Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium tuberculosis Strains

Journal Article · 13 February 2019 · Frontiers in Immunology

DOI: https://doi.org/10.3389/fimmu.2019.00195 · OSTI ID:1571139

Ramaiah, Arunachalam ^[1]; Nayak, Soumya ^[1]; Rakshit, Srabanti ^[1]; Manson, Abigail L. ^[2]; Abeel, Thomas ^[2]; Shanmugam, Sivakumar ^[2]; Sahoo, Pravat Nalini ^[1]; John, Anto Jesuraj Uday Kumar ^[3]; Sundaramurthi, Jagadish Chandrabose ^[2]; Narayanan, Sujatha ^[2]; D'Souza, George ^[3]; von Hoegen, Paul ^[4]; Ottenhoff, Tom H. M. ^[5]; Swaminathan, Soumya ^[6]; Earl, Ashlee M. ^[2]; Vyakarnam, Annapurna ^[7]

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1. Indian Inst. of Science, Bangalore (India). Centre for Infectious Disease Research
2. Broad Inst. of MIT and Harvard, Cambridge, MA (United States)
3. St. John's Research Inst., Bangalore (India). Dept. of Pulmonary Medicine
4. JPT Peptide Technologies GmbH, Berlin (Germany)
5. Leiden Univ. Medical Center, Leiden (Netherlands). Dept. of Infectious Diseases
6. National Inst. for Research in Tuberculosis (ICMR), Chennai (India)
7. Indian Inst. of Science, Bangalore (India). Centre for Infectious Disease Research; King's College London, London (United Kingdom). Dept. of Infectious Diseases, Faculty of Life Sciences & Medicine, School of Immunology and Microbial Sciences

Vaccines that confer protection through induction of adaptive T-cell immunity rely on understanding T-cell epitope (TCE) evolution induced by immune escape. This is poorly understood in tuberculosis (TB), an ancient, chronic disease, where CD4 T-cell immunity is of recognized importance. We probed 905 functionally validated, curated human CD4 T cell epitopes in 79 Mycobacterium tuberculosis (Mtb) whole genomes from India. This screen resulted in identifying 64 mutated epitopes in these strains initially using a computational pipeline and subsequently verified by single nucleotide polymorphism (SNP) analysis. SNP based phylogeny revealed the 79 Mtb strains to cluster to East African Indian (EAI), Central Asian Strain (CAS), and Beijing (BEI) lineages. Eighty-nine percent of the mutated T-cell epitopes (mTCEs) identified in the 79 Mtb strains from India has not previously been reported. These mTCEs were encoded by genes with high nucleotide diversity scores including seven mTCEs encoded by six antigens in the top 10% of rapidly divergent Mtb genes encoded by these strains. Using a T cell functional assay readout, we demonstrate 62% of mTCEs tested to significantly alter CD4 T-cell IFNγ and/or IL2 secretion with associated changes in predicted HLA-DR binding affinity: the gain of function mutations displayed higher predicted HLA-DR binding affinity and conversely mutations resulting in loss of function displayed lower predicted HLA-DR binding affinity. Most mutated antigens belonged to the cell wall/cell processes, and, intermediary metabolism and respiration families though all known Mtb proteins encoded mutations. Analysis of the mTCEs in an SNP database of 5,310 global Mtb strains identified 82% mTCEs to be significantly more prevalent in Mtb strains isolated from India, including 36 mTCEs identified exclusively in strains from India. These epitopes had a significantly higher predicted binding affinity to HLA-DR alleles that were highly prevalent in India compared to HLA-DR alleles rare in India, highlighting HLA-DR maybe an important driver of these mutations. This first evidence of region-specific TCE mutations potentially employed by Mtb to escape host immunity has important implications for TB vaccine design.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: USDOE Office of Science (SC)
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1571139
• Journal Information: Frontiers in Immunology, Journal Name: Frontiers in Immunology Journal Issue: FEB Vol. 10; ISSN 1664-3224
• Publisher: Frontiers Research FoundationCopyright Statement
• Country of Publication: United States
• Language: English