Search: onr:"swepub:oai:DiVA.org:oru-56372" >
Utilizing CMP-Siali...
Utilizing CMP-Sialic Acid Analogs to Unravel Neisseria gonorrhoeae Lipooligosaccharide-Mediated Complement Resistance and Design Novel Therapeutics
-
- Gulati, Sunita (author)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
-
- Schoenhofen, Ian C. (author)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
-
- Whitfield, Dennis M. (author)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
-
show more...
-
- Cox, Andrew D. (author)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
-
Li, Jianjun (author)
-
- Michael, Frank St. (author)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
-
- Vinogradov, Evgeny V. (author)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
-
- Stupak, Jacek (author)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
-
- Zheng, Bo (author)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
-
- Ohnishi, Makoto (author)
- Natl Inst Infect Dis, Tokyo, Japan
-
- Unemo, Magnus (author)
- Region Örebro län,WHO Collaborating Ctr Gonorrhoea & Other STIs, Dept Lab Med Microbiol, Örebro University Hospital, Örebro, Sweden
-
- Lewis, Lisa A. (author)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
-
- Taylor, Rachel E. (author)
- Dept Med, Biomed Sci Grad Program, Univ Calif San Diego, La Jolla CA, USA; Glycobiol Res & Training Ctr, Dept Cellular & Mol Med, Univ Calif San Diego, La Jolla CA, USA
-
- Landig, Corinna S. (author)
- Dept Med, Biomed Sci Grad Program, Univ Calif San Diego, La Jolla CA, USA; Glycobiol Res & Training Ctr, Dept Cellular & Mol Med, Univ Calif San Diego, La Jolla CA, USA
-
- Diaz, Sandra (author)
- Dept Med, Biomed Sci Grad Program, Univ Calif San Diego, La Jolla CA, USA; Glycobiol Res & Training Ctr, Dept Cellular & Mol Med, Univ Calif San Diego, La Jolla CA, USA
-
- Reed, George W. (author)
- Sch Med, Prevent & Behav Med, Univ Massachusetts, Worcester MA, USA
-
- Varki, Ajit (author)
- Dept Med, Biomed Sci Grad Program, Univ Calif San Diego, La Jolla CA, USA; Glycobiol Res & Training Ctr, Dept Cellular & Mol Med, Univ Calif San Diego, La Jolla CA, USA
-
- Rice, Peter A. (author)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
-
- Ram, Sanjay (author)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
-
show less...
-
(creator_code:org_t)
- 2015-12-02
- 2015
- English.
-
In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:12
- Related links:
-
https://doi.org/10.1...
-
show more...
-
https://journals.plo...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- Neisseria gonorrhoeae deploys a novel immune evasion strategy wherein the lacto-N-neotetraose (LNnT) structure of lipooligosaccharide (LOS) is capped by the bacterial sialyltransferase, using host cytidine-5'-monophosphate (CMP)-activated forms of the ninecarbon nonulosonate (NulO) sugar N-acetyl-neuraminic acid (Neu5Ac), a sialic acid (Sia) abundant in humans. This allows evasion of complement-mediated killing by recruiting factor H (FH), an inhibitor of the alternative complement pathway, and by limiting classical pathway activation ("serum-resistance"). We utilized CMP salts of six additional natural or synthetic NulOs, Neu5Gc, Neu5Gc8Me, Neu5Ac9Ac, Neu5Ac9Az, legionaminic acid (Leg5Ac7Ac) and pseudaminic acid (Pse5Ac7Ac), to define structural requirements of Sia-mediated serum-resistance. While all NulOs except Pse5Ac7Ac were incorporated into the LNnT-LOS, only Neu5Gc incorporation yielded high-level serum-resistance and FH binding that was comparable to Neu5Ac, whereas Neu5Ac9Az and Leg5Ac7Ac incorporation left bacteria fully serum-sensitive and did not enhance FH binding. Neu5Ac9Ac and Neu5Gc8Me rendered bacteria resistant only to low serum concentrations. While serum-resistance mediated by Neu5Ac was associated with classical pathway inhibition (decreased IgG binding and C4 deposition), Leg5Ac7Ac and Neu5Ac9Az incorporation did not inhibit the classical pathway. Remarkably, CMP-Neu5Ac9Az and CMP-Leg5Ac7Ac each prevented serum-resistance despite a 100-fold molar excess of CMP-Neu5Ac in growth media. The concomitant presence of Leg5Ac7Ac and Neu5Ac on LOS resulted in uninhibited classical pathway activation. Surprisingly, despite near-maximal FH binding in this instance, the alternative pathway was not regulated and factor Bb remained associated with bacteria. Intravaginal administration of CMP-Leg5Ac7Ac to BALB/c mice infected with gonorrhea (including a multidrug-resistant isolate) reduced clearance times and infection burden. Bacteria recovered from CMP-Leg5Ac7Ac-treated mice were sensitive to human complement ex vivo, simulating in vitro findings. These data reveal critical roles for the Sia exocyclic side-chain in gonococcal serum-resistance. Such CMP-NulO analogs may provide a novel therapeutic strategy against the global threat of multidrug-resistant gonorrhea.
Subject headings
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Gulati, Sunita
-
Schoenhofen, Ian ...
-
Whitfield, Denni ...
-
Cox, Andrew D.
-
Li, Jianjun
-
Michael, Frank S ...
-
show more...
-
Vinogradov, Evge ...
-
Stupak, Jacek
-
Zheng, Bo
-
Ohnishi, Makoto
-
Unemo, Magnus
-
Lewis, Lisa A.
-
Taylor, Rachel E ...
-
Landig, Corinna ...
-
Diaz, Sandra
-
Reed, George W.
-
Varki, Ajit
-
Rice, Peter A.
-
Ram, Sanjay
-
show less...
- About the subject
-
- NATURAL SCIENCES
-
NATURAL SCIENCES
-
and Biological Scien ...
-
and Microbiology
- Articles in the publication
-
PLoS Pathogens
- By the university
-
Örebro University