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

Abstract

The Streptococcus pyogenes phospholipase A 2 (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 slaA 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.

Defining Host Responses during Systemic Bacterial Infection through Construction of a Murine Organ Proteome Atlas

“…Icam1 and Serpina10 may indicate infection in the liver, while Orm2 may indicate progression to the heart. Previous reports have shown that Icam1 expression is induced by GAS's SlaA, increasing the adhesion of human monocytic leukemia cells (Oda et al, 2017). Icam1 deletion mutants have also displayed increased bacterial burden in Mycobacterium infection, further evidence of a role for Icam1 during bacterial infection (de Paula et al, 2017).…”

Co‐opting oxylipin signals in microbial disease

“…ExoU liberates AA from eukaryotic cell membrane, an activity required for its toxicity (Rabin & Hauser, ; Saliba et al, ). Other bacterial phospholipases implicated in host interaction include Streptococcus pyogenes phospholipase A 2 SlaA (Oda et al, ) and the ExoU homologue VipD in Legionella pneumophila (Gaspar & Machner, ; Ku et al, ).…”

“…The L. pneumophila homologue of ExoU, VipD disrupts endosomal membrane lipids and facilitates L. pneumophila escape from endosomal fusion in the Cos‐1 cells (Gaspar & Machner, ). S. pyogenes phospholipase A 2 SlaA increases monocyte adhesion to endothelial cells in vitro (Oda et al, ).…”

Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis

“…Furthermore, pneumococcal phospholipase A2 (PLA2), which is a secreted bacterial enzyme that also modulates inflammation [ 63 ], is a clinical predictor for PM [ 64 ]. PLA2 production is associated with upregulation of adhesion molecules in host vascular endothelial cells [ 65 ].…”