title: Protective Effects of Human and Mouse Soluble Scavenger-Like CD6 Lymphocyte Receptor in a Lethal Model of Polymicrobial Sepsis.
abstract: 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 the intraperitoneal (i.p.) or intravenous (i.v.) route with shCD6 at different doses and time points, either alone or in combination with imipenem/cilastatin (I/C) at a dose of 33 mg/kg of body weight every 8 h. Significantly reduced mortality and proinflammatory cytokine levels were observed by i.p. infusion of a single shCD6 dose (1.25 mg/kg) 1 h 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 6 h after CLP). 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 levels (5 to 10 μg/ml) of mouse sCD6 in serum 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 their use as adjunctive therapy in experimental models of complex and severe polymicrobial sepsis.
authors.affiliation: Grup d'Immunorreceptors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz (CEK), Barcelona, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Martínez-Florensa
authors.affiliation: Grup d'Immunorreceptors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz (CEK), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Consuegra-Fernández
authors.affiliation: Grup d'Immunorreceptors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz (CEK), Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Aranda
authors.affiliation: Grup d'Immunorreceptors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz (CEK), Barcelona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Armiger-Borràs
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain.
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Scala
authors.affiliation: Grup d'Immunorreceptors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz (CEK), Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Carrasco
authors.affiliation: Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Pachón
authors.affiliation: Servei de Microbiologia, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Vila
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
authors.affiliation: Grup d'Immunorreceptors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz (CEK), Barcelona, Spain flozano@clinic.ub.es.|Servei d'Immunologia, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Barcelona, Spain.|Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Francisco
authors.identifier: 0000-0003-1119-4368
authors.initials: F
authors.lastname: Lozano
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D002432:Cecum / Q000293:injuries; D015377:Cilastatin / Q000627:therapeutic use*; D000077728:Cilastatin, Imipenem Drug Combination; D016207:Cytokines / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004338:Drug Combinations; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D015378:Imipenem / Q000627:therapeutic use*; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051116:Receptors, Scavenger / Q000378:metabolism; D018805:Sepsis
chemical_list: D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C062279:CD6 antigen; D016207:Cytokines; D004338:Drug Combinations; D051116:Receptors, Scavenger; D015377:Cilastatin; D015378:Imipenem; D000077728:Cilastatin, Imipenem Drug Combination
keywords: adjunctive therapy; cecal ligation and puncture; polymicrobial peritonitis; scavenger receptors; sepsis; septic shock; soluble CD6