Streptococcus pyogenes Phospholipase A2 Induces the Expression of Adhesion Molecules on Human Umbilical Vein Endothelial Cells and Aorta of Mice.

Masataka Oda,Hisanori Domon,Shigetada Kawabata,Yutaka Terao,Toshihito Isono,Mie Kurosawa,Masaya Yamaguchi,Tomoki Maekawa

doi:10.3389/fcimb.2017.00300

Abstract

The Streptococcus pyogenes phospholipase A2 (SlaA) gene is highly conserved in the M3 serotype of group A S. pyogenes, which often involves hypervirulent clones. However, the role of SlaA in S. pyogenes pathogenesis is unclear. Herein, we report that SlaA induces the expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) via the arachidonic acid signaling cascade. Notably, recombinant SlaA induced ICAM1 and VCAM1 expression in human umbilical vein endothelial cells (HUVECs), resulting in enhanced adhesion of human monocytic leukemia (THP-1) cells. However, C134A, a variant enzyme with no enzymatic activity, did not induce such events. In addition, culture supernatants from S. pyogenes SSI-1 enhanced the adhesion of THP-1 cells to HUVECs, but culture supernatants from the ΔslaA isogenic mutant strain had limited effects. Aspirin, a cyclooxygenase 2 inhibitor, prevented the adhesion of THP-1 cells to HUVECs and did not induce ICAM1 and VCAM1 expression in HUVECs treated with SlaA. However, zileuton, a 5-lipoxygenase inhibitor, did not exhibit such effects. Furthermore, pre-administration of aspirin in mice intravenously injected with SlaA attenuated the transcriptional abundance of ICAM1 and VCAM1 in the aorta. These results suggested that SlaA from S. pyogenes stimulates the expression of adhesion molecules in vascular endothelial cells. Thus, SlaA contributes to the inflammation of vascular endothelial cells upon S. pyogenes infection.

Highlights

Streptococcus pyogenes is a gram-positive bacterium that can cause superficial infections, such as pharyngitis and pyoderma; invasive infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome; and post-infectious diseases, such as rheumatic fever (Cunningham, 2000)
We examined the adhesion of human monocytic leukemia cell line (THP-1) cells to human umbilical vein endothelial cells (HUVECs) and the association of this with the expression of adhesion molecules, such as intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin, and P-selectin, on HUVECs treated with Streptococcus pyogenes phospholipase A2 (SlaA)
We found that the SlaA protein was only detected in culture supernatant from S. pyogenes encoding the slaA gene (Table 1)

Summary

Introduction

Streptococcus pyogenes is a gram-positive bacterium that can cause superficial infections, such as pharyngitis and pyoderma; invasive infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome; and post-infectious diseases, such as rheumatic fever (Cunningham, 2000). S. pyogenes SlaA and Adhesion Molecules (Musser and Krause, 1998; Cunningham, 2000; Fischetti, 2000; Kurosawa et al, 2016) and most of the extracellular molecules possess enzymatic activities against host tissues and the immune system (Terao et al, 2006, 2008; Honda-Ogawa et al, 2013). We identified that M3 serotype strain SSI-1 possesses the phospholipase A2 (PLA2) gene, designated as slaA, on the prophage genome. Beres et al (2004) reported that the enhanced capacity for invasive infection incurred by M3 correlated with the acquisition of prophage genomes encoding the slaA gene. SlaA has a conserved region of amino acid residues found in several secreted PLA2 enzymes, such as those found in snake venom (Pearson et al, 1993)

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