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Utilizing CMP-Siali...
Utilizing CMP-Sialic Acid Analogs to Unravel Neisseria gonorrhoeae Lipooligosaccharide-Mediated Complement Resistance and Design Novel Therapeutics
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- Gulati, Sunita (författare)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
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- Schoenhofen, Ian C. (författare)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
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- Whitfield, Dennis M. (författare)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
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- Cox, Andrew D. (författare)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
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Li, Jianjun (författare)
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- Michael, Frank St. (författare)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
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- Vinogradov, Evgeny V. (författare)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
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- Stupak, Jacek (författare)
- Human Hlth Therapeut Portfolio, Natl Res Council Canada, Ottawa ON, Canada
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- Zheng, Bo (författare)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
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- Ohnishi, Makoto (författare)
- Natl Inst Infect Dis, Tokyo, Japan
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- Unemo, Magnus (författare)
- Region Örebro län,WHO Collaborating Ctr Gonorrhoea & Other STIs, Dept Lab Med Microbiol, Örebro University Hospital, Örebro, Sweden
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- Lewis, Lisa A. (författare)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
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- Taylor, Rachel E. (författare)
- 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
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- Landig, Corinna S. (författare)
- 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
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- Diaz, Sandra (författare)
- 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
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- Reed, George W. (författare)
- Sch Med, Prevent & Behav Med, Univ Massachusetts, Worcester MA, USA
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- Varki, Ajit (författare)
- 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
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- Rice, Peter A. (författare)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
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- Ram, Sanjay (författare)
- Sch Med, Div Infect Dis & Immunol, Univ Massachusetts, Worcester MA, USA
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(creator_code:org_t)
- 2015-12-02
- 2015
- Engelska.
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:12
- Relaterad länk:
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https://doi.org/10.1...
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https://journals.plo...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
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Gulati, Sunita
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Schoenhofen, Ian ...
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Whitfield, Denni ...
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Cox, Andrew D.
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Li, Jianjun
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Michael, Frank S ...
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Vinogradov, Evge ...
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Stupak, Jacek
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Zheng, Bo
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Ohnishi, Makoto
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Unemo, Magnus
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Lewis, Lisa A.
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Taylor, Rachel E ...
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Landig, Corinna ...
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Diaz, Sandra
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Reed, George W.
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Varki, Ajit
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Rice, Peter A.
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Ram, Sanjay
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- NATURVETENSKAP
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NATURVETENSKAP
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och Biologi
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PLoS Pathogens
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Örebro universitet