Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection.
Adult
Animals
B-Lymphocytes
Bacterial Toxins
/ chemistry
Bacterial Vaccines
CD4-Positive T-Lymphocytes
Disease Models, Animal
Female
Hemolysis
Humans
Infant, Newborn
Lipids
/ chemistry
Male
Mice
Mice, Inbred C57BL
Polyenes
/ chemistry
Pregnancy
Premature Birth
/ microbiology
Streptococcal Infections
/ immunology
Streptococcus agalactiae
Vaccination
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 03 2020
20 03 2020
Historique:
received:
29
05
2019
accepted:
27
02
2020
entrez:
22
3
2020
pubmed:
22
3
2020
medline:
18
7
2020
Statut:
epublish
Résumé
Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene's toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens.
Identifiants
pubmed: 32198389
doi: 10.1038/s41467-020-15282-0
pii: 10.1038/s41467-020-15282-0
pmc: PMC7083881
doi:
Substances chimiques
Bacterial Toxins
0
Bacterial Vaccines
0
Lipids
0
Polyenes
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1502Subventions
Organisme : NIAID NIH HHS
ID : T32 AI007509
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007528
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI125907
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI133976
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI100989
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI112619
Pays : United States
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