Tucker Boyd

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.

Works Cited:

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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