Bacterial modulation of host glycosylation - in infection, biotechnology, and therapy
Author
Summary, in English
A majority of the proteins of the immune system are glycosylated and the glycans of IgG
are essential for its functionality. Bacteria display enzymes that modulate the glycans of
the immune system to weaken the host defense and favor bacterial survival. In this thesis
we aimed at exploring bacterial modulation of host glycosylation in infection and to
evaluate the usefulness of bacterial enzymes in biotechnology and for therapeutic use.
The role of IgG endoglycosidase EndoS in streptococcal virulence was evaluated in a
murine model of invasive infection and we found significant contribution when
heterologously expressed. We also discovered and characterized EndoS2, a novel
enzyme specific and conserved in serotype M49 of streptococci, with enzymatic activity
on the glycans of IgG and α1-acid glycoprotein. Enterococcal pathogenesis was studied,
and we found that the endoglycosidase EndoE cleaved glycans of lactoferrin to reduce
the antibacterial functions and to support bacterial growth. A glycoform specificity
difference between EndoS and EndoS2 was observed, and we suggested a method for
quantification of high-mannose glycans on therapeutic antibodies, a key quality attribute.
Finally, we explored the importance of Fc glycosylation of IgE and showed that EndoS
cleaved glycans of this immunoglobulin causing a reduction of the immune cell activation
in vivo, a potential new therapeutic strategy for severe IgE mediated allergies.
In this thesis we demonstrate that glycans are an integral part of the immune system, and
that the study of bacterial effectors of glycosylation paves the way for a deeper
understanding of infections, for novel tools supporting the biotech arena, and for new
therapeutic strategies.
are essential for its functionality. Bacteria display enzymes that modulate the glycans of
the immune system to weaken the host defense and favor bacterial survival. In this thesis
we aimed at exploring bacterial modulation of host glycosylation in infection and to
evaluate the usefulness of bacterial enzymes in biotechnology and for therapeutic use.
The role of IgG endoglycosidase EndoS in streptococcal virulence was evaluated in a
murine model of invasive infection and we found significant contribution when
heterologously expressed. We also discovered and characterized EndoS2, a novel
enzyme specific and conserved in serotype M49 of streptococci, with enzymatic activity
on the glycans of IgG and α1-acid glycoprotein. Enterococcal pathogenesis was studied,
and we found that the endoglycosidase EndoE cleaved glycans of lactoferrin to reduce
the antibacterial functions and to support bacterial growth. A glycoform specificity
difference between EndoS and EndoS2 was observed, and we suggested a method for
quantification of high-mannose glycans on therapeutic antibodies, a key quality attribute.
Finally, we explored the importance of Fc glycosylation of IgE and showed that EndoS
cleaved glycans of this immunoglobulin causing a reduction of the immune cell activation
in vivo, a potential new therapeutic strategy for severe IgE mediated allergies.
In this thesis we demonstrate that glycans are an integral part of the immune system, and
that the study of bacterial effectors of glycosylation paves the way for a deeper
understanding of infections, for novel tools supporting the biotech arena, and for new
therapeutic strategies.
Department/s
Publishing year
2015
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2015:21
Full text
- Available as PDF - 37 MB
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Document type
Dissertation
Publisher
Division of Infection Medicine
Topic
- Infectious Medicine
Keywords
- IgG
- endoglycosidase
- Streptococcus pyogenes
- glycosylation
- EndoS
Status
Published
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-100-2
Defence date
13 March 2015
Defence time
09:00
Defence place
Belfragesalen, BMC D15, Klinikgatan 32, Lund
Opponent
- Dennis Burton (Professor)