureus-induced disease. Three key papers are included in this thesis, each focusing on a biomarker specifically correlating to septic arthritis (SA), severe sepsis and mortality due to S. aureus infection. Paper I investigate gene expression of S100 calcium-binding protein A8/A9 (S100a8/a9) in a murine model of S. aureus-induced septic arthritis. The study demonstrates an early and pronounced upregulation of S100a8/a9 gene expression, before on-set of clinical symptoms, suggesting its association with severity in septic arthritis. Paper II explores histocompatibility 2, D region locus Mb2 (H2-Dmb2) in a mouse model of S. aureus-induced severe sepsis. The study shows that H2-Dmb2 expression varies with sepsis severity and its downregulation is a suggestive indicator of worsening sepsis. Parallel observations for its human ortholog, human Leukocyte Antigen – DM Beta chain (HLA-DMB), in patient cohorts further support its clinical potential in studying sepsis progression. Paper III studies the gene marker, complement receptor -2 (Cr2) in a mouse model of S. aureus-induced severe sepsis that progresses to mortality. Among the molecular signatures identified, early and pronounced downregulation of Cr2 emerged as a distinct indicator of poor outcome. This early transcriptional decline suggests that Cr2 may help identify individuals at highest risk of rapid deterioration during staphylococcal sepsis. In conclusion, findings from both the preclinical data and the patient cohort, collectively highlight the potential of gene expression signatures associated with S. aureus-mediated septic arthritis and sepsis to improve early diagnosis. These in combination with existing markers may assist clinicians in guiding timely therapeutic decisions and improving outcomes in severe staphylococcal infections. Keywords: Staphylococcus aureus, S100a8/a9, septic arthritis, H2-Dmb2, HLA-DMB, sepsis, Cr2, mortality, gene expression, biomarker.