Conserved Bacterial-Binding Peptides of the Scavenger-Like Human Lymphocyte Receptor CD6 Protect From Mouse Experimental Sepsis

Abstract

Sepsis is an unmet clinical need constituting one of the most important causes of death worldwide, a fact aggravated by the appearance of multidrug resistant strains due to indiscriminate use of antibiotics. Host innate immune receptors involved in pathogen-associated molecular patterns (PAMPs) recognition represent a source of broad-spectrum therapies alternative or adjunctive to antibiotics. Among the few members of the ancient and highly conserved scavenger receptor cysteine-rich superfamily (SRCR-SF) sharing bacterial-binding properties there is CD6, a lymphocyte-specific surface receptor. Here, we analyze the bacterial-binding properties of three conserved short peptides (11-mer) mapping at extracellular SRCR domains of human CD6 (CD6.PD1, GTVEVRLEASW; CD6.PD2 GRVEMLEHGEW; and CD6.PD3, GQVEVHFRGVW). All peptides show high binding affinity for PAMPs from Gram-negative (lipopolysaccharide; Kd from 3.5 to 3,000 nM) and Gram-positive (lipoteichoic acid; Kd from 36 to 680 nM) bacteria. The CD6.PD3 peptide possesses broad bacterial-agglutination properties and improved survival of mice undergoing polymicrobial sepsis in a dose- and time-dependent manner. Accordingly, CD6.PD3 triggers a decrease in serum levels of both pro-inflammatory cytokines and bacterial load. Interestingly, CD6.PD3 shows additive survival effects on septic mice when combined with Imipenem/Cilastatin. These results illustrate the therapeutic potential of peptides retaining the bacterial-binding properties of native CD6.

The effect of host genetics on in vitro performance of bovine monocyte-derived macrophages

“…Gram-positive and negative bacteria display various sets of PAMP that consist of in-common and gram-specific PAMP. The gram-specific PAMP are recognized by different sets of pathogen recognition receptors (Mogensen, 2009;Martínez-Florensa et al, 2018). However, NO − is produced through a common pathway following activation of macrophages (Moretti and Blander, 2014;Rath et al, 2014).…”

CD6 deficiency impairs early immune response to bacterial sepsis

“…In addition, LPS binding to membrane-bound CD6 delivers MAPK pathway activation signals via Erk1/2 phosphorylation ( Sarrias et al., 2007 ). Bacterial MAMPs recognition by CD6 maps to short peptide sequences (11-mer long) at each SRCR domain ( Martínez-Florensa et al., 2018 ). Interestingly, infusion of either soluble CD6 protein or CD6-based peptides results in therapeutic effects in mouse models of monobacterial and polymicrobial sepsis ( Martínez-Florensa et al., 2014 , 2017 , 2018 ).…”

“…Bacterial MAMPs recognition by CD6 maps to short peptide sequences (11-mer long) at each SRCR domain ( Martínez-Florensa et al., 2018 ). Interestingly, infusion of either soluble CD6 protein or CD6-based peptides results in therapeutic effects in mouse models of monobacterial and polymicrobial sepsis ( Martínez-Florensa et al., 2014 , 2017 , 2018 ). On this basis, we hypothesize that CD6 + immune cells sense bacterial MAMPs and signal their functional status ( Lenz, 2009 ; Sarrias et al., 2007 ), defining a physiological role for CD6 in the host’s response to bacterial infection.…”

Soluble CD5 and CD6: Lymphocytic Class I Scavenger Receptors as Immunotherapeutic Agents

“…These sequences come from each of the three SRCR extracellular domains of CD6 and are homologous to the 11-mer consensus peptide identified in DMBT-1/SAG, which show bacterial binding properties [101]. Those CD6-derived peptides showed similar capabilities, though differing in their magnitude, regarding interaction with LPS and LTA, bacterial agglutination, and prevention of CLP-induced septic shock [100]. Consequently, these peptides offer cost-effective opportunities for developing new adjunctive alternatives to currently available sepsis treatment.…”

“…Recently, three short CD6-derived peptides have been identified and studied for its bacterialrecognition properties [100]. These sequences come from each of the three SRCR extracellular domains of CD6 and are homologous to the 11-mer consensus peptide identified in DMBT-1/SAG, which show bacterial binding properties [101].…”