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Review
. 2023 Jan 23:14:1122255.
doi: 10.3389/fimmu.2023.1122255. eCollection 2023.

Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility

Phillip Ssekamatte  1 , Obondo James Sande  1 , Reinout van Crevel  2 , Irene Andia Biraro  3
Affiliations
Review

Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility

Phillip Ssekamatte et al. Front Immunol. .

Abstract

Due to the increasing prevalence of diabetes mellitus (DM) globally, the interaction between DM and major global diseases like tuberculosis (TB) is of great public health significance, with evidence of DM having about a three-fold risk for TB disease. TB defense may be impacted by diabetes-related effects on immunity, metabolism, and gene transcription. An update on the epidemiological aspects of DM and TB, and the recent trends in understanding the DM-associated immunologic, metabolic, and genetic mechanisms of susceptibility to TB will be discussed in this review. This review highlights gaps in the incomplete understanding of the mechanisms that may relate to TB susceptibility in type 2 DM (T2DM). Understanding these three main domains regarding mechanisms of TB susceptibility in T2DM patients can help us build practical treatment plans to lessen the combined burden of the diseases in rampant areas.

Keywords: diabetes; gene transcription; immunity; metabolism; tuberculosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
DM pathogenesis. DM is an immune-modulated disease. For T1DM, antigen presentation by B cells and DCs drives the activation of β−cell-specific T cells. In addition, the exposure of B cells to β−cell autoantigens leads to the production of islet β−cell targeting autoantibodies. These lead to β−cell destruction. For T2DM, IFN-γ production by activated CD4+ T cells activates macrophages to produce IL-1β and TNF. This low chronic-grade inflammation causes insulin resistance or inhibits insulin uptake in tissues. In addition, the cytokines cause insulin secretion by β-islet cells to compensate for reduced insulin sensitivity. These stimulate the Islet β cells to produce insulin. Persistent IL-1β and TNF production triggers β-cell islet destruction.
Figure 2
Figure 2
TB pathogenesis. Virulent Mtb that is phagocytosed by alveolar macrophages causes phagosome membrane damage and translocates to the cytoplasm. This results in necrosis and spread to other macrophages and dendritic cells. Mtb is processed and presented to CD4+ T cells that produce IFN-γ, enhancing the phagocytosis of infected macrophages and polymorphonuclear cells. In addition, activated CD8+ T cells produce perforin and granzymes that mediate the cytotoxic activity of infected macrophages.
Figure 3
Figure 3
TB and T2DM immunological dysregulation. Effects of T2DM on the various innate (DC, neutrophil, macrophage, ILC) and adaptive (CTL, Th1, Th2, Th17 and Tregs) immune cells.
Figure 4
Figure 4
Metabolic pathways related to hyperglycemia. Polyol and Hexosamine and PKC pathways cause increased ROS production and uptake resulting in increased mitochondrial stress. AGEs and RAGE production inhibits complement activation and macrophage phagocytosis, as well as promote macrophage apoptosis and increased ROS production. This increases oxidative stress, resulting in increased OxLDL. OxLDL causes lysosomal dysfunction and phagocytosis, which promote bacterial spread.
Figure 5
Figure 5
Gut microbiome, metabolic and genetic dysregulation in T2DM and TB. T2DM upregulates Lactobacillus and Firmicutes taxa of the gut microbiota. Lactobacillus promotes further T2DM development, while Firmicutes upregulate butyrate production. Butyrate inhibits Mtb-induced cytokine production, activation, and antigen presentation by DCs and CTLs. In addition, T2DM lowers specific amino acids and gene transcripts. Collectively, these mechanisms increase TB susceptibility.
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Grants and funding

This project is part of the EDCTP2 programme supported by the European Union (grant number RIA2018CO-2514-PROTID), the Government of Uganda through the Uganda Independence Scholarship Trust Fund (UISTF) and the MRC/UVRI and LSHTM Uganda Research Unit which is jointly funded by the UK Medical Research Council (MRC) part of UK Research and Innovation (UKRI) and the UK Foreign, Commonwealth and Development Office (FCDO) under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union.