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

doi:10.6082/9egpm-c2a48

Published November 29, 2024 | Version v1

Journal article Open

Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis

1. Brigham and Women's Hospital
2. Harvard University
3. University of Chicago
4. Advanced Research and Health

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.

Data availability

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.

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