Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation

ABSTRACT Nontypeable Haemophilus inﬂuenzae (NTHi) is a Gram-negative bacterial pathogen that is adapted exclusively to human hosts. NTHi utilizes sialic acid from the host as a carbon source and as a terminal sugar on the outer membrane glycolipid lipooligosaccharide (LOS). Sialic acid expressed on...

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Autores principales:	Preston S. K. Ng, Christopher J. Day, John M. Atack, Lauren E. Hartley-Tassell, Linda E. Winter, Tal Marshanski, Vered Padler-Karavani, Ajit Varki, Stephen J. Barenkamp, Michael A. Apicella, Michael P. Jennings
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Haemophilus influenzae bacterial metabolism glycobiology microbial pathogenesis sialic acid Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9df602e01e3944e69c87d40bbd3d2636
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spelling	oai:doaj.org-article:9df602e01e3944e69c87d40bbd3d26362021-11-15T15:55:23ZNontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation10.1128/mBio.00422-192150-7511https://doaj.org/article/9df602e01e3944e69c87d40bbd3d26362019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00422-19https://doaj.org/toc/2150-7511ABSTRACT Nontypeable Haemophilus inﬂuenzae (NTHi) is a Gram-negative bacterial pathogen that is adapted exclusively to human hosts. NTHi utilizes sialic acid from the host as a carbon source and as a terminal sugar on the outer membrane glycolipid lipooligosaccharide (LOS). Sialic acid expressed on LOS is critical in NTHi biofilm formation and immune evasion. There are two major forms of sialic acids in most mammals, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter of which is derived from Neu5Ac. Humans lack the enzyme to convert Neu5Ac to Neu5Gc and do not express Neu5Gc in normal tissues; instead, Neu5Gc is recognized as a foreign antigen. A recent study showed that dietary Neu5Gc can be acquired by NTHi colonizing humans and then presented on LOS, which acts as an antigen for the initial induction of anti-Neu5Gc antibodies. Here we examined Neu5Gc uptake and presentation on NTHi LOS. We show that, although Neu5Gc and Neu5Ac are utilized equally well as sole carbon sources, Neu5Gc is not incorporated efficiently into LOS. When equal amounts of Neu5Gc and Neu5Ac are provided in culture media, there is ∼4-fold more Neu5Ac incorporated into LOS, suggesting a bias in a step of the LOS biosynthetic pathway. CMP-Neu5Ac synthetase (SiaB) was shown to have ∼4,000-fold-higher catalytic efficiency for Neu5Ac than for Neu5Gc. These data suggest that NTHi has adapted preferential utilization of Neu5Ac, thus avoiding presentation of the nonhuman Neu5Gc in the bacterial cell surface. The selective pressure for this adaptation may represent the human antibody response to the Neu5Gc xenoantigen. IMPORTANCE Host-adapted bacterial pathogens such as NTHi cannot survive out of their host environment and have evolved host-specific mechanisms to obtain nutrients and evade the immune response. Relatively few of these host adaptations have been characterized at the molecular level. NTHi utilizes sialic acid as a nutrient and also incorporates this sugar into LOS, which is important in biofilm formation and immune evasion. In the present study, we showed that NTHi has evolved to preferentially utilize the Neu5Ac form of sialic acid. This adaptation is due to the substrate preference of the enzyme CMP-Neu5Ac synthetase, which synthesizes the activated form of Neu5Ac for macromolecule biosynthesis. This adaptation allows NTHi to evade killing by a human antibody response against the nonhuman sialic acid Neu5Gc.Preston S. K. NgChristopher J. DayJohn M. AtackLauren E. Hartley-TassellLinda E. WinterTal MarshanskiVered Padler-KaravaniAjit VarkiStephen J. BarenkampMichael A. ApicellaMichael P. JenningsAmerican Society for MicrobiologyarticleHaemophilus influenzaebacterial metabolismglycobiologymicrobial pathogenesissialic acidMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Haemophilus influenzae bacterial metabolism glycobiology microbial pathogenesis sialic acid Microbiology QR1-502
spellingShingle	Haemophilus influenzae bacterial metabolism glycobiology microbial pathogenesis sialic acid Microbiology QR1-502 Preston S. K. Ng Christopher J. Day John M. Atack Lauren E. Hartley-Tassell Linda E. Winter Tal Marshanski Vered Padler-Karavani Ajit Varki Stephen J. Barenkamp Michael A. Apicella Michael P. Jennings Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation
description	ABSTRACT Nontypeable Haemophilus inﬂuenzae (NTHi) is a Gram-negative bacterial pathogen that is adapted exclusively to human hosts. NTHi utilizes sialic acid from the host as a carbon source and as a terminal sugar on the outer membrane glycolipid lipooligosaccharide (LOS). Sialic acid expressed on LOS is critical in NTHi biofilm formation and immune evasion. There are two major forms of sialic acids in most mammals, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter of which is derived from Neu5Ac. Humans lack the enzyme to convert Neu5Ac to Neu5Gc and do not express Neu5Gc in normal tissues; instead, Neu5Gc is recognized as a foreign antigen. A recent study showed that dietary Neu5Gc can be acquired by NTHi colonizing humans and then presented on LOS, which acts as an antigen for the initial induction of anti-Neu5Gc antibodies. Here we examined Neu5Gc uptake and presentation on NTHi LOS. We show that, although Neu5Gc and Neu5Ac are utilized equally well as sole carbon sources, Neu5Gc is not incorporated efficiently into LOS. When equal amounts of Neu5Gc and Neu5Ac are provided in culture media, there is ∼4-fold more Neu5Ac incorporated into LOS, suggesting a bias in a step of the LOS biosynthetic pathway. CMP-Neu5Ac synthetase (SiaB) was shown to have ∼4,000-fold-higher catalytic efficiency for Neu5Ac than for Neu5Gc. These data suggest that NTHi has adapted preferential utilization of Neu5Ac, thus avoiding presentation of the nonhuman Neu5Gc in the bacterial cell surface. The selective pressure for this adaptation may represent the human antibody response to the Neu5Gc xenoantigen. IMPORTANCE Host-adapted bacterial pathogens such as NTHi cannot survive out of their host environment and have evolved host-specific mechanisms to obtain nutrients and evade the immune response. Relatively few of these host adaptations have been characterized at the molecular level. NTHi utilizes sialic acid as a nutrient and also incorporates this sugar into LOS, which is important in biofilm formation and immune evasion. In the present study, we showed that NTHi has evolved to preferentially utilize the Neu5Ac form of sialic acid. This adaptation is due to the substrate preference of the enzyme CMP-Neu5Ac synthetase, which synthesizes the activated form of Neu5Ac for macromolecule biosynthesis. This adaptation allows NTHi to evade killing by a human antibody response against the nonhuman sialic acid Neu5Gc.
format	article
author	Preston S. K. Ng Christopher J. Day John M. Atack Lauren E. Hartley-Tassell Linda E. Winter Tal Marshanski Vered Padler-Karavani Ajit Varki Stephen J. Barenkamp Michael A. Apicella Michael P. Jennings
author_facet	Preston S. K. Ng Christopher J. Day John M. Atack Lauren E. Hartley-Tassell Linda E. Winter Tal Marshanski Vered Padler-Karavani Ajit Varki Stephen J. Barenkamp Michael A. Apicella Michael P. Jennings
author_sort	Preston S. K. Ng
title	Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation
title_short	Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation
title_full	Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation
title_fullStr	Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation
title_full_unstemmed	Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation
title_sort	nontypeable <italic toggle="yes">haemophilus influenzae</italic> has evolved preferential use of <italic toggle="yes">n-</italic>acetylneuraminic acid as a host adaptation
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/9df602e01e3944e69c87d40bbd3d2636
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Nontypeable <italic toggle="yes">Haemophilus influenzae</italic> Has Evolved Preferential Use of <italic toggle="yes">N-</italic>Acetylneuraminic Acid as a Host Adaptation

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