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; Soumya Raychaudhuri

doi:10.1038/s41467-024-54741-w

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

Nat Commun. 2024 Nov 29;15(1):10393. doi: 10.1038/s41467-024-54741-w.

Authors

Yang Luo^#^{1

2

3

4

5

6}, Chuan-Chin Huang^#^{7

8}, Nicole C Howard^#⁹, Xin Wang^#⁹, Qingyun Liu^#^{9

10}, Xinyi Li¹¹, Junhao Zhu⁹, Tiffany Amariuta^{1

2

3

4

5

12

13}, Samira Asgari^{1

2

3

4

5

14}, Kazuyoshi Ishigaki^{1

2

3

4

5

15}, Roger Calderon¹⁶, Sahadevan Raman², Alexandrea K Ramnarine², Jacob A Mayfield², D Branch Moody², Leonid Lecca^{8

17}, Sarah M Fortune^{18

19}, Megan B Murray^{20

21

22}, Soumya Raychaudhuri^{23

24

25

26

27}

Affiliations

¹ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
⁷ Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
⁹ Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
¹¹ Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA.
¹² Halıcıoğlu Data Science Institute, University of California San Diego, La Jolla, CA, USA.
¹³ Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹⁴ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, USA.
¹⁵ Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Kobe, Japan.
¹⁶ Advanced Research and Health, Lima, Peru.
¹⁷ Socios En Salud Sucursal Peru, Lima, Peru.
¹⁸ Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. [email protected].
¹⁹ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. [email protected].
²⁰ Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
²¹ Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
²² Department of Epidemiology, Harvard T.H Chan School of Public Health, Boston, MA, USA. [email protected].
²³ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
²⁴ Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
²⁵ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
²⁶ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. [email protected].
²⁷ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Adult
COVID-19 / genetics
COVID-19 / virology
Cohort Studies
Female
Genome, Bacterial
Host-Pathogen Interactions* / genetics
Humans
Macrophages / microbiology
Male
Mutation
Mycobacterium tuberculosis* / genetics
Mycobacterium tuberculosis* / pathogenicity
Peru / epidemiology
Polymorphism, Single Nucleotide
SARS-CoV-2 / genetics
Thioredoxin-Disulfide Reductase / genetics
Thioredoxin-Disulfide Reductase / metabolism
Tuberculosis* / genetics
Tuberculosis* / microbiology

Substances

Thioredoxin-Disulfide Reductase

Abstract

MeSH terms

Substances

Grants and funding