Variance in Interferon-Gamma Levels Due to Genetic and Epigenetic Mutations Impacts Tuberculosis Susceptibility
Background: Tuberculosis is a globally prevalent disease responsible for over 10 million infections each year caused by Mycobacterium tuberculosis and greatly impacts impoverished areas.1,2 Tuberculosis results from infection and ineffective clearance by alveolar macrophages in the respiratory tract and presents in patients with chronic coughing, dyspnea, and fever.3 Normal resolution of infection involves macrophage activation through interferon-gamma mediated upregulation of the immune response.4 Decreased interferon-gamma levels have been found to correlate with increased tuberculosis susceptibility. Importantly, the mutations behind lower interferon-gamma levels, including the rs1861494 allele and +874 position as well as increased hypermethylation and cAMP, can be further investigated as possible future therapeutic targets to help combat the global tuberculosis pandemic.2,5-6
Objective: The genetic and epigenetic mechanisms by which susceptibility to Mycobacterium tuberculosis increases and involves downregulation of macrophage activation will be explored.
Search Methods: The PubMed database was used to conduct an online search from 2018 to 2023 including the following terms: “tuberculosis”, “susceptibility”, “interferon-gamma”, “polymorphisms”, and “Mycobacterium”.
Results: Studies indicated that specific mutations at the rs1861494 allele were associated with increased tuberculosis infections corresponding to lower interferon-gamma levels.2 This results in decreased macrophage activation and lower apoptosis rates leading to decreased clearance of Mycobacterium that corresponds with fewer reactive oxygen intermediates being generated.2 Additional mutations at the +874 position were also associated with increased susceptibility stemming from unbound NF-kB that led to decreased macrophage activation by interferon-gamma.5 However, no association was found relating to tuberculosis antimicrobial resistance or the development of multidrug-resistant tuberculosis to this mutation.5 Additional epigenetic alterations were associated with altered tuberculosis susceptibility including hypermethylation at the -53 CpG site.6 This hypermethylation prevents the binding of CREB and ATF2 transcription factors, decreasing transcription of the interferon-gamma gene.6 In a normal TH1 response, the -53CpG site is unmethylated to encourage transcription of the IFN-G gene and activation of macrophages. Along with hypermethylation, cAMP levels were associated with a decreased T-lymphocyte response, leading to lowered interferon-gamma levels, reducing macrophage activation and the generation of reactive oxygen intermediates.7 Increased cAMP levels led to elevated protein kinase A activity, resulting in decreased CREB and ATF2 expression that correlates with altered interferon-gamma transcription as a response to the activation of Csk and inhibition of Lck and the corresponding T-cell response by protein kinase A.7 Supporting the importance of interferon-gamma, treatment of multidrug-resistant tuberculosis with interferon-gamma and antibody IgA reduced growth of Mycobacterium tuberculosis and improved frequencies of phagosome-lysosome fusion and bacterial clearance.8
Conclusion: Several studies found decreased interferon-gamma levels that result from genetic mutations, such as at the rs1861494 allele or +874 position. These mutations correlated with increased susceptibility to tuberculosis through less robust macrophage clearance mechanisms.2,5 Additional hypermethylation mutations were associated with tuberculosis infections.6 Consequently, genetic screening for these mutations and use of interferon-gamma supplementation treatment in those affected may offer potential future therapeutic treatments for the resolution of chronic tuberculosis infections and warrants further investigation.
- Ankrah AO, Glaudemans AWJM, Maes A, et al. Tuberculosis. Semin Nucl Med. 2018;48(2):108-130. doi:10.1053/j.semnuclmed.2017.10.005
- Wu S, Wang Y, Zhang M, Wang M, He JQ. Genetic variants in IFNG and IFNGR1 and tuberculosis susceptibility. Cytokine. 2019;123:154775. doi:10.1016/j.cyto.2019.154775
- Natarajan A, Beena PM, Devnikar AV, Mali S. A systemic review on tuberculosis. Indian J Tuberc. 2020;67(3):295-311. doi:10.1016/j.ijtb.2020.02.005
- Ghanavi J, Farnia P, Farnia P, Velayati AA. The role of interferon-gamma and interferon-gamma receptor in tuberculosis and nontuberculous mycobacterial infections. Int J Mycobacteriol. 2021;10(4):349-357. doi:10.4103/ijmy.ijmy_186_21
- Naz A, Ali M, Aslam MA, et al. Influence of single-nucleotide polymorphisms in the IFNG towards susceptibility to tuberculosis in a Pakistani population. Ann Hum Genet. 2019;83(6):426-433. doi:10.1111/ahg.12325
- Álvarez GI, Hernández Del Pino RE, Barbero AM, et al. Association of IFN-γ +874 A/T SNP and hypermethylation of the -53 CpG site with tuberculosis susceptibility. Front Cell Infect Microbiol. 2023;13:1080100. Published 2023 Jan 19. doi:10.3389/fcimb.2023.1080100
- Chung YT, Pasquinelli V, Jurado JO, et al. Elevated Cyclic AMP Inhibits Mycobacterium tuberculosis-Stimulated T-cell IFN-γ Secretion Through Type I Protein Kinase A. J Infect Dis. 2018;217(11):1821-1831. doi:10.1093/infdis/jiy079
- Tran AC, Diogo GR, Paul MJ, et al. Mucosal Therapy of Multi-Drug Resistant Tuberculosis With IgA and Interferon-γ. Front Immunol. 2020;11:582833. Published 2020 Oct 20. doi:10.3389/fimmu.2020.582833