Examination of phase-variable haemoglobin-haptoglobin binding proteins in non-typeable Haemophilus influenzae reveals a diverse distribution of multiple variants

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Phillips, Zachary N
Jennison, Amy
Whitby, Paul W
Stull, Terrence L
Staples, Megan
Atack, John M
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2022
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Abstract

Non-typeable Haemophilus influenzae (NTHi) is a major human pathogen for which there is no globally licensed vaccine. NTHi has a strict growth requirement for iron and encodes several systems to scavenge elemental iron and heme from the host. An effective NTHi vaccine would target conserved, essential surface factors, such as those involved in iron acquisition. Haemoglobin-haptoglobin binding proteins (Hgps) are iron-uptake proteins localized on the outer-membrane of NTHi. If the Hgps are to be included as components of a rationally designed subunit vaccine against NTHi, it is important to understand their prevalence and diversity. Following analysis of all available Hgp sequences, we propose a standardized grouping method for Hgps, and demonstrate increased diversity of these proteins than previously determined. This analysis demonstrated that genes encoding variants HgpB and HgpC are present in all strains examined, and almost 40% of strains had a duplicate, nonidentical hgpB gene. Hgps are also phase-variably expressed; the encoding genes contain a CCAA(n) simple DNA sequence repeat tract, resulting in biphasic ON-OFF switching of expression. Examination of the ON-OFF state of hgpB and hgpC genes in a collection of invasive NTHi isolates demonstrated that 58% of isolates had at least one of hgpB or hgpC expressed (ON). Varying expression of a diverse repertoire of hgp genes would provide strains a method of evading an immune response while maintaining the ability to acquire iron via heme. Structural analysis of Hgps also revealed high sequence variability at the sites predicted to be surface exposed, demonstrating a further mechanism to evade the immune system - through varying the surface, immune-exposed regions of the membrane anchored protein. This information will direct and inform the choice of candidates to include in a vaccine against NTHi.

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FEMS Microbiology Letters

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369

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1

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© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited.

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Proteomics and intermolecular interactions (excl. medical proteomics)

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Life Sciences & Biomedicine

Microbiology

NTHi

invasive disease

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Phillips, ZN; Jennison, A; Whitby, PW; Stull, TL; Staples, M; Atack, JM, Examination of phase-variable haemoglobin-haptoglobin binding proteins in non-typeable Haemophilus influenzae reveals a diverse distribution of multiple variants, FEMS Microbiology Letters, 2022, 369 (1)

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