The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea

ABSTRACT The lipooligosaccharide (LOS) of Neisseria gonorrhoeae plays key roles in pathogenesis and is composed of multiple possible glycoforms. These glycoforms are generated by the process of phase variation and by differences in the glycosyltransferase gene content of particular strains. LOS glyc...

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Autores principales:	Freda E.-C. Jen, Margaret R. Ketterer, Evgeny A. Semchenko, Christopher J. Day, Kate L. Seib, Michael A. Apicella, Michael P. Jennings
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Neisseria gonorrhea lipooligosaccharide (LOS) keto-deoxyoctanoate (KDO) gonococcal vaccine N-acetylneuraminic acid (Neu5Ac) sialic acid Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e792e6f0b6e749d4b2e0efbf84976f51
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spelling	oai:doaj.org-article:e792e6f0b6e749d4b2e0efbf84976f512021-11-10T18:37:48ZThe Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea10.1128/mBio.03666-202150-7511https://doaj.org/article/e792e6f0b6e749d4b2e0efbf84976f512021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03666-20https://doaj.org/toc/2150-7511ABSTRACT The lipooligosaccharide (LOS) of Neisseria gonorrhoeae plays key roles in pathogenesis and is composed of multiple possible glycoforms. These glycoforms are generated by the process of phase variation and by differences in the glycosyltransferase gene content of particular strains. LOS glycoforms of N. gonorrhoeae can be terminated with an N-acetylneuraminic acid (Neu5Ac), which imparts resistance to the bactericidal activity of serum. However, N. gonorrhoeae cannot synthesize the CMP-Neu5Ac required for LOS biosynthesis and must acquire it from the host. In contrast, Neisseria meningitidis can synthesize endogenous CMP-Neu5Ac, the donor molecule for Neu5Ac, which is a component of some meningococcal capsule structures. Both species have an almost identical LOS sialyltransferase, Lst, that transfers Neu5Ac from CMP-Neu5Ac to the terminus of LOS. Lst is homologous to the LsgB sialyltransferase of nontypeable Haemophilus influenzae (NTHi). Studies in NTHi have demonstrated that LsgB can transfer keto-deoxyoctanoate (KDO) from CMP-KDO to the terminus of LOS in place of Neu5Ac. Here, we show that Lst can also transfer KDO to LOS in place of Neu5Ac in both N. gonorrhoeae and N. meningitidis. Consistent with access to the pool of CMP-KDO in the cytoplasm, we present data indicating that Lst is localized in the cytoplasm. Lst has previously been reported to be localized on the outer membrane. We also demonstrate that KDO is expressed as a terminal LOS structure in vivo in samples from infected women and further show that the anti-KDO monoclonal antibody 6E4 can mediate opsonophagocytic killing of N. gonorrhoeae. Taken together, these studies indicate that KDO expressed on gonococcal LOS represents a new antigen for the development of vaccines against gonorrhea. IMPORTANCE The emergence of multidrug-resistant N. gonorrhoeae strains that are resistant to available antimicrobials is a current health emergency, and no vaccine is available to prevent gonococcal infection. Lipooligosaccharide (LOS) is one of the major virulence factors of N. gonorrhoeae. The sialic acid N-acetylneuraminic acid (Neu5Ac) is present as the terminal glycan on LOS in N. gonorrhoeae. In this study, we made an unexpected discovery that KDO can be incorporated as the terminal glycan on LOS of N. gonorrhoeae by the alpha-2,3-sialyltransferase Lst. We showed that N. gonorrhoeae express KDO on LOS in vivo and that the KDO-specific monoclonal antibody 6E4 can direct opsonophagocytic killing of N. gonorrhoeae. These data support further development of KDO-LOS structures as vaccine antigens for the prevention of infection by N. gonorrhoeae.Freda E.-C. JenMargaret R. KettererEvgeny A. SemchenkoChristopher J. DayKate L. SeibMichael A. ApicellaMichael P. JenningsAmerican Society for MicrobiologyarticleNeisseria gonorrhealipooligosaccharide (LOS)keto-deoxyoctanoate (KDO)gonococcal vaccineN-acetylneuraminic acid (Neu5Ac)sialic acidMicrobiologyQR1-502ENmBio, Vol 12, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neisseria gonorrhea lipooligosaccharide (LOS) keto-deoxyoctanoate (KDO) gonococcal vaccine N-acetylneuraminic acid (Neu5Ac) sialic acid Microbiology QR1-502
spellingShingle	Neisseria gonorrhea lipooligosaccharide (LOS) keto-deoxyoctanoate (KDO) gonococcal vaccine N-acetylneuraminic acid (Neu5Ac) sialic acid Microbiology QR1-502 Freda E.-C. Jen Margaret R. Ketterer Evgeny A. Semchenko Christopher J. Day Kate L. Seib Michael A. Apicella Michael P. Jennings The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea
description	ABSTRACT The lipooligosaccharide (LOS) of Neisseria gonorrhoeae plays key roles in pathogenesis and is composed of multiple possible glycoforms. These glycoforms are generated by the process of phase variation and by differences in the glycosyltransferase gene content of particular strains. LOS glycoforms of N. gonorrhoeae can be terminated with an N-acetylneuraminic acid (Neu5Ac), which imparts resistance to the bactericidal activity of serum. However, N. gonorrhoeae cannot synthesize the CMP-Neu5Ac required for LOS biosynthesis and must acquire it from the host. In contrast, Neisseria meningitidis can synthesize endogenous CMP-Neu5Ac, the donor molecule for Neu5Ac, which is a component of some meningococcal capsule structures. Both species have an almost identical LOS sialyltransferase, Lst, that transfers Neu5Ac from CMP-Neu5Ac to the terminus of LOS. Lst is homologous to the LsgB sialyltransferase of nontypeable Haemophilus influenzae (NTHi). Studies in NTHi have demonstrated that LsgB can transfer keto-deoxyoctanoate (KDO) from CMP-KDO to the terminus of LOS in place of Neu5Ac. Here, we show that Lst can also transfer KDO to LOS in place of Neu5Ac in both N. gonorrhoeae and N. meningitidis. Consistent with access to the pool of CMP-KDO in the cytoplasm, we present data indicating that Lst is localized in the cytoplasm. Lst has previously been reported to be localized on the outer membrane. We also demonstrate that KDO is expressed as a terminal LOS structure in vivo in samples from infected women and further show that the anti-KDO monoclonal antibody 6E4 can mediate opsonophagocytic killing of N. gonorrhoeae. Taken together, these studies indicate that KDO expressed on gonococcal LOS represents a new antigen for the development of vaccines against gonorrhea. IMPORTANCE The emergence of multidrug-resistant N. gonorrhoeae strains that are resistant to available antimicrobials is a current health emergency, and no vaccine is available to prevent gonococcal infection. Lipooligosaccharide (LOS) is one of the major virulence factors of N. gonorrhoeae. The sialic acid N-acetylneuraminic acid (Neu5Ac) is present as the terminal glycan on LOS in N. gonorrhoeae. In this study, we made an unexpected discovery that KDO can be incorporated as the terminal glycan on LOS of N. gonorrhoeae by the alpha-2,3-sialyltransferase Lst. We showed that N. gonorrhoeae express KDO on LOS in vivo and that the KDO-specific monoclonal antibody 6E4 can direct opsonophagocytic killing of N. gonorrhoeae. These data support further development of KDO-LOS structures as vaccine antigens for the prevention of infection by N. gonorrhoeae.
format	article
author	Freda E.-C. Jen Margaret R. Ketterer Evgeny A. Semchenko Christopher J. Day Kate L. Seib Michael A. Apicella Michael P. Jennings
author_facet	Freda E.-C. Jen Margaret R. Ketterer Evgeny A. Semchenko Christopher J. Day Kate L. Seib Michael A. Apicella Michael P. Jennings
author_sort	Freda E.-C. Jen
title	The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea
title_short	The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea
title_full	The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea
title_fullStr	The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea
title_full_unstemmed	The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea
title_sort	lst sialyltransferase of <named-content content-type="genus-species">neisseria gonorrhoeae</named-content> can transfer keto-deoxyoctanoate as the terminal sugar of lipooligosaccharide: a glyco-achilles heel that provides a new strategy for vaccines to prevent gonorrhea
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/e792e6f0b6e749d4b2e0efbf84976f51
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The Lst Sialyltransferase of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea

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