Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: tularemia [ICD11:
1B94 
, ICD11:
XN0BX ];
infection due to Francisella tularensis [ICD11:
XN0BX ]
NCBI PubMed ID: 30872471Publication DOI: 10.1073/pnas.1900144116Journal NLM ID: 7505876Publisher: National Academy of Sciences
Correspondence: D.L. Kasper <dennis_kasper
hms.harvard.edu>
Institutions: Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, Department of Microbiology, Evelo Biosciences, Cambridge, MA 02139, The Lautenberg Center for Immunology and Cancer Research, Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
Francisella tularensis is the causative agent of tularemia, a category A bioterrorism agent. The lipopolysaccharide (LPS) O antigen (OAg) of F. tularensis has been considered for use in a glycoconjugate vaccine, but conjugate vaccines tested so far have failed to confer protection necessary against aerosolized pulmonary bacterial challenge. When F. tularensis OAg was purified under standard conditions, the antigen had a small molecular size [25 kDa, low molecular weight (LMW)]. Using milder extraction conditions, we found the native OAg had a larger molecular size [80 kDa, high molecular weight (HMW)], and in a mouse model of tularemia, a glycoconjugate vaccine made with the HMW polysaccharide coupled to tetanus toxoid (HMW-TT) conferred better protection against intranasal challenge than a conjugate made with the LMW polysaccharide (LMW-TT). To further investigate the role of OAg size in protection, we created an F. tularensis live vaccine strain (LVS) mutant with a significantly increased OAg size [220 kDa, very high molecular weight (VHMW)] by expressing in F. tularensis a heterologous chain-length regulator gene (wzz) from the related species Francisella novicida Immunization with VHMW-TT provided markedly increased protection over that obtained with TT glycoconjugates made using smaller OAgs. We found that protective antibodies recognize a length-dependent epitope better expressed on HMW and VHMW antigens, which bind with higher affinity to the organism.
O antigen, Francisella, glycoconjugate vaccine, intracellular pathogen, antibody affinity
Structure type: polymer chemical repeating unit ; 25000-80000
Location inside paper: fig.S2(A), F. tularensis LVS
Compound class: O-antigen
Contained glycoepitopes: IEDB_151083,IEDB_221847,IEDB_221848
Methods: 1H NMR, SDS-PAGE, DNA techniques, ELISA, biological assays, serological methods, HPSEC, immunoblotting, immunization, conjugation
NCBI Taxonomy refs (TaxIDs): 263Reference(s) to other database(s): GTC:G46610QC
Show glycosyltransferases
There is only one chemically distinct structure:
Found 
report error