Investigating the role of immune-endocrine alterations during type 2 diabetes associated with changes in Mycobacterium tuberculosis growth

Klazen, Jessica (2017-03)

Thesis (MSc)--Stellenbosch University, 2017.

Thesis

Background There is a high co-prevalence between type 2 diabetes (DM2) and other infectious diseases. This is particularly problematic with the rise in co-prevalence between DM2 and Tuberculosis (TB). However, the underlying association between TB and DM2 is still poorly understood. We hypothesize that immune-endocrine alterations in latently infected individuals with DM2 are associated with reduced Mycobacterium tuberculosis (Mtb)-killing efficacy. We aimed to determine whether Mtb phagocytosis and/or killing efficacy of peripheral blood mononuclear cells (PBMCs) and monocytes (MNs) from close contacts (CCs) of TB patients with or without DM2 is altered and its association with physiological changes characteristic of DM2. In addition, we aimed to identify immune modulatory properties of endogenous hormones such as cortisol, leptin and insulin on PBMCs and MNs of latently infected individuals. Materials and methods First, we compared the bacterial burden in PBMCs and MNs of TB close contacts with normal to poorly controlled glycemia during an Mtb infection. We investigated the association between glycemic control, cells counts and hormone signatures, with bacterial burden in DM2 patients. Secondly, we treated PBMCs and MNs with cortisol, leptin and insulin to determine whether these hormones influenced bacterial burden, mycobacterium induced cytokine production and phenotypes of CD4+ and CD8+ T cells. Results Bacterial burden was increased in DM2 patients when compared to healthy participants in both PBMCs and MNs. High bacterial burden was associated poor glycemic control. DM2 patients had higher levels of neutrophil counts, white cell counts (WCC) and lymphocyte counts, but low percentage MNs in whole blood compared to healthy participants. Cortisol levels remained unchanged between the groups, however, there was a negative correlation between cortisol and interferon-γ (IFN-γ) (p=0.03, r=0.52) in the DM2 group. Cortisol, leptin and insulin did not influence the bacterial burden in both PBMCs and MNs. However, the hormones influenced the Mtb induced cytokine production in PBMCs. Cortisol decreased the production of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, TNF-β, IL-8, IFN-γ and granulocyte-macrophage colony stimulating factor (GM-CSF). Leptin decreased the production of IL-1RA, IL-13, IL-5, fibroblast growth factor (FGF)-2. Insulin decreased the production of vascular endothelial growth factor (VEGF), IL-1RA and increased the production of IL-5. Conclusion In DM2, phagocytosis and killing efficacy of PBMCs and MNs from CC of TB patients were associated with physiological changes characteristic to DM2. Poor bacterial control in DM2 was associated with hyperglycemia, chronic inflammation induced by increased WCC, neutrophil, and lymphocyte counts. The level of cortisol in DM2 individuals negatively correlated with IFN-γ, thus suppressing Th1 response. Furthermore, the study indicate that endogenous hormones such as cortisol, leptin and insulin could potentially mediate some cytokine response in DM2 patients. Cortisol potentially suppress macrophage activation or Th1 activity, which could lead to poor bacterial control. Whereas, leptin upregulates Th1 response that may improve bacterial control. However, its role still remains undetermined. The role of insulin is debatable as it may either induce a Th2 response, which could lead to poor bacterial control, or may a play a role in preventing the spread of Mtb to other organs by decreasing the production of VEGF. Therefore, during DM2, immune alterations and hyperglycemia are associated with decreased bacterial control, and that endocrine factors such as cortisol would suppress Th1 response, regardless whether it is elevated or not. Thus, would potentially exacerbate bacterial control in cases where DM2 is worsened by other complications.

Agtergrond Daar is 'n hoë mede-voorkoms tussen tipe 2-diabetes (DM2) en met ander aansteeklike siektes, wat op sy beurt baie druk op gesondheidsorg plaas, in gemeenskappe met beperkte hulpbronne. Dit is veral 'n probleem met die styging in mede-voorkoms tussen DM2 en Tuberkulose (TB). Maar die onderliggende verband tussen TB en DM2 is steeds onduidelik. Ons hipotese stel voor dat immuun-endokriene afwykings in latente infekte individue met DM2 verband hou met verminderde doodmaak doeltreffendheid van Mycobacterium tuberculosis (Mtb). Ons het gepoog om vas te stel of Mtb fagositose en of uitwissing geaffekteer word in perifere bloed mononukleêre selle (PBMCs) en monosiete (MNS) van nabye kontakte van TB-pasiënte (CC) met of sonder DM2 verander en die verbintenis met fisiologiese veranderinge, kenmerkend aan DM2, te bepaal. Verder bepaal ons watter immuun-regulerende eienskappe endogene hormone soos kortisol, leptien en insulien op PBMCs en MNS tydens Mtb infeksie het. Metodes Eerstens, vergelyk ons die bakteriële las in PBMCs en MNS van CCs met normale en hoë bloedsuiker vlakke. Ons ondersoek die verband tussen glukemiese beheer, sel tellings en hormoon patrone, met bakteriële las in die selle van DM2 pasiënte. Tweedens, het ons PBMCs en MNS met kortisol, leptien en insulien behandel om te bepaal hoe hierdie hormone bakteriële las beïnvloed, sitokien produksie na Mtb infeksies asook fenotipe van CD4+ and CD8+ T sells. Resultate Bakteriële las is verhoog in DM2 pasiënte in vergelyking met gesonde deelnemers in beide PBMCs en MNS. Hoë bakteriële las hou verband met swak glukemiese beheer. DM2 pasiënte het hoër neutrofiele, wit sel en limfosiet tellings maar 'n laer persentasie MNS in bloed in vergelyking met gesonde deelnemers. Kortisol vlakke het onveranderd gebly tussen die groepe, terwyl daar 'n negatiewe korrelasie tussen kortisol en interferon-γ (IFN-γ) was (p = 0,03, r = 0.52). Kortisol, leptien en insulien het geen invloed op die bakteriële las in beide PBMCs en MNS.,maar die hormone beïnvloed die sitokien produksie van PBMCs wat met Mtb geinfekteer is. Kortisol inhibeer die produksie van interlukin (IL) -1β, IL-6, tumer nekrose faktor (TNF) -α, TNF-β, IL-8, IFN-γ en granulocyte-makrofaag kolonie stimulerende faktor (GM-CSF). Leptien inhibeer die produksie van IL-1RA, IL-13, IL-5, fibroblast groeifaktor (FGF) -2. Insulien inhibeer die produksie van vaskulêre endoteel groeifaktor (VEGF) en IL-1RA en stimuleer die produksie van IL-5. Afsluiting Swak bakteriële beheer in DM2 is toegeskryf aan hoë bloedsuiker vlakke, chroniese inflammasie veroorsaak deur 'n toename in wit bloed, neutrofiel en limfosiet sel tellings. . Die vlak van kortisol in DM2 individue was negatief gekorreleer met IFN-γ, dus kon potensieel Th1 reaksie onderdruk. Endogene hormone soos kortisol, leptien en insulien kan sommige cytokine-reaksie by DM2 pasiënte bemiddel. Kortisol verminder óf makrofage aktivering of Th1 aktiwiteit, wat kan lei tot swak bakteriële beheer. Leptien aan die ander kant induseer ‘n Th1 reaksie wat bakteriële beheer kan verbeter. Die rol van insulien is onduidelik, aangesien dit ook 'n Th2 reaksie kan induseer, wat kan lei tot swak bakteriële beheer, of dalk 'n 'n rol speel in die voorkoming van die verspreiding van Mtb na ander organe deur die produksie van VGEF te verminder. Tydens DM2 is immuun veranderings en hoë bloedsuiker vlakke geassosieer met verlaagde bakteriële beheer, en dat endokriene faktore soos kortisol sou Th1 reaksie onderdruk, ongeag of dit verhoog is of nie. Dus, sou potensieel vererger bakteriële beheer in gevalle waar DM2 is vererger word deur ander komplikasies.

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