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The structural diversity of lipopolysaccharides expressed by genetically defined clinical isolates of nontypeable Haemophilus influenzae
Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nontypeable Haemophilus influenzae (NTHi) is an important cause of otitis media and respiratory tract infections. Its lipopolysaccharide (LPS) molecule, an outer membrane component, is a major virulence factor of NTHi. The LPS molecule may also be an efficient target for antibodies which might be protective against NTHi disease. The present thesis describes the structural analyses of the LPS from a number of NTHi clinical isolates. These isolates have been selected to be representative of the genetic diversity in the natural population of NTHi. The studies revealed extended inter- and intrastrain variability in LPS expression but also the presence of a conserved structural element. Several novel structural features were found, including epitopes not previously observed in Haemophilus influenzae LPS. The studies were performed using nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry and different chemical degradations of the LPS as the principal methods.

Place, publisher, year, edition, pages
Stockholm: Karolinska Instiutet , 2003. , 52 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:sh:diva-32070ISBN: 91-7349-584-0 (print)OAI: oai:DiVA.org:sh-32070DiVA: diva2:1074648
Public defence
2003-08-29, Hörsalen, plan 4, NOVUM, Hälsovägen 7, Huddinge, 10:00 (English)
Opponent
Supervisors
Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved
List of papers
1. A new structural type for Haemophilus influenzae lipopolysaccharide: Structural analysis of the lipopolysaccharide from nontypeable Haemophilus influenzae strain 486
Open this publication in new window or tab >>A new structural type for Haemophilus influenzae lipopolysaccharide: Structural analysis of the lipopolysaccharide from nontypeable Haemophilus influenzae strain 486
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2001 (English)In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 268, no 7, 2148-2159 p.Article in journal (Refereed) Published
Abstract [en]

Structural elucidation of the sialylated lipopolysaccharide (LPS) of non-typeable Haemophilus influenzae (NTHi) strain 486 has been achieved by the application of high-field NMR techniques and ESI-MS along with composition and linkage analyses on O-deacylated LPS and oligosaccharide samples. It was found that the LPS contains the common element of H. influenzae, L-alpha -D-Hepp-(1-->2)][PEtn-->6]-L-alpha -D-Hepp-(1-->3)-[beta -D-Glcp-( 1-->4)]-L-alpha -D-Hepp-(1-->5)- [PPEtn-->4]-alpha -Kdop- (2-->6)-Lipid A, but instead of glycosyl substitution of the terminal heptose residue (HepIII) at the O2 position observed in other H. influenzae strains, HepIII is chain elongated at the O3 position by either lactose or sialyllactose (i.e. alpha -Neu5Ac(2-->3)-beta -D-Galp-(1-->4)-beta -D-Glcp). The LPS is substituted by an O-acetyl group linked to the O2 position of HepIII and phosphocholine (PCho) which was located at the O6 position of a terminal alpha -D-Glcp, residue attached to the central heptose, a molecular environment different from what has been reported earlier for PCho. In addition, minor substitution by O-linked glycine to the LPS was observed. By investigation of LPS from a lpsA mutant of NTHi strain 486, it was demonstrated that the lpsA gene product also is responsible for chain extension from HepIII in this strain. The involvement of lic1 in expression of PCho was established by investigation of a lic1 mutant of NTHi strain 486.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-15863 (URN)10.1046/j.1432-1327.2001.02094.x (DOI)000168004300028 ()11277939 (PubMedID)2-s2.0-0034856665 (Scopus ID)
Available from: 2012-03-12 Created: 2012-03-09 Last updated: 2017-12-07Bibliographically approved
2. Structural analysis of the lipopolysaccharide from nontypeable Haemophilus influenzae strain 1003
Open this publication in new window or tab >>Structural analysis of the lipopolysaccharide from nontypeable Haemophilus influenzae strain 1003
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2002 (English)In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 269, no 3, 808-818 p.Article in journal (Refereed) Published
Abstract [en]

Structural analysis of the lipopolysaccharide (LPS) of nontypeable Haemophilus influenzae strain 1003 has been achieved by the application of high-field NMR techniques, ESI-MS. capillary electrophoresis coupled to ESI-MS. composition and linkage analyses on O-deacylated LPS and core oligosaccharide material. It was found that the LPS contains the common structural element of H. influenzae, L-alpha-D-Hepp-(1 --> 2)-[PEtn --> 6]-L-alpha-D-Hepp-(1 --> 3)-[beta-D-Glcp-(1 --> 4)]-L-alpha-D-Hepp-(1 --> 5)-[PP Etn --> 4]-alpha-Kdop-(2 --> 6)-Lipid A. in which the beta-D-Glcp residue is substituted by phosphocholine at O-6 and an acetyl group at O-4. A second acetyl group is located at O-3 of the distal heptose residue (HepIII). HepIII is chain elongated at O-2 by either a beta-D-Glcp residue (major), lactose or sialyllactose (minor, i.e. alpha-Neu5Ac-(2 --> 3)-beta-D-Galp-(1 --> 4)-beta-D-Glcp), where a third minor acetylation site was identified at the glucose residue. Disialylated species were also detected. In addition. a minor substitution of ester-linked glycine at HepIII and Kdo was observed.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-15817 (URN)10.1046/j.0014-2956.2001.02707.x (DOI)000174059100008 ()11846782 (PubMedID)2-s2.0-0036178439 (Scopus ID)
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved
3. Structural diversity in lipopolysaccharide expression in nontypeable Haemophilus influenzae - Identification of L-glycero-D-manno-heptose in the outer-core region in three clinical isolates
Open this publication in new window or tab >>Structural diversity in lipopolysaccharide expression in nontypeable Haemophilus influenzae - Identification of L-glycero-D-manno-heptose in the outer-core region in three clinical isolates
2003 (English)In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 4, 610-624 p.Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-15640 (URN)10.1046/j.1432-1033.2003.03399.x (DOI)000180844900006 ()12581201 (PubMedID)2-s2.0-0037293036 (Scopus ID)
Available from: 2012-02-23 Created: 2012-02-22 Last updated: 2017-12-07Bibliographically approved
4. Structural characterization of a novel branching pattern in the lipopolysaccharide from nontypeable Haemophilus influenzae
Open this publication in new window or tab >>Structural characterization of a novel branching pattern in the lipopolysaccharide from nontypeable Haemophilus influenzae
2003 (English)In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 14, 2979-2991 p.Article in journal (Refereed) Published
Abstract [en]

Structural analysis of the lipopolysaccharide (LPS) from nontypeable Haemophilus influenzae strain 981 has been achieved using NMR spectroscopy and ESI-MS on O-deacylated LPS and core oligosaccharide (OS) material as well as by ESI-MSn on permethylated dephosphorylated OS. A heterogeneous glycoform population was identified, resulting from the variable length of the OS branches attached to the glucose residue in the common structural element of H. influenzae LPS, L-alpha-d-Hepp -(1-->2)-[P Etn-->6]-L-alpha-d-Hepp -(1-->3)-[beta-d-Glcxp-(1-->4)]-L-alpha-d-Hepp -(1-->5)-[PP Etn-->4]-alpha-Kdop -(2-->6)-Lipid A. Notably, the O-6 position of the beta-d-Glcp residue was either substituted by P Cho or the disaccharide branch beta-d-Galp-(1-->4)-d-alpha-d-Hepp, while the O-4 position was substituted by the globotetraose unit, beta-d-Galp NAc-(1-->3)-alpha-d-Galp -(1-->4)-beta-d-Galp -(1-->4)-beta-d-Glcp, or sequentially truncated versions thereof. This is the first time a branching sugar residue has been reported in the outer-core region of H. influenzae LPS. Additionally, a P Etn group was identified at O-3 of the distal heptose residue in the inner-core.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-15541 (URN)10.1046/j.1432-1033.2003.03675.x (DOI)000183959900008 ()12846831 (PubMedID)2-s2.0-19244383477 (Scopus ID)
Available from: 2012-02-21 Created: 2012-02-21 Last updated: 2017-12-07Bibliographically approved

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