Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice

Abstract

Gram-positive bacterial pathogens that secrete cytotoxic pore-forming toxins, such as Staphylococcus aureus and Streptococcus pneumoniae, cause a substantial burden of disease. Inspired by the principles that govern natural toxin-host interactions, we have engineered artificial liposomes that are tailored to effectively compete with host cells for toxin binding. Liposome-bound toxins are unable to lyse mammalian cells in vitro. We use these artificial liposomes as decoy targets to sequester bacterial toxins that are produced during active infection in vivo. Administration of artificial liposomes within 10 h after infection rescues mice from septicemia caused by S. aureus and S. pneumoniae, whereas untreated mice die within 24-33 h. Furthermore, liposomes protect mice against invasive pneumococcal pneumonia. Composed exclusively of naturally occurring lipids, tailored liposomes are not bactericidal and could be used therapeutically either alone or in conjunction with antibiotics to combat bacterial infections and to minimize toxin-induced tissue damage that occurs during bacterial clearance.

Pneumolysin activates neutrophil extracellular trap formation

“…Notwithstanding direct cytotoxic effects [12][13][14][15][16][17][18] and proinflammatory actions of the toxin [24,25], indirect activities related to activation of NETosis, including cytotoxic and pro-thrombotic activities of NETs [14,15,18], are also likely to contribute to toxin-mediated pulmonary and cardiac injury. These findings underscore the potential of Ply-targeted therapies such as macrolide and macrolidelike antibiotics which are potent inhibitors of the production of Ply [44], as well as cholesterol-rich liposomes which neutralize the toxin [45]. In addition, pharmacological inhibitors of peptidylarginine deiminases, key enzymes in the induction of NETosis, are currently in preclinical development [46].…”

Пригнічення Бактеріальних Факторів Вірулентності Як Метод Лікування Бактеріальних Пневмоній

“…[16] разработали ис-кусственные липосомы, которые связывают бак-териальные токсины -α-токсин, пневмолизин Streptococcus pneumoniae. Применение данных липо-сом у экспериментальных животных предотвраща-ло развитие фатальной септицемии у мышей.…”

Annexins in Translational Research: HIDDEN Treasures to Be Found

“…This annexin-mediated resealing, blebbing, and subsequent shedding of the affected PM domains as pore-containing microvesicles is cell-protective and thus might constitute a vital part of the host cell innate immune response. The importance of the rapid and effective toxin removal for the host protection has been impressively demonstrated in vivo, as the administration of artificial liposomes that effectively compete with the host cell membranes sequester such toxins and successfully prevent the development of severe sepsis in a murine staphylococcal sepsis model [151]. Another example of a pathogen exploiting the host cell PM repair mechanism is the induction of lysosomal exocytosis during the host cell entry process of adenoviruses [152].…”