Sequence variability of BamA and FadL candidate vaccinogens
suggests divergent evolutionary paths of Treponema pallidum
outer membrane proteins

J 2025

Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of Treponema pallidum outer membrane proteins

BETTIN, Everton B; Farhang AGHAKHANIAN; Christopher M HENNELLY; Wentao CHEN; Timothy C DAVENPORT et al.

Základní údaje

Originální název

Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of Treponema pallidum outer membrane proteins

Autoři

Vydání

Journal of Bacteriology, Washington, American Society for Microbiology, 2025, 0021-9193

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10606 Microbiology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.000 v roce 2024

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/25:00142262

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

syphilis; outer membrane proteins; protein variability; whole-genome sequencing; vaccines

Štítky

14110513, NIVB_LF, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 14. 10. 2025 08:01, Mgr. Tereza Miškechová

Anotace

V originále

Knowledge of Treponema pallidum subspecies pallidum (TPA) outer membrane protein (OMP) sequence variability is essential for understanding spirochete proliferation within endemic populations as well as the design of a globally effective syphilis vaccine. Our group has identified extracellular loops (ECLs) of TPA BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore TPA strain diversity, we mapped the variability of BamA and FadL orthologs in 186 TPA strains from Malawi, China, and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols- and three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the TPA strains, effectively segregating within clades and largely clustering by subclades. Finally, we noted that BamA and FadL candidate ECL vaccinogens, previously shown to elicit antibodies that kill treponemes during in vitro cultivation, are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing the selection of vaccine targets.IMPORTANCESyphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of TPA OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six TPA OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of TPA. Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.

Návaznosti

LX22NPO5103, projekt VaV

Název: Národní institut virologie a bakteriologie (Akronym: NIVB)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Národní institut virologie a bakteriologie, 5.1 EXCELES

Citovat

BETTIN, Everton B; Farhang AGHAKHANIAN; Christopher M HENNELLY; Wentao CHEN; Timothy C DAVENPORT; Simon T HACKL; Andre A GRASSMANN; Fabio VARGAS-CELY; Sebastian SILVA; Jonny A GARCIA-LUNA; Lady G RAMIREZ; Yinbo JIANG; Ligang YANG; Heping ZHENG; Bin YANG; Petra POSPÍŠILOVÁ; David ŠMAJS; Mitch M MATOGA; Irving F HOFFMAN; Eduardo LOPEZ-MEDINA; Kay NIESELT; M Anthony MOODY; Arlene C SENA; Juan C SALAZAR; Jonathan B PARR; Melissa J CAIMANO; Kelly L HAWLEY a Justin D RADOLF. Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of Treponema pallidum outer membrane proteins. Journal of Bacteriology. Washington: American Society for Microbiology, 2025, roč. 207, č. 8, s. 1-21. ISSN 0021-9193. Dostupné z: https://doi.org/10.1128/jb.00159-25.

@article{2525760,
   author = {Bettin, Everton B and Aghakhanian, Farhang and Hennelly, Christopher M and Chen, Wentao and Davenport, Timothy C and Hackl, Simon T and Grassmann, Andre A and VargasandCely, Fabio and Silva, Sebastian and GarciaandLuna, Jonny A and Ramirez, Lady G and Jiang, Yinbo and Yang, Ligang and Zheng, Heping and Yang, Bin and Pospíšilová, Petra and Šmajs, David and Matoga, Mitch M and Hoffman, Irving F and LopezandMedina, Eduardo and Nieselt, Kay and Moody, M Anthony and Sena, Arlene C and Salazar, Juan C and Parr, Jonathan B and Caimano, Melissa J and Hawley, Kelly L and Radolf, Justin D},
   article_location = {Washington},
   article_number = {8},
   doi = {https://doi.org/10.1128/jb.00159-25},
   keywords = {syphilis; outer membrane proteins; protein variability; whole-genome sequencing; vaccines},
   language = {eng},
   issn = {0021-9193},
   journal = {Journal of Bacteriology},
   title = {Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of Treponema pallidum outer membrane proteins},
   url = {https://journals.asm.org/doi/10.1128/jb.00159-25},
   volume = {207},
   year = {2025}
}

TY  - JOUR
ID  - 2525760
AU  - Bettin, Everton B - Aghakhanian, Farhang - Hennelly, Christopher M - Chen, Wentao - Davenport, Timothy C - Hackl, Simon T - Grassmann, Andre A - Vargas-Cely, Fabio - Silva, Sebastian - Garcia-Luna, Jonny A - Ramirez, Lady G - Jiang, Yinbo - Yang, Ligang - Zheng, Heping - Yang, Bin - Pospíšilová, Petra - Šmajs, David - Matoga, Mitch M - Hoffman, Irving F - Lopez-Medina, Eduardo - Nieselt, Kay - Moody, M Anthony - Sena, Arlene C - Salazar, Juan C - Parr, Jonathan B - Caimano, Melissa J - Hawley, Kelly L - Radolf, Justin D
PY  - 2025
TI  - Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of Treponema pallidum outer membrane proteins
JF  - Journal of Bacteriology
VL  - 207
IS  - 8
SP  - 1-21
EP  - 1-21
PB  - American Society for Microbiology
SN  - 00219193
KW  - syphilis
KW  - outer membrane proteins
KW  - protein variability
KW  - whole-genome sequencing
KW  - vaccines
UR  - https://journals.asm.org/doi/10.1128/jb.00159-25
N2  - Knowledge of Treponema pallidum subspecies pallidum (TPA) outer membrane protein (OMP) sequence variability is essential for understanding spirochete proliferation within endemic populations as well as the design of a globally effective syphilis vaccine. Our group has identified extracellular loops (ECLs) of TPA BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore TPA strain diversity, we mapped the variability of BamA and FadL orthologs in 186 TPA strains from Malawi, China, and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols- and three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the TPA strains, effectively segregating within clades and largely clustering by subclades. Finally, we noted that BamA and FadL candidate ECL vaccinogens, previously shown to elicit antibodies that kill treponemes during in vitro cultivation, are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing the selection of vaccine targets.IMPORTANCESyphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of TPA OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six TPA OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of TPA. Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.
ER  -

BETTIN, Everton B; Farhang AGHAKHANIAN; Christopher M HENNELLY; Wentao CHEN; Timothy C DAVENPORT; Simon T HACKL; Andre A GRASSMANN; Fabio VARGAS-CELY; Sebastian SILVA; Jonny A GARCIA-LUNA; Lady G RAMIREZ; Yinbo JIANG; Ligang YANG; Heping ZHENG; Bin YANG; Petra POSPÍŠILOVÁ; David ŠMAJS; Mitch M MATOGA; Irving F HOFFMAN; Eduardo LOPEZ-MEDINA; Kay NIESELT; M Anthony MOODY; Arlene C SENA; Juan C SALAZAR; Jonathan B PARR; Melissa J CAIMANO; Kelly L HAWLEY a Justin D RADOLF. Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of Treponema pallidum outer membrane proteins. \textit{Journal of Bacteriology}. Washington: American Society for Microbiology, 2025, roč.~207, č.~8, s.~1-21. ISSN~0021-9193. Dostupné z: https://doi.org/10.1128/jb.00159-25.

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