Blood immune profiles reveal a CXCR3/CCR5 axis of dysregulation in early sepsis

Sepsis is defined as a systemic inflammatory host response syndrome after serious microbial infection, which requires prompt treatment to lower the risk of complications and death. However, early sepsis recognition can be a challenge at presentation when patients show symptoms difficult to distinguish from other acute conditions. We designed a pilot study to explore whether blood immune signatures could reveal early specific indicator profiles for patients meeting sepsis criteria upon admission at the hospital Emergency Department. We analysed blood samples from study-recruited sepsis-suspected patients (N=20) and of age-spanning healthy volunteers (N=12), using flow cytometry-based assays. 25 circulating inflammatory cytokines and chemokines (CCs) were measured from blood plasma, while freshly isolated unfixed blood leukocytes were immunophenotyped to ascertain major cell subsets representation and expression of activation markers, including chemokine receptors. We found that beside IL-6 and sCD14, blood levels of CXCL9 and CXCL10 (two ligands of CXCR3) show good separation between healthy controls and sepsis-suspected patients. The abundance of CD4+ T cells was significantly reduced while the expression of chemokine receptors was altered on monocytes, B and all T cells from patients. In particular, we report substantial losses of CCR5-expressing monocytes and CXCR3/CCR5 double positive T cells. Full dataset analysis and post-hoc subgrouping of patients according to their diagnosis on discharge (confirmed or unconfirmed sepsis), identified CXCR3/CCR5 double expression on T cells as a separating characteristic within the study. Overall, our observational study suggests a new CCR5 and CXCL9-10/CXCR3 axis of dysregulation in early sepsis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement this study was funded by the University of York and an Elsie May Sykes Research Award administrated by Research & Development at The York Hospital. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was sponsored by The York Teaching Hospital NHS Foundation Trust and received ethical approval from Yorkshire & The Humber - Leeds West Research Ethics Committee (REC reference 19/YH/0394) for IRAS project ID: 269597. The study also received local ethical approvals from the University of York Biology ethics committee (BEC) and the HYMS ethics committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors