Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control

Gómez, Diana I.; Twahirwa, Marcel; Schlesinger, Larry S.; Restrepo, Blanca I.

doi:10.1016/j.tube.2012.10.003

Cited by 83 publications

(80 citation statements)

References 38 publications

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“…Our findings indicate reduced binding and/or phagocytosis of Mtb by monocytes from DM patients versus non-DM controls. 36 This difference was only observed in media with high concentrations of autologous serum (p=0.03 with 20% serum). This suggests the defect in Mtb entry into DM monocytes lies, in part, in serum opsonins that deposit on the bacterial surface (C3b/iC3b and/or natural antibodies), and/or in their corresponding complement or Fcγ receptors.…”

Section: Impact Of Dm On the Natural History Of Tbmentioning

confidence: 93%

“…This is indirectly supported by the consistent relationship between blood glucose or HbA 1c levels and immune response outcomes in TB. 21,22,36,37 Furthermore, in a longitudinal cohort study, poorly-controlled DM (and not DM in itself) was associated with a higher risk of TB development. 12 However little is known about the underlying mechanisms.…”

Section: Mechanisms For Dysfunctional Immunity To Mtb In Dmmentioning

confidence: 99%

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Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus

Restrepo¹,

Schlesinger²

2013

Tuberculosis

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Tuberculosis (TB) is known to be fueled by HIV as well as social and economic factors. With progression of the diabetes mellitus (DM) pandemic in countries where TB is also endemic, focus is increasing on the potential links between DM and TB. Despite the magnitude of the DM-TB association woldwide, it is striking how little we know about the underlying biology that promotes this association which is a major concern to public health. In this review we summarize current findings regarding the alterations in the innate and adaptive immune responses of DM patients to Mycobacterium tuberculosis (Mtb). Current findings suggest underperforming innate immunity followed by a hyper-reactive cellular response to Mtb, but the contribution of these altered responses to TB susceptibility or to the more adverse clinical outcomes of TB patients with DM remains unclear. Elucidating the basic mechanisms underlying the higher susceptibility of DM patients to TB should lead to a strategy for stratification of the millions of DM patients worldwide into those with the highest TB risk for targeted TB prevention.

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Section: Impact Of Dm On the Natural History Of Tbmentioning

confidence: 93%

Section: Mechanisms For Dysfunctional Immunity To Mtb In Dmmentioning

confidence: 99%

Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus

Restrepo¹,

Schlesinger²

2013

Tuberculosis

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“…and phagocytosis of M. tuberculosis, and this defect is attributable to alterations in the diabetic monocyte as well as in serum opsonins [8][9][10] . Efficient phagocytosis and proper adaptive immune priming are necessary to activate cell-mediated immune responses that restrict M. tuberculosis growth, and delayed or altered responses likely contribute to diabetic TB susceptiblity 11 .…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes

Ronacher

Crevel

Critchley

et al. 2017

Chest

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There is growing interest in the re-emerging interaction between type 2 diabetes (DM) and tuberculosis (TB), but the underlying biological mechanisms are poorly understood despite their possible implications in clinical management. Experts in epidemiological, public health, basic science and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-ocurrence of TB and DM. We identified gaps in current knowlege of altered immunity in DM patients during TB, where most studies suggest an under-performing innate immunity, but exaggerated adaptive immunity to Mycobacterium tuberculosis. Various molecular mechanisms and pathways that may underly these observations in the DM host. These include signaling induced by excess advanced glycation end products (AGE) and their receptor (RAGE), higher levels of reactive oxidative species and oxidative stress, epigenetic changes due to chronic hyperglycemia, altered nuclear receptors and/or differences in cell metabolism (immuno-metabolism). Studies in humans at different stages of DM (no DM, pre-DM and DM) or TB (latent or active TB) should be complemented with findings in animal models, which provide the unique opportunity to study early events in the host-pathogen interaction. Such studies could also help identify biomarkers that will complement clinical studies in order to tailor the prevention of TB-DM, or avoid the adverse TB treatment outcomes that are more likely in these patients. Such studies will also inform new approaches to host-directed therapies. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Summary box• Type 2 diabetes is a syndrome characterised by a range of metabolic (e.g. hyperglycemia, hyperlipidemia), inflammatory, vascular and other changes that may all contribute to increasing TB susceptibility and pathology.• Monocytes and macrophages from diabetic patients and mice have defects leading to altered interactions with M. tuberculosis and delayed adaptive immune responses.• Most human studies have been conducted in patients with active TB, where those with TB-DM comorbidity are characterised by increased secretion of Th1, Th17 and Th2 cytokines. However, the few studies in individuals at risk for TB (LTBI) suggest a different cytokine profile.• Molecular pathways that involve AGE/RAGE, ROS, nuclear receptors and cellular metabolism are potential targets for host-directed therapies to reduce TB susceptibility or pathology in DM patients.• Animal models for TB-DM can improve our understanding of underlying mechanisms and effective treatment approaches for the comorbidity of TB and DM. IntroductionType 2 diabetes mellitus (DM) increases the risk of many infectious diseases, including tuberculosis 1 (TB), and it is now recognized that the increasing DM prevalence in high TB incidence countries such as Sub-Saharan Africa (SSA) is a challenge to TB control. 2 The known association between a chronic syndome like DM and an infectious disease like TB requires the near term development...

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“…For this we infect human blood monocytes from TB-naïve hosts with diabetes (versus no diabetes) with Mtb, and then evaluate differences in the host-pathogen outcomes. Current findings indicate that diabetic monocytes have significantly reduced association (binding and phagocytosis) of Mtb and this defect appears to be attributed to alterations in the diabetic monocyte as well as in serum opsonins for Mtb, particularly the C3 component of complement which mediates Mtb phagocytosis [20;21]. These in-vitro findings in humans are consistent with in-vivo observations in mice with chronic DM where there is also a reduced uptake of Mtb by alveolar macrophages within 2 weeks of infection [19].…”

Section: Dysfunctional Innate and Adaptive Immunity To Mtb In Dm Pmentioning

confidence: 99%

Impact of diabetes on the natural history of tuberculosis

Restrepo¹,

Schlesinger²

2014

Diabetes Research and Clinical Practice

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Tuberculosis (TB) is the number one bacterial killer worldwide and the current increase in type 2 diabetes mellitus patients (DM), particularly in countries where TB is also endemic, has led to the re-emerging importance of DM2 as a risk factor for TB. There is an urgent need to implement strategies for TB prevention among the millions of DM patients exposed to Mycobacterium tuberculosis (Mtb) worldwide, but knowledge is limited on how and when DM2 alters the natural history of this infection. In this review we summarize the current epidemiological, clinical and immunologic studies on TB and DM and discuss the clinical and public health implications of these findings. Specifically, we evaluate the mechanisms by which DM patients have a higher risk of Mtb infection and TB development, present with signs and symptoms indicative of a more infectious TB infection, and are more likely to have adverse TB treatment outcomes, including death. Emphasis is placed on type 2 DM given its higher prevalence in contemporary times, but the underlying role of hyperglycemia and of type 1 DM is also discussed.

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Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control

Cited by 83 publications

References 38 publications

Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus

Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes

Impact of diabetes on the natural history of tuberculosis

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