Genetic and immunological investigation of patients with mycobacterial diseases

Date

2023-8

Author

Tank, Umut

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Mycobacteria are widespread bacteria with huge diversity that can be found in many environments. Although over one-third of the human population is infected with Mycobacterium species, only a small proportion develops clinical disease. Inborn defects of IL-12/IFN-γ immunity have been shown to underlie susceptibility to mycobacterial diseases in otherwise healthy individuals; however, genetic causes are still unknown in many cases. The present study aims to discover novel disease- causing variations by performing whole-exome sequencing (WES) on the genomic DNA of 6 patients with mycobacterial diseases and to investigate immune responses in leukocytes of the patients. Potential loss-of-function and missense variants with minor allele frequency of less than 1% were retained in the WES analysis. However, no candidate mutations in genes associated with anti-mycobacterial immunity were revealed. We also found that IL-12/IFN-γ axis was functionally intact in leukocytes of the patients. TNF responses to different TLR ligands were comparable between CD14+ monocytes from the patients and healthy donors. Last, we characterized a candidate heterozygous missense variant (p.M559V) in TBK1 in a tuberculosis patient. We found that TBK1 with p.M559V had a similar expression as the wild type (WT) when transiently transfected in HEK293 cells. There was also similar induction of IFN-b- and ISRE-dependent luciferase activity in HEK293 cells over-expressing TBK1 with p.M559V compared to the WT. These findings indicated that the p.M559V was likely benign. Further studies can include more patients and utilize whole genome sequencing in trio designs, including the parents of patients, in order to capture all true genetic variations.

Subject Keywords

Mycobacterial diseases, Human genetics, Whole exome sequencing, IFN-γ, IL-12

URI

https://hdl.handle.net/11511/105131

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Graduate School of Natural and Applied Sciences, Thesis