The HMW2 adhesin of non-typeable Haemophilus influenzae is a human-adapted lectin that mediates high-affinity binding to 2–6 linked N-acetylneuraminic acid glycans

Atack, John M.; Day, Christopher J.; Poole, Jessica; Brockman, Kenneth L.; Bakaletz, Lauren O.; Barenkamp, Stephen J.; Jennings, Michael P.

doi:10.1016/j.bbrc.2018.06.126

Cited by 20 publications

(20 citation statements)

References 30 publications

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“…A number of human-adapted bacterial pathogens also specifically target Neu5Ac in preference to Neu5Gc; for example, Streptococcus pneumoniae preferentially recognizes and utilizes Neu5Ac (71), and the toxin produced by Salmonella enterica serovar Typhi has a much higher affinity for cells with Neu5Ac-containing glycan structures than for those containing Neu5Gc (72). We recently reported that two major adhesins of NTHi, the HMW1/2 proteins, preferentially bind Neu5Ac sialic acid-containing glycans over Neu5Gc-containing glycans (73), demonstrating that NTHi preferentially binds glycans present in the human host. Our findings reported in this study indicate the molecular basis for a further host adaptation in NTHi.…”

Section: Discussionmentioning

confidence: 99%

Nontypeable Haemophilus influenzae Has Evolved Preferential Use of N- Acetylneuraminic Acid as a Host Adaptation

Day

Atack

et al. 2019

mBio

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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.

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Section: Discussionmentioning

confidence: 99%

Nontypeable Haemophilus influenzae Has Evolved Preferential Use of N- Acetylneuraminic Acid as a Host Adaptation

Day

Atack

et al. 2019

mBio

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“…As the number of TCTTTCA (n) repeats in this SSR increases, the level of expression of HMW1/2 decreases [26]. HMW1/2 are required for binding to related host cell receptors in the human airway [27,28], but they are also highly immunogenic, and are currently being investigated as a candidate for a vaccine against NTHi [29,30].…”

Section: Phase-variable Expression Of Genes Via Genetic Mechanismsmentioning

confidence: 99%

Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments

Phillips

Tram

Seib

et al. 2019

Biochemical Society Transactions

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Phase-variation of genes is defined as the rapid and reversible switching of expression — either ON-OFF switching or the expression of multiple allelic variants. Switching of expression can be achieved by a number of different mechanisms. Phase-variable genes typically encode bacterial surface structures, such as adhesins, pili, and lipooligosaccharide, and provide an extra contingency strategy in small-genome pathogens that may lack the plethora of ‘sense-and-respond’ gene regulation systems found in other organisms. Many bacterial pathogens also encode phase-variable DNA methyltransferases that control the expression of multiple genes in systems called phasevarions (phase-variable regulons). The presence of phase-variable genes allows a population of bacteria to generate a number of phenotypic variants, some of which may be better suited to either colonising certain host niches, surviving a particular environmental condition and/or evading an immune response. The presence of phase-variable genes complicates the determination of an organism's stably expressed antigenic repertoire; many phase-variable genes are highly immunogenic, and so would be ideal vaccine candidates, but unstable expression due to phase-variation may allow vaccine escape. This review will summarise our current understanding of phase-variable genes that switch expression by a variety of mechanisms, and describe their role in disease and pathobiology.

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“…The HMW1 protein binds to host cell glycans as cellular receptors, specifically α2-3-sialyllactosamine (2-3 SLN) ( 19 ). We recently demonstrated that HMW2, which is ∼65% identical to HMW1, binds the related glycan α2-6-sialyllactosamine (2-6 SLN), with high specificity for 2-6 SLN containing N -acetylneuraminic acid (Neu5Ac), the form of sialic acid expressed by humans ( 20 ). Intriguingly, 2-3 SLN is found mainly in the lower human respiratory tract, whereas 2-6 SLN is found throughout the entire respiratory tract but predominates in the upper airway ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

The Nontypeable Haemophilus influenzae Major Adhesin Hia Is a Dual-Function Lectin That Binds to Human-Specific Respiratory Tract Sialic Acid Glycan Receptors

Atack

Day

Poole

et al. 2020

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NTHi is a human-adapted pathogen that colonizes the human respiratory tract. Strains of NTHi express multiple adhesins; however, there is a unique, mutually exclusive relationship between the major adhesins Hia and HMW1 and HMW2 (HMW1/2). Approximately 25% of NTHi strains express Hia, a phase-variable autotransporter protein that has a critical role in colonization of the host nasopharynx. The remaining 75% of strains express HMW1/2. Previous work has shown that the HMW1 and HMW2 proteins mediate binding to 2-3- and 2-6-linked sialic acid glycans found in the human respiratory tract. Here, we show that the high-affinity binding domain of Hia, binding domain 1 (BD1), is responsible for binding to α2-6-sialyllactosamine (2-6 SLN) glycans. BD1 is highly specific for glycans that incorporate the form of sialic acid expressed by humans, N-acetylneuraminic acid (Neu5Ac). We further show that Hia has lower-affinity binding activity for 2-3-linked sialic acid and that this binding activity is mediated via a distinct domain. Thus, Hia with its dual binding activities functionally mimics the combined activities of the HMW1 and HMW2 adhesins. In addition, we show that Hia has a role in biofilm formation by strains of NTHi that express the adhesin. Knowledge of the binding affinity of this major NTHi adhesin and putative vaccine candidate will direct and inform development of future vaccines and therapeutic strategies for this important pathogen. IMPORTANCE Host-adapted bacterial pathogens like NTHi have evolved specific mechanisms to colonize their restricted host niche. Relatively few of the adhesins expressed by NTHi have been characterized as regards their binding affinity at the molecular level. In this work, we show that the major NTHi adhesin Hia preferentially binds to Neu5Ac-α2-6-sialyllactosamine, the form of sialic acid expressed in humans. The receptors targeted by Hia in the human airway mirror those targeted by influenza A virus and indicates the broad importance of sialic acid glycans as receptors for microbes that colonize the human airway.

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The HMW2 adhesin of non-typeable Haemophilus influenzae is a human-adapted lectin that mediates high-affinity binding to 2–6 linked N-acetylneuraminic acid glycans

Cited by 20 publications

References 30 publications

Nontypeable Haemophilus influenzae Has Evolved Preferential Use of N- Acetylneuraminic Acid as a Host Adaptation

Nontypeable Haemophilus influenzae Has Evolved Preferential Use of N- Acetylneuraminic Acid as a Host Adaptation

Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments

The Nontypeable Haemophilus influenzae Major Adhesin Hia Is a Dual-Function Lectin That Binds to Human-Specific Respiratory Tract Sialic Acid Glycan Receptors

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