Browsing by Author "Tabb, David L."

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    Microbial function and genital inflammation in young South African women at high risk of HIV infection
    (BMC (part of Springer Nature), 2020-11-21) Alisoltani, Arghavan; Manhanzva, Monalisa T.; Potgieter, Matthys; Balle, Christina; Bell, Liam; Ross, Elizabeth; Iranzadeh, Arash; du Plessis, Michelle; Radzey, Nina; McDonald, Zac; Calder, Bridget; Allali, Imane; Mulder, Nicola; Dabee, Smritee; Barnabas, Shaun; Gamieldien, Hoyam; Godzik, Adam; Blackburn, Jonathan M.; Tabb, David L.; Bekker, Linda-Gail; Jaspan, Heather B.; Passmore, Jo-Ann S.; Masson, Lindi
    Background: Female genital tract (FGT) inflammation is an important risk factor for HIV acquisition. The FGT microbiome is closely associated with inflammatory profile; however, the relative importance of microbial activities has not been established. Since proteins are key elements representing actual microbial functions, this study utilized metaproteomics to evaluate the relationship between FGT microbial function and inflammation in 113 young and adolescent South African women at high risk of HIV infection. Women were grouped as having low, medium, or high FGT inflammation by K-means clustering according to pro-inflammatory cytokine concentrations. Results: A total of 3186 microbial and human proteins were identified in lateral vaginal wall swabs using liquid chromatography-tandem mass spectrometry, while 94 microbial taxa were included in the taxonomic analysis. Both metaproteomics and 16S rRNA gene sequencing analyses showed increased non-optimal bacteria and decreased lactobacilli in women with FGT inflammatory profiles. However, differences in the predicted relative abundance of most bacteria were observed between 16S rRNA gene sequencing and metaproteomics analyses. Bacterial protein functional annotations (gene ontology) predicted inflammatory cytokine profiles more accurately than bacterial relative abundance determined by 16S rRNA gene sequence analysis, as well as functional predictions based on 16S rRNA gene sequence data (p < 0.0001). The majority of microbial biological processes were underrepresented in women with high inflammation compared to those with low inflammation, including a Lactobacillus-associated signature of reduced cell wall organization and peptidoglycan biosynthesis. This signature remained associated with high FGT inflammation in a subset of 74 women 9 weeks later, was upheld after adjusting for Lactobacillus relative abundance, and was associated with in vitro inflammatory cytokine responses to Lactobacillus isolates from the same women. Reduced cell wall organization and peptidoglycan biosynthesis were also associated with high FGT inflammation in an independent sample of ten women. Conclusions: Both the presence of specific microbial taxa in the FGT and their properties and activities are critical determinants of FGT inflammation. Our findings support those of previous studies suggesting that peptidoglycan is directly immunosuppressive, and identify a possible avenue for biotherapeutic development to reduce inflammation in the FGT.
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    A serum circulating miRNA signature for short-term risk of progression to active tuberculosis among household contacts
    (Frontiers Media, 2018) Duffy, Fergal J.; Thompson, Ethan; Downing, Katrina; Suliman, Sara; Mayanja-Kizza, Harriet; Boom, W. Henry; Thiel, Bonnie; Weiner III, January; Kaufmann, Stefan H. E.; Dover, Drew; Tabb, David L.; Dockrell, Hazel M.; Ottenhoff, Tom H. M.; Tromp, Gerard; Scriba, Thomas J.; Zak, Daniel E.; Walzl, Gerhard; GC6-74 Consortium
    ENGLISH ABSTRACT: Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of c-miRNA measurements in the serum of adult household contacts (HHCs) of TB index cases from South Africa and Uganda and developed a c-miRNA-based signature of risk for progression to active TB. This c-miRNA-based signature significantly discriminated HHCs within 6 months of progression to active disease from HHCs that remained healthy in an independent test set [ROC area under the ROC curve (AUC) 0.74, progressors < 6 Mo to active TB and ROC AUC 0.66, up to 24 Mo to active TB], and complements the predictions of a previous cellular mRNA-based signature of TB risk.
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    Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients
    (BioMed Central, 2020-02-04) Oluwole, Oluwafemi G.; Kuivaniemi, Helena; Abrahams, Shameemah; Haylett, William L.; Vorster, Alvera A.; Van Heerden, Carel J.; Kenyon, Colin P.; Tabb, David L.; Fawale, Michael B.; Sunmonu, Taofiki A.; Ajose, Abiodun; Olaogun, Matthew O.; Rossouw, Anastasia C.; Van Hillegondsberg, Ludo S.; Carr, Jonathan; Ross, Owen A.; Komolafe, Morenikeji A.; Tromp, Gerard; Bardien, Soraya
    Background: The prevalence of Parkinson’s disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients. Methods: We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2’s protein structure was investigated by molecular modelling. Results: We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein. Conclusions: We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.