ORCID Profile
0000-0002-5517-373X
Current Organisation
Stellenbosch University
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Publisher: Springer Science and Business Media LLC
Date: 04-05-2021
Publisher: Public Library of Science (PLoS)
Date: 24-08-2023
DOI: 10.1371/JOURNAL.PGEN.1010888
Abstract: Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and show no evidence of immune sensitization to Mycobacterium tuberculosis ( Mtb ) as defined by persistently negative tuberculin skin tests (TST) and interferon gamma release assays (IGRA). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to in iduals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil s les from 17 HITTIN (PMN HITTIN ) and 11 HIT (PMN HIT ) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. Since there was no significant differential transcriptional response at 1h between infected PMN HITTIN and PMN HIT , we focused on the 6h timepoint. When compared to uninfected PMN, PMN HITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated differentially expressed genes (DEGs) (absolute cutoff of a log 2 FC of 0.2, FDR 0.05) whereas PMN HIT demonstrated 3816 significantly upregulated and 3794 significantly downregulated DEGs following 6h Mtb infection. Contrasting the log 2 FC 6h infection response to Mtb from PMN HITTIN against PMN HIT , 2285 genes showed significant differential response between the two groups. Overall PMN HITTIN had a lower fold change response to Mtb infection compared to PMN HIT . According to pathway enrichment, Apoptosis and NETosis were differentially regulated between HITTIN and HIT PMN responses after 6h Mtb infection. To corroborate the blunted NETosis transcriptional response measured among HITTIN, fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMN HITTIN compared to PMN HIT , showing that PMN HITTIN have a distinct response to Mtb .
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.YEXCR.2018.12.022
Abstract: Leucine-rich repeat kinase 2 (LRRK2) is important in various cellular processes including mitochondrial homeostasis and mutations in this gene lead to Parkinson's disease (PD). However, the full spectrum of LRRK2's functions remain to be elucidated. The translocase of outer mitochondrial membrane (TOM) complex is essential for the import of almost all nuclear-encoded mitochondrial proteins and is fundamental for cellular survival. Using co-immunoprecipitation, super-resolution structured illumination microscopy (SR-SIM), and 3D virtual reality (VR) assisted co-localization analysis techniques we show that wild-type and mutant (G2019S) LRRK2 associate and co-localize with subunits of the TOM complex, either under basal (dimethyl sulfoxide, DMSO) or stress-induced (carbonyl cyanide m-chlorophenyl hydrazine, CCCP) conditions. Interestingly, LRRK2 interacted with TOM40 under both DMSO and CCCP conditions, and when the PD causing mutation, G2019S was introduced, the association was not altered. Moreover, overexpression of G2019S LRRK2 resulted in the formation of large, perinuclear aggregates that co-localized with the TOM complex. Taken together, this is the first study to show that both WT and mutant LRRK2 associate with the TOM complex subunits. These findings provide additional evidence for LRRK2's role in mitochondrial function which has important implications for its role in PD pathogenesis.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: Informa UK Limited
Date: 02-01-2016
No related grants have been discovered for Ben Loos.