Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

Abstract

Background People living with diabetes have an increased risk of developing active tuberculosis and are more likely to have poor tuberculosis-treatment outcomes, which may impact on control of tuberculosis as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in active tuberculosis patients relative to healthy individuals. The effects of diabetes and intermediate hyperglycaemia on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-tuberculosis comorbidity. Methods Whole blood samples were collected from active tuberculosis patients with diabetes (HbA1c ≥6.5%) or intermediate hyperglycaemia (HbA1c 5.7-6.5%), tuberculosis-only patients and healthy controls in four countries: South Africa, Romania, Indonesia and Peru. Differential blood gene expression was determined by RNA-seq (n=249). Results Diabetes increased the magnitude of gene expression change in the host transcriptome in tuberculosis, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with intermediate hyperglycaemia and tuberculosis exhibited blood transcriptomes much more similar to diabetes-tuberculosis patients than to patients with only tuberculosis. Both diabetes-tuberculosis and intermediate hyperglycaemia-tuberculosis patients had a decreased type I interferon response relative to tuberculosis-only patients. Conclusions Co-morbidity in individuals with both tuberculosis and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type 1 interferon responses in co-morbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with intermediate hyperglycaemia, showing that altered immunity to tuberculosis may also be present in this group. The TB disease outcomes in individuals with intermediate hyperglycaemia diagnosed with TB should be investigated further.

Pre-Diabetes Increases Tuberculosis Disease Severity, While High Body Fat Without Impaired Glucose Tolerance Is Protective

“…Increased susceptibility of T2D patients to TB is well established, however, whether pre-diabetes also predisposes to more severe manifestations of pulmonary TB remains elusive as large population-based studies on the association of pre-diabetes and TB have not been performed to date. Blood transcriptomic signatures from TB patients with pre-diabetes are more similar to those from TB patients with T2D compared to TB patients without any form of dysglycemia ( Eckold et al., 2020 ). This suggests that impaired immune responses to Mtb occur already during the early stages of dysglycemia in pre-diabetes.…”

“…Increased susceptibility of T2D patients to TB has been attributed to poor glycemic control ( Critchley et al., 2018 ). However, immune dysfunction and altered immunity to TB has also been demonstrated in individuals with pre-diabetes ( Kumar et al., 2014 ; Eckold et al., 2020 ). Strikingly, blood transcriptomic profiles of TB patients with pre-diabetes are more similar to TB patients with T2D than those without any form of dysglycemia ( Eckold et al., 2020 ).…”

“…However, immune dysfunction and altered immunity to TB has also been demonstrated in individuals with pre-diabetes ( Kumar et al., 2014 ; Eckold et al., 2020 ). Strikingly, blood transcriptomic profiles of TB patients with pre-diabetes are more similar to TB patients with T2D than those without any form of dysglycemia ( Eckold et al., 2020 ). Whether pre-diabetes increases susceptibility to TB and TB disease severity remains unknown and it is also not clear which immunological mechanisms underlie obesity associated resistance vs. diabetes associated susceptibility to TB.…”

Pre-diabetes increases tuberculosis disease severity, while high body fat without impaired glucose tolerance is protective

“…While prediabetic animals in our model showed lower Ccl2 mRNA at 8-weeks p.i., protein concentrations of CCL2 were not significantly different. Eckhold et al found reduced type I IFN responses in blood transcriptomic signatures from TB patients with pre-diabetes (Eckold et al, 2020). We did not observe reduced Ifnb1 mRNA expression in blood, however, IFN-b concentrations were significantly reduced in lungs of pre-diabetic mice at 8 weeks p.i.. A HFD-based model of T2D and TB recently demonstrated moderately higher Mtb burden in the early stages of infection at 2 weeks, but not during late infection, and reduced IFN-g production in HFD-fed diabetic mice (Alim et al, 2020), which is consistent with our data in this pre-diabetes model.…”

“…However, immune dysfunction and altered immunity to TB has also been demonstrated in individuals with pre-diabetes (Kumar et al, 2014;Eckold et al, 2020). Strikingly, blood transcriptomic profiles of TB patients with pre-diabetes are more similar to TB patients with T2D than those without any form of dysglycemia (Eckold et al, 2020). Whether pre-diabetes increases susceptibility to TB and TB disease severity remains unknown.…”