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Infect Immun. 2018 Jul 23;86(8). pii: e00285-18. doi: 10.1128/IAI.00285-18. Print 2018 Aug.

A Novel Sialylation Site on Neisseria gonorrhoeae Lipooligosaccharide Links Heptose II Lactose Expression with Pathogenicity.

Author information

1
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA sanjay.ram@umassmed.edu.
2
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
3
Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
4
Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, Canada.
5
Department of STD, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China.
6
Department of Medicine and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
7
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA.

Abstract

Sialylation of lacto-N-neotetraose (LNnT) extending from heptose I (HepI) of gonococcal lipooligosaccharide (LOS) contributes to pathogenesis. Previously, gonococcal LOS sialyltransterase (Lst) was shown to sialylate LOS in Triton X-100 extracts of strain 15253, which expresses lactose from both HepI and HepII, the minimal structure required for monoclonal antibody (MAb) 2C7 binding. Ongoing work has shown that growth of 15253 in cytidine monophospho-N-acetylneuraminic acid (CMP-Neu5Ac)-containing medium enables binding to CD33/Siglec-3, a cell surface receptor that binds sialic acid, suggesting that lactose termini on LOSs of intact gonococci can be sialylated. Neu5Ac was detected on LOSs of strains 15253 and an MS11 mutant with lactose only from HepI and HepII by mass spectrometry; deleting HepII lactose rendered Neu5Ac undetectable. Resistance of HepII lactose Neu5Ac to desialylation by α2-3-specific neuraminidase suggested an α2-6 linkage. Although not associated with increased factor H binding, HepII lactose sialylation inhibited complement C3 deposition on gonococci. Strain 15253 mutants that lacked Lst or HepII lactose were significantly attenuated in mice, confirming the importance of HepII Neu5Ac in virulence. All 75 minimally passaged clinical isolates from Nanjing, China, expressed HepII lactose, evidenced by reactivity with MAb 2C7; MAb 2C7 was bactericidal against the first 62 (of 75) isolates that had been collected sequentially and were sialylated before testing. MAb 2C7 effectively attenuated 15253 vaginal colonization in mice. In conclusion, this novel sialylation site could explain the ubiquity of gonococcal HepII lactose in vivo Our findings reinforce the candidacy of the 2C7 epitope as a vaccine antigen and MAb 2C7 as an immunotherapeutic antibody.

KEYWORDS:

Neisseria gonorrhoeae; complement; factor H; lipooligosaccharide; monoclonal antibodies; serum resistance; sialic acid; therapeutic

PMID:
29844237
PMCID:
PMC6056883
DOI:
10.1128/IAI.00285-18
[Indexed for MEDLINE]
Free PMC Article

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