University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology; Department of Medicine, Preventive and Behavioral Medicine
Publication Date
4-17-2018
Document Type
Article Preprint
Disciplines
Bacterial Infections and Mycoses | Immunology of Infectious Disease | Immunopathology | Immunoprophylaxis and Therapy | Microbiology
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 mAb 2C7 binding. Ongoing work has shown that growth of 15253 in cytidine monophospho-N-acetylneuraminic acid (CMP-Neu5Ac)-containing media enables binding to CD33/Siglec-3, a cell surface receptor that binds sialic acid, suggesting that lactose termini on LOS of intact gonococci can be sialylated. Neu5Ac was detected on LOSs of strains 15253 and a MS11 mutant with only lactose 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. 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 reiterate the candidacy of the 2C7 epitope as a vaccine antigen and mAb 2C7 as an immunotherapeutic antibody.
Keywords
Neisseria gonorrhoeae lipooligosaccharide, sialylation, lactose, 15253, mAb 2C7, mutation, microbiology
Rights and Permissions
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
10.1101/302968
Source
bioRxiv 302968; doi: https://doi.org/10.1101/30296. Link to preprint on bioRxiv service.
Related Resources
Now published in Infection and Immunity doi: 10.1128/iai.00285-18
Journal/Book/Conference Title
bioRxiv
Repository Citation
Ram, Sanjay; Gulati, Sunita; Lewis, Lisa A.; Chakraborti, Srinjoy; Zheng, Bo; de Oliveira, Rosane B.; Reed, George W.; Cox, Andrew D.; Li, Jianjun; St. Michael, Frank; Stupak, Jacek; Su, Xiao-Hong; Saha, Sudeshna; Landig, Corinna S.; Varki, Ajit; and Rice, Peter A., "A novel sialylation site on Neisseria gonorrhoeae lipooligosaccharide links heptose II lactose expression with pathogenicity" (2018). University of Massachusetts Medical School Faculty Publications. 1498.
https://escholarship.umassmed.edu/faculty_pubs/1498
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Bacterial Infections and Mycoses Commons, Immunology of Infectious Disease Commons, Immunopathology Commons, Immunoprophylaxis and Therapy Commons, Microbiology Commons