Browsing by Author "Naidoo, Jerolen"

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    An African perspective on genetically diverse human induced pluripotent stem cell lines
    (2024-10) Hurrell, Tracey; Naidoo, Jerolen; Ntlhafu, Tiro; Scholefield, Janine
    Human induced pluripotent stem cell-derived models are a well-established preclinical tool, with the ability to retain the genetics of the individual from which they are derived. Here we comment on the global representation and accessibility of such cellular tools from African population groups.
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    Functional applications of human microbiome diversity studies
    (Academic Press, 2024) Nkera-Gutabara, Claudine; Hurrell, Tracey; Naidoo, Jerolen; Das, S; Dash, HJ
    The human microbiome refers to the collection of symbiotic, pathogenic, and commensal microorganisms that co-inhabit discrete sites across the human body and play a crucial role in human physiology, health, and disease. The average human body houses more bacterial cells than it does human ones, and this has led to the human microbiome being referred to as the second genome of its host. Perturbation of the natural balance of microbes within the human body, referred to as dysbiosis, has been associated with human pathologies including neurodegenerative diseases, tuberculosis, fatty liver disease, obesity, cancer, and human immunodeficiency virus. The pervasive impact of the microbiome on various aspects of human physiology is also becoming increasingly appreciated as understanding around the various gut–organ axes (e.g., gut–brain, gut–liver) continue to emerge and evolve. Importantly, the microbiome is readily influenced and shaped by environmental factors including lifestyle, diet, and environmental exposures. This dynamic nature of the microbiome enables the detection of changes in microbiome profiles, which are indicative of potential disease risk before the onset of more permanent health effects. The human microbiome is also readily malleable to noninvasive interventions like prebiotics, postbiotics, and lifestyle changes. This further posits the microbiome as attractive target for therapeutic interventions and as the next frontier for health innovation. Several international research efforts, catalyzed by the human microbiome project, have thus sought to propel the clinical relevance of microbiome research, through the accurate identification of outlier signatures indicative of disease onset and risk. In this chapter, we discuss the human microbiome, its role in human health, the factors that regulate it, and the functional applications of microbiome research.
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    Lnc-ing inflammation to disease
    (Portland Press LTD, 2017-08) Magagula, L; Gagliardi, M; Naidoo, Jerolen; Mhlanga, Musa
    Termed 'master gene regulators' long ncRNAs (lncRNAs) have emerged as the true vanguard of the 'noncoding revolution'. Functioning at a molecular level, in most if not all cellular processes, lncRNAs exert their effects systemically. Thus, it is not surprising that lncRNAs have emerged as important players in human pathophysiology. As our body's first line of defense upon infection or injury, inflammation has been implicated in the etiology of several human diseases. At the center of the acute inflammatory response, as well as several pathologies, is the pleiotropic transcription factor NF- ß. In this review, we attempt to capture a summary of lncRNAs directly involved in regulating innate immunity at various arms of the NF- ß pathway that have also been validated in human disease. We also highlight the fundamental concepts required as lncRNAs enter a new era of diagnostic and therapeutic significance.
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    Systems biology tools to understand the role of host miRNAs in infection: a closer look at HIV
    (Caister Academic Press, 2014-06) Naidoo, Jerolen; Brackin, R; Khutlang, Rethabile; Savulescu, A; Mhlanga, Musa
    The discovery of mammalian microRNAs (miRNAs) has greatly enhanced our appreciation for the complexity associated with the regulation of the mammalian transcriptional landscape. Endogenous miRNA pathways mediate the targeted and subtle variations in gene expression required to drive complex biological processes that must be coordinated both spatially and temporally within cells and tissues. It is not surprising then that the dysregulation of miRNA function has been implicated in various models of disease and pathogenesis. Increasing interest in miRNA function has facilitated the transfer of many existing technologies to miRNA-based formats. Expression-based tools like RNAseq and qPCR microarray technologies, as well as the use of synthetic molecules to inhibit or enhance miRNA functions have been employed to identify and characterize distinct miRNA expression profiles in various models of infection. In this chapter we take a closer look at the application of some of the existing tools for miRNA-based analyses with a focus on host–pathogen interactions. Aspects pertinent to high-content miRNA-based screens are also discussed using an HIV screening workflow as a backdrop to address the important considerations associated with miRNA-based studies.
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    The generation of human induced pluripotent stem cell lines from individuals of Black African ancestry in South Africa
    (2024-12) Naidoo, Jerolen; Hurrell, Tracey; Scholefield, Janine
    The lack of equitable representation of African diversity in scientific resources, such as genome-wide association studies and human induced pluripotent stem cell (hiPSC) repositories, has perpetuated inequalities in the advancement of health research. HiPSCs could be transformative in regenerative and precision medicine, therefore, the generation of diverse lines is critical in the establishment of African-relevant preclinical cellular models. HiPSC lines were derived from two healthy donors of Black African ancestry using Sendai virus reprogramming of dermal fibroblasts, and characterised to confirm stemness markers, trilineage differentiation, and genetic integrity. These hiPSCs represent a valuable resource for modelling African relevant disease biology.
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    Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA
    (Frontiers Media SA, 2018-08) Barichievy, Samantha; Naidoo, Jerolen; Boullé, M; Scholefield, Janine; Parihar, SP; Coussens, AK; Brombacher, F; Sigal, A; Mhlanga, Musa M
    An emerging realization of infectious disease is that pathogens can cause a high incidence of genetic instability within the host as a result of infection-induced DNA lesions. These often lead to classical hallmarks of cancer, one of which is the ability to evade apoptosis despite the presence of numerous genetic mutations that should be otherwise lethal. The Human Immunodeficiency Virus type 1 (HIV-1) is one such pathogen as it induces apoptosis in CD4+ T cells but is largely non-cytopathic in macrophages. As a consequence there is long-term dissemination of the pathogen specifically by these infected yet surviving host cells. Apoptosis is triggered by double-strand breaks (DSBs), such as those induced by integrating retroviruses like HIV-1, and is coordinated by the p53-regulated long noncoding RNA lincRNA-p21. As is typical for a long noncoding RNA, lincRNA-p21 mediates its activities in a complex with one of its two protein binding partners, namely HuR and hnRNP-K. In this work, we monitor the cellular response to infection to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus does so by securing the pro-survival MAP2K1/ERK2 cascade early upon entry, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21. By sequestering the lincRNA-p21 partner HuR in the nucleus, HIV-1 enables lincRNA-p21 degradation. Simultaneously, the virus permits transcription of pro-survival genes by sequestering lincRNA-p21's other protein partner hnRNP-K in the cytoplasm via the MAP2K1/ERK2 pathway. Of particular note, this MAP2K1/ERK2 pro-survival cascade is switched off during T cell maturation and is thus unavailable for similar viral manipulation in mature CD4+ T cells. We show that the introduction of MAP2K1, ERK2, or HDM2 inhibitors in HIV-infected macrophages results in apoptosis, providing strong evidence that the viral-mediated apoptotic block can be released, specifically by restoring the nuclear interaction of lincRNA-p21 and its apoptosis protein partner hnRNP-K. Together, these results reveal a unique example of pathogenic control over mammalian apoptosis and DNA damage via a host long noncoding RNA, and present MAP2K1/ERK2 inhibitors as a novel therapeutic intervention strategy for HIV-1 infection in macrophages.