Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

Petrlova, JitkaDepartment of Clinical Sciences, Division of Dermatology and Venereology, Lund Universit (författare)

Thrombin-derived C-terminal peptides (TCPs), including a major 11-kDa fragment (TCP96), are produced through cleavage by human neutrophil elastase and aggregate lipopolysaccharide (LPS) and the Gram-negative bacterium Escherichia coli. However, the physiological roles of TCP96 in controlling bacterial infections and reducing LPS-induced inflammation are unclear. Here, using various biophysical methods, in silico molecular modeling, microbiological and cellular assays, and animal models, we examined the structural features and functional roles of recombinant TCP96 (rTCP96) in the aggregation of multiple bacteria and the Toll-like receptor (TLR) agonists they produce. We found that rTCP96 aggregates both Gram-negative and Gram-positive bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa, and their cell-wall components LPS, lipid A, and lipoteichoic acid (LTA). The Gram-negative bacteria E. coli and P. aeruginosa were particularly sensitive to aggregation-induced bacterial permeabilization and killing. As a proof of concept, we show that rTCP96 reduces LPS-induced NF-κB activation in human monocytes, as well as in mouse models of LPS-induced subcutaneous inflammation. Moreover, in a mouse model of subcutaneous inoculation with P. aeruginosa, rTCP96 reduced bacterial levels. Together, these results link TCP-mediated aggregation of endotoxins and bacteria in vitro to attenuation of inflammation and bacterial levels in vivo.

Petruk, GannaDepartment of Clinical Sciences, Division of Dermatology and Venereology, Lund University, Lund SE-22184, Sweden (författare)
Huber, Roland G.Bioinformatics Institute (A*STAR), Singapore SG-138671 (författare)
McBurnie, Eilish W.Bioinformatics Institute (A*STAR), Singapore SG-138671; Department of Chemistry, University of Southampton, Southampton UK-SO17 1BJ, United Kingdom (författare)
van der Plas, Mariena J.A.Department of Clinical Sciences, Division of Dermatology and Venereology, Lund University, Lund SE-22184, Sweden; Department of Pharmacy, University of Copenhagen, Copenhagen DK-2100, Denmark (författare)
Bond, Peter J. (författare)
Puthia, ManojDepartment of Clinical Sciences, Division of Dermatology and Venereology, Lund University, Lund SE-22184, Sweden (författare)
Schmidtchen, ArturDepartment of Clinical Sciences, Division of Dermatology and Venereology, Lund University, Lund SE-22184, Sweden; Department of Biomedical Sciences, Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen DK-2400, Denmark (författare)
Department of Clinical Sciences, Division of Dermatology and Venereology, Lund UniversitDepartment of Clinical Sciences, Division of Dermatology and Venereology, Lund University, Lund SE-22184, Sweden (creator_code:org_t)

Ingår i:Journal of Biological Chemistry: Elsevier295:11, s. 3417-34300021-92581083-351X

Av författaren/redakt...: Petrlova, Jitka; Petruk, Ganna; Huber, Roland G.; McBurnie, Eilish ...; van der Plas, Ma ...; Bond, Peter J.; visa fler...; Puthia, Manoj; Schmidtchen, Art ...; visa färre...

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