Streptococcal pyogenic exotoxin B (SpeB) boosts the contact system via binding of a-1 antitrypsin

TY - JOUR

T1 - Streptococcal pyogenic exotoxin B (SpeB) boosts the contact system via binding of a-1 antitrypsin

AU - Meinert Niclasen, Louise

AU - Olsen, Johan G

AU - Dagil, Robert

AU - Qing, Zhang

AU - Sørensen, Ole E

AU - Kragelund, Birthe B

PY - 2011/2/15

Y1 - 2011/2/15

N2 - The Streptococcus pyogenes cysteine protease SpeB (streptococcal pyrogenic exotoxin B) is important for the invasive potential of the bacteria, but its production is down-regulated following systemic infection. This prompted us to investigate if SpeB potentiated the host immune response after systemic spreading. Addition of SpeB to human plasma increased plasma-mediated bacterial killing and prolonged coagulation time through the intrinsic pathway of coagulation. This effect was independent of the enzymatic activity of SpeB and was mediated by a noncovalent medium-affinity binding and modification of the serpin A1AT (α-1 antitrypsin). Consequently, addition of A1AT to plasma increased bacterial survival. Sequestration of A1AT by SpeB led to enhanced contact system activation, supported by increased bacterial growth in prekallikrein deficient plasma. In a mouse model of systemic infection, administration of SpeB reduced significantly bacterial dissemination. The findings reveal an additional layer of complexity to host-microbe interactions that may be of benefit in the treatment of severe bacterial infections.

AB - The Streptococcus pyogenes cysteine protease SpeB (streptococcal pyrogenic exotoxin B) is important for the invasive potential of the bacteria, but its production is down-regulated following systemic infection. This prompted us to investigate if SpeB potentiated the host immune response after systemic spreading. Addition of SpeB to human plasma increased plasma-mediated bacterial killing and prolonged coagulation time through the intrinsic pathway of coagulation. This effect was independent of the enzymatic activity of SpeB and was mediated by a noncovalent medium-affinity binding and modification of the serpin A1AT (α-1 antitrypsin). Consequently, addition of A1AT to plasma increased bacterial survival. Sequestration of A1AT by SpeB led to enhanced contact system activation, supported by increased bacterial growth in prekallikrein deficient plasma. In a mouse model of systemic infection, administration of SpeB reduced significantly bacterial dissemination. The findings reveal an additional layer of complexity to host-microbe interactions that may be of benefit in the treatment of severe bacterial infections.

KW - Animals

KW - Bacterial Proteins

KW - Chemotaxis

KW - Exotoxins

KW - Humans

KW - Leukocytes, Mononuclear

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Protein Binding

KW - Streptococcal Infections

KW - Streptococcus pyogenes

KW - alpha 1-Antitrypsin

U2 - 10.1042/BJ20100984

DO - 10.1042/BJ20100984

M3 - Journal article

C2 - 21080914

SN - 0264-6021

VL - 434

SP - 123

EP - 132

JO - Biochemical Journal

JF - Biochemical Journal

IS - 1

ER -