Browsing by Author "Ioana, Mihai"

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    Human monocytic suppressive cells promote replication of mycobacterium tuberculosis and alter stability of in vitro generated granulomas
    (Frontiers Media, 2018) Agrawal, Neha; Streata, Ioana; Pei, Gang; Weiner, January; Kotze, Leigh; Bandermann, Silke; Lozza, Laura; Walzl, Gerhard; Du Plessis, Nelita; Ioana, Mihai; Kaufmann, Stefan H. E.; Dorhoi, Anca
    ENGLISH ABSTRACT: Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
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    Impact of intermediate hyperglycaemia as well as diabetes on immune dysfunction in tuberculosis
    (Oxford University Press, 2020-01) Eckold, Clare; Kumar, Vinod; Weiner, January; Alisjahbana, Bachti; Riza, Anca-Lelia; Ronacher, Katharina; Coronel, Jorge; Kerry-Barnard, Sarah; Malherbe, Stephanus T.; Kleynhans, Leanie; Stanley, Kim; Ruslami, Rovina; Ioana, Mihai; Ugarte-Gil, Cesar; Walzl, Gerhard; van Crevel, Reinout; Wijmenga, Cisca; Critchley, Julia A.; Dockrell, Hazel M.; Cliff, Jacqueline M.
    Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 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 TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.