Human Genomics of Mycobacterium tuberculosis Infection and Disease
Purpose of Review
The study of the genetic basis of tuberculosis pathogenesis has benefited from powerful technological innovations, a more structured definition of latent and clinical manifestations of the disease, and the application of functional genomic approaches. This short review aims to summarize recent advances and to provide a link with results of previous human genetic studies of tuberculosis susceptibility.
Transcriptomics has been shown to be a useful tool to predict progression from latency to clinical disease while functional genomics has traced the molecular events that link pathogen-triggered gene expression and host genetics. Resistance to infection with Mycobacterium tuberculosis has been revealed to be strongly impacted by host genetics. Host genomics of clinical disease has been shown to be most powerful when focusing on carefully selected clinical entities and possibly by considering host-pathogen combinations.
Future studies need to build on the latest molecular findings to define disease subtypes to successfully elucidate the human genetic component in tuberculosis pathogenesis.
KeywordsTuberculosis Host genomics of tuberculosis Functional genomics of tuberculosis Transcript biomarkers Human genetics of infection
Research in the authors’ laboratory is supported by grants from the Canadian Institutes of Health Research (CIHR; FDN-143332) and the National Institutes of Health (NIH; R01 AI124349).
Compliance with Ethical Standards
Conflict of Interest
Both authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 1.World Health Organization. Global tuberculosis report 2016.Google Scholar
- 15.• Pacis A, Tailleux L, Morin AM, Lambourne J, MacIsaac JL, Yotova V, et al. Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res. 2015;25(12):1801–11. Demonstration of epigenetic remodelling of dendritic cells by Mtb. CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Blischak JD, Tailleux L, Mitrano A, Barreiro LB, Gilad Y. Mycobacterial infection induces a specific human innate immune response. Sci Rep. 2015;5.Google Scholar
- 22.• Zak DE, Penn-Nicholson A, Scriba TJ, Thompson E, Suliman S, Amon LM, et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016;387(10035):2312–22. Description of a blood transcriptomics signature for progression to clinical disease. CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Ma N, Zalwango S, Malone LL, Nsereko M, Wampande EM, Thiel BA, et al. Clinical and epidemiological characteristics of individuals resistant to M. tuberculosis infection in a longitudinal TB household contact study in Kampala, Uganda. BMC Infect Dis. 2014;14:352.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.• Cobat A, Gallant CJ, Simkin L, Black GF, Stanley K, Hughes J, et al. Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J Exp Med. 2009;206(12):2583–91. Identification of two major loci controlling TST-intensity and negativity. CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Cobat A, Hoal EG, Gallant CJ, Simkin L, Black GF, Stanley K, et al. Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis. Clin Infect Dis. 2013;57(7):963–70.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Jabot-Hanin F, Cobat A, Feinberg J, Grange G, Remus N, Poirier C, et al. Major loci on chromosomes 8q and 3q control interferon gamma production triggered by bacillus Calmette-Guerin and 6-kDa early secretory antigen target, respectively, in various populations. J Infect Dis. 2016;213(7):1173–9.CrossRefPubMedGoogle Scholar
- 43.• Grant AV, El Baghdadi J, Sabri A, El Azbaoui S, Alaoui-Tahiri K, Abderrahmani Rhorfi I, et al. Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region. Am J Hum Genet. 2013;92(3):407–14. Positional identification of TOX as early onset TB susceptibility gene. CrossRefPubMedPubMedCentralGoogle Scholar
- 56.• Sobota RS, Stein CM, Kodaman N, Scheinfeldt LB, Maro I, Wieland-Alter W, et al. A locus at 5q33.3 confers resistance to tuberculosis in highly susceptible individuals. Am J Hum Genet. 2016;98(3):514–24. Use of a highly selected phenotype to identify strong genetic TB resistance markers. CrossRefPubMedPubMedCentralGoogle Scholar
- 57.• Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell. 2012;148(3):434–46. Identifcation of a genetic polymorphism for treatment stratification of TBM patients. CrossRefPubMedPubMedCentralGoogle Scholar