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Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis
Luo, Yang; Huang, Chuan-Chin; Howard, Nicole C.; Wang, Xin; Liu, Qingyun; Li, Xinyi; Zhu, Junhao; Amariuta, Tiffany; Asgari, Samira; Ishigaki, Kazuyoshi; Calderon, Roger; Raman, Sahadevan; Ramnarine, Alexandrea K.; Mayfield, Jacob A.; Moody, D. Branch; Lecca, Leonid; Fortune, Sarah M.; Murray, Megan B.; Raychaudhuri, Soumya
2024
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Abstract

Infectious disease is the result of interactions between host and pathogen and can depend on genetic variations in both. We conduct a genome-to-genome study of paired human and Mycobacterium tuberculosis genomes from a cohort of 1556 tuberculosis patients in Lima, Peru. We identify an association between a human intronic variant (rs3130660, OR = 10.06, 95%CI: 4.87 − 20.77, P = 7.92 × 10−8) in the FLOT1 gene and a subclavaluee of Mtb Lineage 2. In a human macrophage infection model, we observe hosts with the rs3130660-A allele exhibited stronger interferon gene signatures. The interacting strains have altered redox states due to a thioredoxin reductase mutation. We investigate this association in a 2020 cohort of 699 patients recruited during the COVID-19 pandemic. While the prevalence of the interacting strain almost doubled between 2010 and 2020, its infection is not associated with rs3130660 in this recent cohort. These findings suggest a complex interplay among host, pathogen, and environmental factors in tuberculosis dynamics.

Details

Title
Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis
Author
Luo, Yang : Brigham and Women’s Hospital : (http://orcid.org/0000-0001-7385-6166)
Huang, Chuan-Chin : Brigham and Women’s Hospital
Howard, Nicole C. : Harvard University
Wang, Xin : Harvard University : (http://orcid.org/0000-0002-6930-3347)
Liu, Qingyun : Harvard University : (http://orcid.org/0000-0002-2284-5050)
Li, Xinyi : University of Chicago
Zhu, Junhao : Harvard University : (http://orcid.org/0000-0002-3301-5677)
Amariuta, Tiffany : Brigham and Women’s Hospital
Asgari, Samira : Brigham and Women’s Hospital
Ishigaki, Kazuyoshi : Brigham and Women’s Hospital
Calderon, Roger : Advanced Research and Health : (http://orcid.org/0000-0001-8932-0489)
Raman, Sahadevan : Brigham and Women’s Hospital : (http://orcid.org/0000-0001-5309-8169)
Ramnarine, Alexandrea K. : Brigham and Women’s Hospital : (http://orcid.org/0000-0003-3096-8648)
Mayfield, Jacob A. : Brigham and Women’s Hospital : (http://orcid.org/0000-0002-5762-6755)
Moody, D. Branch : Brigham and Women’s Hospital : (http://orcid.org/0000-0003-2306-3058)
Lecca, Leonid : Harvard University
Fortune, Sarah M. : Harvard University : (http://orcid.org/0000-0001-7565-9975)
Murray, Megan B. : Brigham and Women’s Hospital : (http://orcid.org/0000-0003-0443-1986)
Raychaudhuri, Soumya : Brigham and Women’s Hospital : (http://orcid.org/0000-0002-1901-8265)
Content Type
Article
Published in
Nature Communications
Identifier(s)
DOI: https://doi.org/10.1038/s41467-024-54741-w
Data availability statement

The human genotyping data generated in this study have been deposited in the dbGAP database under accession code phs002025.v1.p1[https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs002025.v1.p1] and phs003718.v1 [https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id= phs003718.v1.p1]. The Mycobacterium tuberculosis whole genome sequences in this study have been deposited in the BioProject database under accession code PRJNA1039243. The RNA sequencing data generated in this study have been deposited in the GEO database under accession code GSE262379. The eQTL Catalog release v6 database can be downloaded at https://ftp.ebi.ac.uk/pub/databases/spot/eQTL/. The Genotype Tissue Expression (GTEx release v8) database can be downloaded at https://gtexportal.org/home/protectedDataAccess. The whole-genome sequences of Mtb strains were obtained at the NCBI Sequence Read Archive (SRA) database (https://www.ncbi.nlm.nih.gov/sra) with Study ID listed in the Supplementary Data. The Mtb reference assembly (H37Rv NC_000962.3) can be downloaded at https://www.ncbi.nlm.nih.gov/nuccore/CP003248. Source data are provided with this paper.

All code for generating the figures presented in the manuscript are available at Luo, Y., Huang, C-C., Howard, N.C., Wang X., Liu Q.Y., et al. Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis, https://github.com/yang-luo-lab/TB-g2g, https://doi.org/10.5281/zenodo.13321932, 2024.

Funding Information
TB Research Unit Network, National Institutes of Health, U19 AI111224
NHGRI, U01 HG009379
Kennedy Trust, KTRR Senior Research Fellowship, KENN202109
T32 AI007535
U19 AI165573
U19162584
P01 AI181898
U19 AI142793
Publication Date
2024-11-29
Language
English
Copyright Statement

© 2024. The Author(s)

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Biological Sciences Division > Genetics, Genomics, and Systems Biology
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Record Created
2024-11-30

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