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

Yang Luo, Chuan-Chin Huang, Nicole C. Howard, Xin Wang, Qingyun Liu, Xinyi Li, Junhao Zhu, Tiffany Amariuta, Samira Asgari, Kazuyoshi Ishigaki, Roger Calderon, Sahadevan Raman, Alexandrea K. Ramnarine, Jacob A. Mayfield, D. Branch Moody, Leonid Lecca, Sarah M. Fortune (), Megan B. Murray () and Soumya Raychaudhuri ()
Additional contact information
Yang Luo: Harvard Medical School
Chuan-Chin Huang: Brigham and Women’s Hospital
Nicole C. Howard: Harvard T. H. Chan School of Public Health
Xin Wang: Harvard T. H. Chan School of Public Health
Qingyun Liu: Harvard T. H. Chan School of Public Health
Xinyi Li: University of Chicago
Junhao Zhu: Harvard T. H. Chan School of Public Health
Tiffany Amariuta: Harvard Medical School
Samira Asgari: Harvard Medical School
Kazuyoshi Ishigaki: Harvard Medical School
Roger Calderon: Advanced Research and Health
Sahadevan Raman: Harvard Medical School
Alexandrea K. Ramnarine: Harvard Medical School
Jacob A. Mayfield: Harvard Medical School
D. Branch Moody: Harvard Medical School
Leonid Lecca: Harvard Medical School
Sarah M. Fortune: Harvard T. H. Chan School of Public Health
Megan B. Murray: Brigham and Women’s Hospital
Soumya Raychaudhuri: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54741-w

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