Point Mutations in TbpA Abrogate Human Transferrin Binding in Neisseria gonorrhoeae

Greenawalt, Ashley Nicole; Stoudenmire, Julie L.; Lundquist, Karl; Noinaj, Nicholas; Gumbart, James C.; Cornelissen, Cynthia Nau

doi:10.1128/iai.00414-22

Cited by 4 publications

(4 citation statements)

References 72 publications

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“…This region could have a significant role in the interaction of HpuB with hHb, and in ensuring heme extraction from Hb as seen previously with loop 3 helices of both TbpA and TdfJ (43,62,63). Therefore, acquiring a highresolution structure of HpuB, either by protein x-ray crystallography or cryo-electron microcopy, will help better inform the choice of future mutational targets on the extracellular loops as in other studies (43,62,63). As previously published, Transferrin-Binding Protein B (TbpB) and factor H binding protein (fHbp) mutants that are unable to bind host ligands demonstrated better vaccine potential (33)(34)(35).…”

Section: Discussionmentioning

confidence: 79%

“…We demonstrated the importance of residues 538-544 which constitute a hypothetical α-helical region in loop 7. This region could have a significant role in the interaction of HpuB with hHb, and in ensuring heme extraction from Hb as seen previously with loop 3 helices of both TbpA and TdfJ (43,62,63). Therefore, acquiring a highresolution structure of HpuB, either by protein x-ray crystallography or cryo-electron microcopy, will help better inform the choice of future mutational targets on the extracellular loops as in other studies (43,62,63).…”

Section: Discussionmentioning

confidence: 85%

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Investigating the importance of surface exposed loops in the gonococcal HpuB transporter for hemoglobin binding and utilization

Awate,

Ng,

Stoudenmire

et al. 2023

Preprint

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Neisseria gonorrhoeaeis the etiological agent of the sexually-transmitted infection gonorrhea and a global health challenge since no protective immunity results from infection and far fewer treatment options are available with increasing antimicrobial resistance. With no efficacious vaccines, researchers are exploring new targets for vaccine development and innovative therapeutics. The outer membrane TonB-dependent transporters (TdTs) produced byN. gonorrhoeaeare considered promising antigen targets as they are highly conserved and play crucial roles in overcoming nutritional immunity. One of these TdTs, the hemoglobin transport system comprised of HpuA and HpuB, allowsN. gonorrhoeaeto acquire iron from hemoglobin (hHb). In the current study, mutations in thehpuBgene were generated to better understand the structure-function relationships in HpuB. This study is one of the first to demonstrate thatN. gonorrhoeaecan bind to and utilize hemoglobin produced by animals other than humans. This study also determined that when HpuA is absent, mutations targeting extracellular loop 7 of HpuB led to defective hHb binding and utilization. However, when the lipoprotein HpuA is present, these loop 7 mutants recovered their ability to bind hHB, although their growth phenotype remained significantly impaired. Interestingly, loop 7 contains putative heme binding motifs and a hypothetical α-helical region. Taken together, these results highlight the importance of loop 7 in the functionality of HpuB in binding hHb, and extracting and internalizing iron.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 85%

Investigating the importance of surface exposed loops in the gonococcal HpuB transporter for hemoglobin binding and utilization

Awate,

Ng,

Stoudenmire

et al. 2023

Preprint

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“…Finney et al showed that antibodies against these proteins can protect against Neisseria lactamica meningococcal infection in rabbits (Finney et al, 2008). The TBDR transporter of Neisseria gonorrhoeae, i.e., TbpB, has also been targeted for vaccine design, in addition to TbpA, and shown to invoke an immune response in mice (Greenawalt, 2021). Additionally, several vaccine candidates Frontiers in Molecular Biosciences frontiersin.org targeting TBDRs have been developed for various bacterial pathogens, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumonia (Wang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Chimeric vaccine design against the conserved TonB-dependent receptor-like β-barrel domain from the outer membrane tbpA and hpuB proteins of Kingella kingae ATCC 23330

Mashraqi,

Alzamami,

Alturki

et al. 2023

Front. Mol. Biosci.

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Kingella kingae is a Gram-negative bacterium that primarily causes pediatric infections such as septicemia, endocarditis, and osteoarticular infections. Its virulence is attributed to the outer membrane proteins having implications in bacterial adhesion, invasion, nutrition, and host tissue damage. TonB-dependent receptors (TBDRs) play an important role in nutrition and were previously implicated as vaccine targets in other bacteria. Therefore, we targeted the conserved β-barrel TBDR domain of these proteins for designing a vaccine construct that could elicit humoral and cellular immune responses. We used bioinformatic tools to mine TBDR-containing proteins from K. kingae ATCC 23330 and then predict B- and T-cell epitopes from their conserved β-barrel TDR domain. A chimeric vaccine construct was designed using three antigenic epitopes, covering >98% of the world population and capable of inciting humoral and adaptive immune responses. The final construct elicited a robust immune response. Docking and dynamics simulation showed good binding affinity of the vaccine construct to various receptors of the immune system. Additionally, the vaccine was predicted to be safe and non-allergenic, making it a promising candidate for further development. In conclusion, our study demonstrates the potential of immunoinformatics approaches in designing chimeric vaccines against K. kingae infections. The chimeric vaccine we designed can serve as a blueprint for future experimental studies to develop an effective vaccine against this pathogen, which can serve as a potential strategy to prevent K. kingae infections.

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“…The prototype system in N. gonorrhoeae is the transferrin receptor, comprised of the TbpA transporter and the TbpB lipoprotein that increases the affinity of TbpA for transferrin. Structural analysis of TbpA co-crystalized with human transferrin reveals the helix finger of TbpA directly extends within a cleft on the C-lobe of human transferrin to extract iron [19,20]. The outer membrane receptors are energized by the proton motive force harnessed by TonB, ExbB, and ExbD, which pull on the "plug domain" to physically open each receptor to enable transport; hence, they are collectively known as "Tdfs," for TonB-dependent family members.…”

Section: How Does N Gonorrhoeae Use Outer Membrane Receptors For Huma...mentioning

confidence: 99%

Metal piracy by Neisseria gonorrhoeae to overcome human nutritional immunity

Liyayi

Forehand²,

Ray³

et al. 2023

PLoS Pathog

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Point Mutations in TbpA Abrogate Human Transferrin Binding in Neisseria gonorrhoeae

Cited by 4 publications

References 72 publications

Investigating the importance of surface exposed loops in the gonococcal HpuB transporter for hemoglobin binding and utilization

Investigating the importance of surface exposed loops in the gonococcal HpuB transporter for hemoglobin binding and utilization

Chimeric vaccine design against the conserved TonB-dependent receptor-like β-barrel domain from the outer membrane tbpA and hpuB proteins of Kingella kingae ATCC 23330

Metal piracy by Neisseria gonorrhoeae to overcome human nutritional immunity

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