Streptococcus pneumoniae pneumolysin and neuraminidase A convert high-density lipoproteins into pro-atherogenic particles

Abstract

High-density lipoproteins (HDLs) are a group of different subpopulations of sialylated particles that have an essential role in the reverse cholesterol transport (RCT) pathway. Importantly, changes in the protein and lipid composition of HDLs may lead to the formation of particles with reduced atheroprotective properties. Here, we show that Streptococcus pneumoniae pneumolysin (PLY) and neuraminidase A (NanA) impair HDL function by causing chemical and structural modifications of HDLs. The proteomic, lipidomic, cellular, and biochemical analysis revealed that PLY and NanA induce significant changes in sialic acid, protein, and lipid compositions of HDL. The modified HDL particles have reduced cholesterol acceptor potential from activated macrophages, elevated levels of malondialdehyde adducts, and show significantly increased complement activating capacity. These results suggest that accumulation of these modified HDL particles in the arterial intima may present a trigger for complement activation, inflammatory response, and thereby promote atherogenic disease progression.

Reduced binding of apoE4 to complement factor H promotes amyloid‐β oligomerization and neuroinflammation

“…HDL was isolated from plasma of iNPH patients with apoE23 ( n = 2) or apoE44 ( n = 2) genotype by sequential flotation in an ultracentrifugation using potassium‐bromide for density adjustment as previously described (Syed et al , 2021). The methodology of the preparations was as follows: Plasma VLDL and LDL ( d < 1.063 g/ml) and total HDL (1.063 < d < 1.210 g/ml).…”

Pneumonia-Induced Inflammation, Resolution and Cardiovascular Disease: Causes, Consequences and Clinical Opportunities

“…48,49 In mouse and rabbit models, infiltration of C pneumoniae into the atherosclerotic environment lead to the acceleration of plaque progression and resulted in a more unstable plaque phenotype and in human macrophages, induced the secretion of matrix metalloproteinase-9. [50][51][52][53][54][55] Also, pneumolysin-an important virulence factor released by S pneumoniae that can translocate from the lungs and into circulation-can convert highdensity lipoprotein into proatherogenic molecules in humans, 56 in addition to stimulating cardiac injury in a mouse model of pneumonia. 57 However, the detection of pathogens in atherosclerotic plaques or myocardium of humans in the context of acute pneumonia or systemic infections has not been reported.…”

The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy

“…A third potential mechanism of Ply-mediated cardiotoxicity, albeit unexplored in the setting of experimental pneumococcal infection, involves the interaction of Ply and pneumococcal neuraminidase A (NanA) with high-density lipoproteins [ 77 ]. In this study, Syed et al observed that exposure of HDL particles to the combination of Ply and NanA in vitro resulted in significant alterations to the sialic acid, protein, and lipid composition of the lipoproteins.…”

“…In this study, Syed et al observed that exposure of HDL particles to the combination of Ply and NanA in vitro resulted in significant alterations to the sialic acid, protein, and lipid composition of the lipoproteins. These alterations in molecular structure were associated with oxidative damage and pro-inflammatory activity, as well as increased complement activity, resulting in increased pro-atherogenic potential [ 77 ].…”