Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signaling cascades

Abstract

Infection with group B streptococcus (GBS) is the most common cause of early onset neonatal sepsis in many countries, leading to neonatal morbidity and mortality. There is much evidence for a direct involvement of platelets in the pathogenesis of inflammation and sepsis. Several bacteria are known to directly interact with platelets leading to activation and aggregation, a phenomenon also observed with GBS. Here, we demonstrate that GBS rapidly bound to platelets; however, only strains isolated from septic patients bound fibrinogen on their surface and induced platelet thromboxane synthesis, platelet aggregation, and P-selectin (CD62P) expression. In contrast, GBS strains isolated from healthy newborns or healthy pregnant women induced only shape change, but not platelet thromboxane synthesis, platelet aggregation, or CD62P expression. All GBS strains investigated were able to activate FcgammaRIIA receptor signaling pathways including phospholipase C gamma2 (PLCgamma2), as well as calcium/calmodulin-dependent myosin kinase II (CaMKII) and phosphorylation of myosin light chain (MLC). In contrast, protein kinase C (PKC) was exclusively activated by GBS strains isolated from septic patients, and p38 mitogen activated protein kinase (p38 MAP kinase) was preferentially activated by septic GBS strains. Furthermore, stress signaling kinase SEK1/MKK4 and focal adhesion kinase (FAK) were activated by all tested GBS strains in a FcgammaRIIA-independent way. This study demonstrates that septic, but not colonizing, GBS strains bind fibrinogen on their surface, and that septic GBS strains influence platelet function not only via the FcgammaRIIA receptor, but also via pathways distinct from IgG-mediated signalling. These mechanisms lead to platelet aggregation and secretion, thereby possibly modulating the pathophysiologic course of GBS infections.

Infection of Human Coronary Artery Endothelial Cells by Group B Streptococcus Contributes to Dysregulation of Apoptosis, Hemostasis, and Innate Immune Responses

“…Our own group could previously demonstrate that GBS is able to induce platelet aggregation [30]. In consequence, upregulated expression of HMOX-1 could reflect a protective mechanism against thrombotic complications after infection with GBS.…”

“…In addition, overexpression of HMOX-1 might lead to elevated bilirubin levels [30], potentially interfering the change from fetal to adult hemoglobin [31]. Hyperbilirubinemia might be responsible for neurological long-term sequelae, observed after GBS newborn infections [32].…”

“…Urokinase-type plasminogen activator upregulation might explain the simultaneously observed hemorrhagic and thrombotic complications during GBS sepsis [30]. Cocultivation of HCAEC with S. agalactiae revealed marked upregulation of urokinase, as determined by ELISA assays.…”

The Underestimated Role of Platelets in Severe Infection a Narrative Review

“…A direct interaction (Figure 1A) occurs when a bacterial adhesin binds directly to a platelet receptor [11,12]. An indirect interaction (Figure 1B) occurs when a bacterial adhesin binds to a plasma protein (or other soluble elements of the immune system such as immunoglobulins and complement proteins) which bridge the bacteria to a specific receptor on the platelet surface [11][12][13][14][15]. See Table 1 [16,17].…”

Streptococcus agalactiae Non-Pilus, Cell Wall-Anchored Proteins: Involvement in Colonization and Pathogenesis and Potential as Vaccine Candidates

“…S agalactiae clinical isolates bearing FbsA elicit an FBG-dependent, specific aggregation of platelets, suggesting that FbsA may play an important role in thrombus formation and S. agalactiae -induced endocarditis ( 56 ). Notably, Siauw et al showed that septic GBS strains bind FBG, induce thromboxane synthesis and platelet aggregation, while colonizing GBS strains cause only shape change of platelets ( 91 ). Liu et al also found that strains of GBS isolated from septic arthritis can induce platelet aggregation and activation via the elevation of platelet Toll-like receptor 2 expression ( 92 ).…”