Abstract
Cholesterol is highly abundant within all human body cells and modulates critical cellular functions related to cellular plasticity, metabolism, and survival. The cholesterol-binding toxin pneumolysin represents an essential virulence factor of Streptococcus pneumoniae in establishing pneumonia and other pneumococcal infections. Thus, cholesterol scavenging of pneumolysin is a promising strategy to reduce S. pneumoniae induced lung damage. There may also be a second cholesterol-dependent mechanism whereby pneumococcal infection and the presence of pneumolysin increase hepatic sterol biosynthesis. Here we investigated a library of polymer particles varying in size and composition that allow for the cellular delivery of cholesterol and their effects on cell survival mechanisms following pneumolysin exposure. Intracellular delivery of cholesterol by nanocarriers composed of Eudragit E100–PLGA rescued pneumolysin-induced alterations of lipid homeostasis and enhanced cell survival irrespective of neutralization of pneumolysin.
Highlights
Cholesterol is a steroid metabolite produced in small amounts by all nucleated cells of the human body
We investigated a library of polymer particles varying in size and composition that allow for the cellular delivery of cholesterol and their effects on cell survival mechanisms following pneumolysin exposure
We previously showed that the host responds to pneumococcal pneumonia with the induction of hepatic cholesterol biosynthesis [12]
Summary
Cholesterol is a steroid metabolite produced in small amounts by all nucleated cells of the human body. Hepatocytes are the leading producers of cholesterol and control sterol homeostasis by internalizing and secreting cholesterol in lipoproteins. Some pathogens have developed cholesterol-dependent cytolysins (CDCs) to recognize cholesterol in plasma membranes to identify and attack eukaryotic cells. PLY is a critical virulence factor of S. pneumoniae and empowers the pathogen to cause life-threatening infections such as pneumonia, meningitis, and sepsis [3]. Monomers of the toxin bind in a stoichiometric ratio of 1:1 to cholesterol, resulting in the assembly and formation of a multimeric transmembrane pore complex that causes a rapid loss of membrane integrity with altered cellular ion homeostasis and cell lysis [4]. PLY mediates cell damage within the lung, breaching the alveolar epithelial barrier and enables pneumococcal tissue invasion [5]
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