Phagocytosis via Complement or Fc-Gamma Receptors Is Compromised in Monocytes from Type 2 Diabetes Patients with Chronic Hyperglycemia

Restrepo, Blanca I.; Twahirwa, Marcel; Rahbar, Mohammad H.; Schlesinger, Larry S.

doi:10.1371/journal.pone.0092977

Cited by 98 publications

(67 citation statements)

References 39 publications

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“…T2DM may favor the development and adverse treatment outcomes of TB due to the presence of hyperglycemia (Dooley & Chaisson, 2009;Ruslami et al, 2010;Singla et al, 2006), Th1 and Th17 response once TB infection has developed (Bashar et al, 2001;Restrepo, Twahirwa, Rahbar, & Schlesinger, 2014;van Crevel, Dockrell, & Consortium, 2014). Future studies should address the impact of the increase of T2DM prevalence on TB.…”

Section: Discussionmentioning

confidence: 98%

The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes

Perez-Navarro

Restrepo²,

Fuentes-Domínguez³

et al. 2017

Tuberculosis

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2 AbstractObjective: To evaluate the effect size of type 2 diabetes mellitus (T2DM) on tuberculosis (TB) treatment outcomes and multi drug resistance (MDR). Methods:A cohort with 507 individuals with diagnosed TB included 183 with coexistence of T2DM and TB (TB-T2DM). Participants were identified at the time of TB diagnosis and followed during the course of TB treatment. Then we computed relative risks and adjustments by Cox proportional hazards for outcome variables (drug resistance, death, relapse, treatment failure), and the size of their effect as Cohen's-d. Results:Patients with TB-T2DM were more likely to remain positive for acid-fast bacilli after two months of anti-TB treatment RR= [2.01 (95% CI: 1.3, 3.1)], to have drug resistant (DR) [OR 3.5 (1.8, 6.7)] and multi-drug resistant (MDR) TB [OR 3.5 (1.8, 7.1)]. The Cohen's-d for DR or MDR in T2DM was 0.69 when compared with non-DM subjects. The T2DM patients had higher odds of resistance to isoniazid (OR 3.9, 95% CI 2.01, 7.9), rifampicin (OR 3.4, 95%CI: 1.6, 7.2) and pyrazinamide (OR 9.4, 95% CI 2.8, 25.6), and their effect sizes were ≥ 0.67. Patients with TB-T2DM (versus no DM) were more likely to present with MDR TB (HR 3.1; 95% CI 1.7, 5.8; p <0.001), treatment failure (HR 2.04; 95% CI 1.07, 3.8; p 0.02) and relapse (HR 2.1; 95% CI 1.2, 3.8; p 0.002), with effect sizes ≥0.39. Conclusion:T2DM showed a substantial contribution to the presence of DR or MDR-TB and to adverse clinical outcomes during and after TB treatment. Our findings support the importance for routine screening of T2DM among newly-diagnosed TB patients in order to stratify them for immediate DR assessment, and highlight the need for clinical trials to evaluate variations to the standard TB treatment in TB-T2DM to prevent adverse treatment outcomes.Keywords: Tuberculosis, type 2 diabetes mellitus, effect, size 3 IntroductionThe overall prevalence of diabetes mellitus (DM) has increased rapidly as a result of an aging population, urbanization and associated changes lifestyle during the last decades. The International Diabetes Federation (IDF) estimated in 2015 the worldwide prevalence of type 2 diabetes mellitus (T2DM) was 8.8% (415 million people) (IDF). In Mexico, the prevalence of T2DM increased by 4.7% from 1998 to 2012, with a morbidity rate of 358.2 per 100 000 in 2012 (Sistema.Nacional. de.Vigilancia.Epidemiológica, 2013). Meanwhile, the World Health Organization (WHO) reported 9.5 million new cases of TB in 2014 and 1.5 million deaths.( WHO, 2015) In Mexico, the tuberculosis (TB) incidence was 23 per 100,000, reflecting a serious public health problem (Delgado-Sanchez et al., 2015).The increase in prevalence of T2DM has had a significant impact on tuberculosis comorbidity, with prevalence rates ranging from 10% to 30%, mainly affecting developing countries, including Some studies report that T2DM increased two to three times the risk of TB (Dooley & Chaisson, 2009;Jeon & Murray, 2008;Perez-Navarro et al., 2015), and diminishes the success of treatment cure (Baker et al., 2011...

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Section: Discussionmentioning

confidence: 98%

The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes

Perez-Navarro

Restrepo²,

Fuentes-Domínguez³

et al. 2017

Tuberculosis

Self Cite

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“…recent studies on TB and diabetes highlight the importance of using autologous serum with macrophages to maintain undefined soluble immune factors [312], and 5) similarities and differences among mammalian macrophage sources. As we gain more knowledge about macrophage responses in the context of organ-specific microenvironments, our understanding of the molecular details underlying the pivotal M.tb -macrophage interactions occurring during TB will become more defined.…”

Section: Discussionmentioning

confidence: 99%

Macrophage immunoregulatory pathways in tuberculosis

Rajaram

Dodd

et al. 2014

Seminars in Immunology

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108

104

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Macrophages, the major host cells harboring Mycobacterium tuberculosis (M.tb), are a heterogeneous cell type depending on their tissue of origin and host they are derived from. Significant discord in macrophage responses to M.tb exists due to differences in M.tb strains and the various types of macrophages used to study tuberculosis (TB). This review will summarize current concepts regarding macrophage responses to M.tb infection, while pointing out relevant differences in experimental outcomes due to the use of divergent model systems. A brief description of the lung environment is included since there is increasing evidence that the alveolar macrophage (AM) has immunoregulatory properties that can delay optimal protective host immune responses. In this context, this review focuses on selected macrophage immunoregulatory pattern recognition receptors (PRRs), cytokines, negative regulators of inflammation, lipid mediators and microRNAs (miRNAs).

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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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Phagocytosis via Complement or Fc-Gamma Receptors Is Compromised in Monocytes from Type 2 Diabetes Patients with Chronic Hyperglycemia

Cited by 98 publications

References 39 publications

The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes

The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes

Macrophage immunoregulatory pathways in tuberculosis

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

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