Identification of candidate HLA-E binding peptides from Mycobacterium tuberculosis using phage secretome library screening and computational modeling
- 1School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa
- 2Discipline of Microbiology, School of Agriculture and Science, College of Agriculture, Engineering and Science, University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa
- 3Igagasi Biotech (Pty) Ltd, TIA Bioprocessing Platform, Durban, KwaZulu-Natal, South Africa
Abstract
Background: Mycobacterium tuberculosis (Mtb) remains a primary global health challenge, particularly in HIV-co-infected populations where viral Nef-mediated downregulation of classical MHC-I molecules impairs T-cell immunity. Conversely, the non-classical MHC-Ib molecule, HLA-E, is resistant to Nef-mediated evasion, representing an attractive, non-polymorphic pathway for investigating potential Mtb-specific CD8+ T-cell activation targets.
Methods: This study utilized an exploratory in vitro screening and in silico modeling framework to identify candidate HLA-E-binding Mtb peptides. Candidate ligands were screened by biopanning an Mtb F15/LAM4/KZN phage secretome library against immobilized recombinant HLA-E*01:03. Identified peptides were characterized via DNA sequencing, and their predicted structural–mechanical interactions were evaluated using molecular docking and normal mode analysis (NMA).
Results: Phage selection yielded distinct Mtb-derived peptide fragments, including components from known immunogenic antigens Rv1980c (Mpt64) and Rv2875 (Mpt70), alongside conserved hypothetical proteins such as Rv1566c. Structural profiling predicted groove-directed anchoring within the modeled HLA-E binding cleft, displaying a spatial preference for pockets E and F. Computational molecular scoring prioritized favorable candidates (e.g., Rv2972c at −87.49 kcal/mol), while NMA indicated that these prioritized Mtb peptides possess a higher degree of predicted conformational plasticity (eigenvalues as low as 9.13 × 10-6) compared to the rigid Mtb44 baseline (1.37 × 10–4).
Conclusion: These findings map an exploratory Mtb peptide repertoire demonstrating computational feasibility for flexible HLA-E groove accommodation. By providing a structural foundation for candidate peptide prioritization, these results lay the groundwork for future investigations into unconventional CD8+ T-cell activation and the rational design of next-generation TB vaccines tailored for high-burden TB/HIV co-infection settings.
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BibTeX
@article{masondo2026identification,
title = {{Identification of candidate HLA-E binding peptides from Mycobacterium tuberculosis using phage secretome library screening and computational modeling}},
author = {Nkanyezi Masondo and Michelle Lucille Gordon and Thamsanqa Emmanuel Chiliza},
journal = {Frontiers in Cellular and Infection Microbiology},
year = {2026},
month = oct,
doi = {10.3389/fcimb.2026.1724374},
url = {https://doi.org/10.3389/fcimb.2026.1724374},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Identification of candidate HLA-E binding peptides from Mycobacterium tuberculosis using phage secretome library screening and computational modeling
AU - Nkanyezi Masondo
AU - Michelle Lucille Gordon
AU - Thamsanqa Emmanuel Chiliza
PY - 2026
DA - 2026/10/21
JO - Frontiers in Cellular and Infection Microbiology
DO - 10.3389/fcimb.2026.1724374
UR - https://doi.org/10.3389/fcimb.2026.1724374
AB - Background: Mycobacterium tuberculosis (Mtb) remains a primary global health challenge, particularly in HIV-co-infected populations where viral Nef-mediated downregulation of classical MHC-I molecules impairs T-cell immunity. Conversely, the non-classical MHC-Ib molecule, HLA-E, is resistant to Nef-mediated evasion, representing an attractive, non-polymorphic pathway for investigating potential Mtb-specific CD8+ T-cell activation targets. Methods: This study utilized an exploratory in vitro screening and in silico modeling framework to identify candidate HLA-E-binding Mtb peptides. Candidate ligands were screened by biopanning an Mtb F15/LAM4/KZN phage secretome library against immobilized recombinant HLA-E*01:03. Identified peptides were characterized via DNA sequencing, and their predicted structural–mechanical interactions were evaluated using molecular docking and normal mode analysis (NMA). Results: Phage selection yielded distinct Mtb-derived peptide fragments, including components from known immunogenic antigens Rv1980c (Mpt64) and Rv2875 (Mpt70), alongside conserved hypothetical proteins such as Rv1566c. Structural profiling predicted groove-directed anchoring within the modeled HLA-E binding cleft, displaying a spatial preference for pockets E and F. Computational molecular scoring prioritized favorable candidates (e.g., Rv2972c at −87.49 kcal/mol), while NMA indicated that these prioritized Mtb peptides possess a higher degree of predicted conformational plasticity (eigenvalues as low as 9.13 × 10-6) compared to the rigid Mtb44 baseline (1.37 × 10–4). Conclusion: These findings map an exploratory Mtb peptide repertoire demonstrating computational feasibility for flexible HLA-E groove accommodation. By providing a structural foundation for candidate peptide prioritization, these results lay the groundwork for future investigations into unconventional CD8+ T-cell activation and the rational design of next-generation TB vaccines tailored for high-burden TB/HIV co-infection settings.
SN - 2235-2988
ER -