Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis
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<sup>-8</sup>) 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.
Authors
- Megan Murray (ORCID: https://orcid.org/0000-0003-0443-1986)
- D. Branch Moody (ORCID: https://orcid.org/0000-0003-2306-3058)
- Jacob A. Mayfield (ORCID: https://orcid.org/0000-0002-5762-6755)
- Alexandrea K. Ramnarine (ORCID: https://orcid.org/0000-0003-3096-8648)
- Junhao Zhu (ORCID: https://orcid.org/0000-0002-3301-5677)
- Sahadevan Raman (ORCID: https://orcid.org/0000-0001-5309-8169)
- Leonid Lecca (ORCID: https://orcid.org/0000-0003-1363-3985)
- Yang Luo (ORCID: https://orcid.org/0000-0001-7385-6166)
- Xin Wang (ORCID: https://orcid.org/0000-0002-6930-3347)
- Kazuyoshi Ishigaki (ORCID: https://orcid.org/0000-0003-2881-0657)
- Róger Calderón (ORCID: https://orcid.org/0000-0001-8932-0489)
- Soumya Raychaudhuri (ORCID: https://orcid.org/0000-0002-1901-8265)
- Samira Asgari (ORCID: https://orcid.org/0000-0002-2347-8985)
- Sarah M. Fortune (ORCID: https://orcid.org/0000-0001-7565-9975)
- Nicole C. Howard (ORCID: https://orcid.org/0000-0003-0805-5914)
- Xinyi Li (ORCID: https://orcid.org/0000-0003-4370-9231)
- Qingyun Liu (ORCID: https://orcid.org/0000-0002-2284-5050)
- Chuan‐Chin Huang
- Tiffany Amariuta
Institutions
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- University of California San Diego (US)
- University of Oxford (GB)
- University of Chicago (US)
- EsSALUD (PE)
- RIKEN Center for Integrative Medical Sciences (JP)
- Harvard Global Health Institute (US)
- Genomic Health (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1038/s41467-024-54741-w
- Citations
- 18
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 7.00
Funders
- Kennedy Trust for Rheumatology Research
- National Institutes of Health
- National Human Genome Research Institute