Sepsis still constitutes an unmet clinical need, which could benefit from novel adjunctive strategies to conventional antibiotic therapy. The soluble form of the scavenger-like human CD6 lymphocyte receptor (shCD6) binds to key pathogenic components from Gram-positive and -negative bacteria, and shows time- and dose-dependent efficacy in mouse models of monobacterial sepsis. The objective of the present work was to demonstrate the effectiveness of infusing mouse and human sCD6 by different systemic routes, either alone or as adjunctive therapy to gold-standard antibiotics, in a lethal model of polymicrobial sepsis. To this end, C57BL/6 mice undergoing high-grade septic shock induced by cecal ligation and puncture (CLP, ≥90% lethality) were infused via i.p. or i.v. with shCD6 at different doses and time-points, either alone or in combination with Imipenem/Cilastatin (I/C, 33 mg/Kg/8h). Significant reduced mortality, pro-inflammatory cytokine levels and bacterial load was observed by i.p. infusion of a single shCD6 dose (1.25 mg/kg) 1h pre- or post-CLP. When using the i.v. route, mice survival was significantly extended by starting shCD6 infusion at later time-points post-CLP (up to +6h). Significant adjunctive effects on mouse survival were observed by i.p or i.v. infusion of shCD6 in combination with i.p I/C post-CLP. Similar results were obtained in mice expressing high sustained serum levels (5-10 μg/mL) of mouse sCD6 by means of transduction with hepatotropic adeno-associated virus (AAV). Taken together, the data support the conserved antibacterial effects of human and mouse sCD6, and its use as adjunctive therapy in experimental models of complex and severe polymicrobial sepsis.
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