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Marakalala, Mohlopheni

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Marakalala

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Mohlopheni

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Marakalala, Mohlopheni
Author's Publications: search.filters.isAuthorOfPublication.225d4e9e-5768-4203-9652-5579d2cee7ef

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    The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
    (American Society for Microbiology, 2017) Kurthkoti, Krishna; Amin, Hamel; Marakalala, Mohlopheni; Ghanny, Saleena; Subbian, Selvakumar; Sakatos, Alexandra; Livny, Jonathan; Fortune, Sarah; Berney, Michael; Rodriguez, G. Marcela
    ABSTRACT This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis. We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of M. tuberculosis under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. M. tuberculosis mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies.
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    Inflammatory signaling in human Tuberculosis granulomas is spatially organized
    (2016) Marakalala, Mohlopheni; Raju, Ravikiran; Sharma, Kirti; Zhang, Yanjia; Eugenin, Eliseo A.; Prideaux, Brendan; Daudelin, Isaac B.; Chen, Pei-Yu; Booty, Matthew Gregory; Kim, Jin Hee; Eum, Seok Yong; Via, Laura E.; Behar, Samuel M.; Barry, Clifton E.; Mann, Matthias; Dartois, Véronique; Rubin, Eric
    Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased fashion. Using laser capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas possess a pro-inflammatory environment characterized by anti-microbial peptides, ROS and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum possesses a comparatively anti-inflammatory signature. These findings are consistent across a set of six subjects and in rabbits. While the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. The protein and lipid snapshots of human and rabbit lesions analysed here suggest that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.