Prediabetes is associated with the modulation of antigen-specific Th1/Tc1 and Th17/Tc17 responses in latent Mycobacterium tuberculosis infection

Kumar, Nathella Pavan; Moideen, Kadar; Dolla, Chandrakumar; Kumaran, Paul; Babu, Subash

doi:10.1371/journal.pone.0178000

Cited by 17 publications

(20 citation statements)

References 24 publications

(43 reference statements)

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“…Immunological differences in DM-TB compared to TB only include enhanced proinflammatory responses [ 12 ], and increased circulating cytokines have also been described in IH-TB [ 41 ]. Immune abnormalities are detectable in individuals latently infected with M. tuberculosis with IH [ 42 ], and it is possible that concurrent intermediate hyperglycemia and latent TB infection drives the development of both diseases, in a similar manner to the synergism between TB and HIV disease. This may indicate a relationship between moderate HbA1c values and TB susceptibility that warrants careful clinical considerations, and investigation of clinical disease outcome.…”

Section: Discussionmentioning

confidence: 99%

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

Eckold

Kumar

Weiner

et al. 2020

Clinical Infectious Diseases

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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.

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Section: Discussionmentioning

confidence: 99%

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

Eckold

Kumar

Weiner

et al. 2020

Clinical Infectious Diseases

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“…To further characterize the role of CD4 + and CD8 + T‐cell cytokines in LTB with coincident PDM, Kumar et al . studied the baseline, mycobacterial antigen and mitogen‐stimulated T‐cell cytokine responses in LTB individuals with (LTB‐PDM) or without (LTB‐NDM) concomitant PDM.…”

Section: Effect Of Pre‐diabetes In Tb Patientsmentioning

confidence: 99%

Influence of diabetes mellitus on immunity to human tuberculosis

2017

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SummaryType 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease.

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“…γδ T cells can produce Th1 (TNFα, IFNγ) cytokines which are crucial for immune protection against viruses and intracellular microbes ( O’Brien et al, 2009 ; Bonneville et al, 2010 ). Our previous studies have shown that antigen-specific Th1 responses in CD4 + T cells were reduced in LTB DM and LTB PDM comorbidities ( Kumar et al, 2017 ). Our findings suggest that the frequencies of γδ T cells expressing Th1 cytokines (mainly IFNγ, TNFα) are also decreased in the LTB DM and LTB PDM groups compared to the LTB NDM group.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, IL-22 is produced by a wide range of cells, which includes Th1, Th17, γδ T cells, and innate immune cells like innate lymphoid cells (ILCs) ( Toussirot et al, 2018 ; Cella et al, 2019 ). Our earlier study has shown that antigen-specific Th17 responses in CD4 + T cells were reduced in LTB DM and LTB PDM comorbidities ( Kumar et al, 2017 ). Our current study demonstrates diminished frequencies of γδ T cells expressing IL-17 family cytokines in LTB DM or LTB PDM comorbidity.…”

Section: Discussionmentioning

confidence: 99%

“…LTB DM is associated with decreased systemic and Mtb antigen-specific levels of type 1 and type 17 cytokines ( Kumar et al, 2014 ). The previous study has also shown that LTB PDM was characterized by decreased antigen-specific frequencies of T helper (Th)1/T cytotoxic (Tc)1 and Th17/Tc17 cells ( Kumar et al, 2017 ). Likewise, non-conventional T cells play a crucial function in protecting against TB disease, especially in early infection stages ( De Libero and Mori, 2014 ; Huang, 2016 ; Meermeier et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Decreased Frequencies of Gamma/Delta T Cells Expressing Th1/Th17 Cytokine, Cytotoxic, and Immune Markers in Latent Tuberculosis-Diabetes/Pre-Diabetes Comorbidity

Kathamuthu

Kumar

Moideen

et al. 2021

Front. Cell. Infect. Microbiol.

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Antigen-specific gamma-delta (γδ) T cells are important in exhibiting anti-mycobacterial immunity, but their role in latent tuberculosis (LTB) with diabetes mellitus (DM) or pre-DM (PDM) and non-DM comorbidities have not been studied. Thus, we have studied the baseline, mycobacterial (PPD, WCL), and positive control antigen-stimulated γδ T cells expressing Th1 (IFNγ, TNFα, IL-2) and Th17 (IL-17A, IL-17F, IL-22) cytokine as well as cytotoxic (perforin [PFN], granzyme [GZE B], granulysin [GNLSN]) and immune (GMCSF, PD-1, CD69) markers in LTB (DM, PDM, NDM) comorbidities by flow cytometry. In the unstimulated (UNS) condition, we did not observe any significant difference in the frequencies of γδ T cells expressing Th1 and Th17 cytokine, cytotoxic, and immune markers. In contrast, upon PPD antigen stimulation, the frequencies of γδ T cells expressing Th1 (IFNγ, TNFα) and Th17 (IL-17F, IL-22) cytokine, cytotoxic (PFN, GZE B, GNLSN), and immune (CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Similarly, upon WCL antigen stimulation, the frequencies of γδ T cells expressing Th1 (TNFα) and Th17 (IL-17A, IL-22) cytokine, cytotoxic (PFN), and immune (PD-1, CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Finally, upon P/I stimulation we did not observe any significant difference in the γδ T cell frequencies expressing cytokine, cytotoxic, and immune markers between the study populations. The culture supernatant levels of IFNγ, TNFα, and IL-17A cytokines were significantly increased in LTB DM and PDM after stimulation with Mtb antigens compared to LTB NDM individuals. Therefore, diminished γδ T cells expressing cytokine, cytotoxic, and other immune markers and elevated levels of cytokines in the supernatants is a characteristic feature of LTB PDM/DM co-morbidities.

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Prediabetes is associated with the modulation of antigen-specific Th1/Tc1 and Th17/Tc17 responses in latent Mycobacterium tuberculosis infection

Cited by 17 publications

References 24 publications

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

Influence of diabetes mellitus on immunity to human tuberculosis

Decreased Frequencies of Gamma/Delta T Cells Expressing Th1/Th17 Cytokine, Cytotoxic, and Immune Markers in Latent Tuberculosis-Diabetes/Pre-Diabetes Comorbidity

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