9 results on '"Jacobs, Muazzam"'
Search Results
2. Machine Learning Demonstrates Dominance of Physical Characteristics over Particle Composition in Coal Dust Toxicity
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Kamanzi, Conchita, primary, Becker, Megan, additional, Von Holdt, Johanna, additional, Hsu, Nai-Jen, additional, Konečný, Petr, additional, Broadhurst, Jennifer, additional, and Jacobs, Muazzam, additional
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- 2024
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3. Cell type-specific gene expression dynamics during human brain maturation
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Steyn, Christina, primary, Mishi, Ruvimbo, additional, Fillmore, Stephanie, additional, Verhoog, Matthijs B., additional, More, Jessica, additional, Rohlwink, Ursula K., additional, Melvill, Roger, additional, Butler, James, additional, Enslin, Johannes M. N., additional, Jacobs, Muazzam, additional, Quiñones, Sadi, additional, Dulla, Chris G., additional, Raimondo, Joseph V., additional, Figaji, Anthony, additional, and Hockman, Dorit, additional
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- 2023
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4. BCG‐mediated protection against M. tuberculosis is sustained post‐malaria infection independent of parasite virulence
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Tangie, Emily, primary, Walters, Avril, additional, Hsu, Nai‐jen, additional, Fisher, Michelle, additional, Magez, Stefan, additional, Jacobs, Muazzam, additional, and Keeton, Roanne, additional
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- 2021
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5. BCG‐mediated protection against M. tuberculosis is sustained post‐malaria infection independent of parasite virulence.
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Tangie, Emily, Walters, Avril, Hsu, Nai‐jen, Fisher, Michelle, Magez, Stefan, Jacobs, Muazzam, and Keeton, Roanne
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TUBERCULOSIS ,MYCOBACTERIUM tuberculosis ,MYCOBACTERIA ,VACCINE trials ,PLASMODIUM berghei ,VACCINE effectiveness - Abstract
Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette‐Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Co‐infections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesized that virulence‐dependent co‐infection with Plasmodium species could alter the BCG‐specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non‐virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG‐induced efficacy against M. tuberculosis infection. We demonstrate that malaria co‐infection modulates both B‐ and T‐cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria‐driven immune regulation may have serious consequences in the early clinical trials of novel vaccines, which rely on vaccine‐specific T‐cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Immune control of Mycobacterium tuberculosis is dependent on both soluble TNFRp55 and soluble TNFRp75.
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Keeton, Roanne, du Toit, Jan Pierre, Hsu, Nai‐Jen, Dube, Felix, and Jacobs, Muazzam
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MYCOBACTERIUM tuberculosis ,TUMOR necrosis factor receptors ,LABORATORY mice ,TRANSGENIC mice ,DENDRITIC cells ,VIRAL shedding - Abstract
Tuberculosis presents a global health challenge, and tumour necrosis factor (TNF) signalling is required for host immunity against Mycobacterium tuberculosis (Mtb). TNF receptor shedding, however, compromises effective immunity by reducing bioactive TNF through the formation of inactive complexes. In this study, we first compared the effect of total soluble TNF receptors using a transgenic p55ΔNS/p75−/− murine strain on host protection during a low‐dose aerosol Mtb H37Rv challenge. We report that the presence of membrane‐bound TNFRp55 alone in the absence of TNFRp75 results in superior control of a primary Mtb infection where p55ΔNS/p75−/− hyperactive dendritic cells displayed an increased capacity to induce a hyperactive Mtb‐specific CD4+ T‐cell response. p55ΔNS/p75−/− dendritic cells expressed a higher frequency of MHCII and increased MFIs for both CD86 and MHCII, while CD4+ T cells had higher expression of CD44 and IFN‐γ. Next, the relative contributions of soluble TNFRp55 and soluble TNFRp75 to host protection against either primary Mtb infection or during reactivation of latent tuberculosis were delineated by comparing the experimental outcomes of control C57BL/6 mice to transgenic p55ΔNS/p75−/−, p55ΔNS and p75−/− mouse strains. We found that soluble TNFRp55 is redundant for immune regulation during the chronic stages of a primary Mtb infection. However, TNFRp55 together with soluble TNFRp75 has a crucial role in immune regulation of reactivation of latent tuberculosis. [ABSTRACT FROM AUTHOR]
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- 2021
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7. The characterisation of dendritic cell, microglial, macrophage and T cell responses during mycobacterial infection of the central nervous system
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Kgoadi, Khanyisile, Jacobs, Muazzam, and Keeton, Roanne
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Clinical Science and Immunology - Abstract
Background: Tuberculosis (TB) remains a global health challenge and a quarter of the global population is infected with latent TB. It is a single infection that causes most deaths and was the number one cause of death in South Africa in 2017. Bacille Calmette-Guerin (BCG) remains the only licensed vaccine for protection against TB. Although TB primarily occurs as a pulmonary infection after inhalation of Mycobacterium tuberculosis (M. tuberculosis) bacilli, it can disseminate to other organs causing extra-pulmonary TB (EPTB). Approximately 5-15% of EPTB cases are attributed to central nervous system tuberculosis (CNS-TB) which commonly manifests as TB meningitis. CNS-TB is a severe form of TB associated with high morbidity and about 50% mortality due to inconclusive diagnosis and treatment challenges. Children and immunocompromised adults like those coinfected with HIV/AIDS are higher risk groups for the development of CNS-TB. Pathogenesis of CNS-TB occurs as a secondary infection during haematogenous dissemination of pulmonary TB to the brain parenchyma and meninges where inflammation occurs after rupture of rich foci into the subarachnoid space. Mechanisms by which M. tuberculosis infects the CNS and specific cell types targeted are not fully characterized. Little is understood of the cells that regulate CNS-TB, their respective functions, their cellular interactions, and contributions to the overall protection of the CNS. Most studies have focussed on microglia and macrophages as the preferential targeted antigen-presenting cells (APCs) by M. tuberculosis and neglected dendritic cells (DCs) to an extent because no consensus had been reached regarding the presence of DCs in a healthy CNS. Both myeloid (APCs) and T cells contribute to protection against CNS-TB. This study characterized the dendritic cell, microglial, macrophage, and T cell responses during mycobacterial infection of the CNS. We also investigated the modulation of T cells by DCs during CNS-TB. Methodology and Results: Wild-type female C57BL/6J mice were intracerebrally (i.c.) infected with M. tuberculosis H37Rv or Mycobacterium bovis BCG while control animals were saline inoculated and naive mice. Mice were euthanized at weeks 2, 4, 6, and organs harvested for experimental analysis. Histology results detected acid-fast bacilli using Ziehl-Neelsen (ZN) stain in the brains of M. tuberculosis and BCG i.c. infected mice, respectively. This was accompanied by a high degree of inflammatory responses in the brain ventricles and meninges of infected mice as compared to saline control mice shown by Hematoxylin and Eosin (H & E) staining. Although controlled brain bacterial burdens were demonstrated from homogenates of M. tuberculosis or BCG infected mice, dissemination to the spleen and lungs occurred. The histopathological results showed the successful reproduction of the murine CNS-TB infection model. For immunophenotyping, flow cytometry analysis of single-cell suspensions generated from brains and cervical lymph nodes were characterized for phenotypic and functional profiles. We detected the recruitment of macrophages and DCs to the brain from the periphery and an expansion of brain APCs (microglia, brain infiltrating macrophages, and DCs) during mycobacterial infection of the CNS. Brain APCs from infected animals displayed highly activated and mature phenotypes as shown by increased numbers of these cells expressing MHCII, co-stimulatory CD86 molecule, pro-inflammatory cytokines (IFNg, TNFa, IL-1b, IL-6, IL-12) and an anti-inflammatory cytokine (IL-10) in comparison to saline control mice. We also demonstrated preferential recruitment of mature conventional DCs (CD11c+, MHCII+) that express chemokine receptor-7 (CCR7) to the brain and cervical lymph nodes (CLNs), a phenomenon that may have contributed to the recruitment and expansion of predominantly effector CD4+ T cells than CD8+ T cells (CD44+CD62L-) to the brain and CLNs during mycobacterial infection of the CNS. Increased numbers of recruited CD4+ T cells and CD8+ T cells expressed T-bet [T-helper (Th1) transcription factor) in the brain and CLNs post-infection. At week 4 post intracerebral infection, increased numbers of these T cells expressed both T-bet and FoxP3 (regulatory transcription factor) during CNS-TB and identified a higher frequency of polyfunctional IFNg+TGF-b+CD4+ T cells than IFNg+TGF-b+IL-10+CD4+ T cells. M. tuberculosis-infected DCs from CLNs of CNS-TB mice were cocultured with naïve CD3+ T cells to generate a DC-T cell coculture, cells were sorted using fluorescence-activated cell sorting (FACS). DC-T cell coculture demonstrated increased percentage expression of IFNg, IL-4, IL-10 and TGF-b responses by CD4+ T cells and CD8+ T cells during CNS-TB. Our in vitro coculture findings validated in vivo findings of recruited brain CD4+ T cell cytokine responses that showed a combination of Th1 and regulatory T cell immune responses. Conclusion: We successfully reproduced the CNS-TB murine model, which proved valuable in studying immune responses. The functional mature phenotypes of detected brain APCs (microglia, brain infiltrating macrophages, DCs) suggest their capabilities of inducing antigen-specific T cell responses that contributed to initiating and mediating immunity during mycobacterial infection of the CNS. Our study findings suggest protection against mycobacterial infection of the CNS was achieved by characterized cells based on reduced brain bacterial burdens and 100% animal survival rate. Detrimental disease outcome was prevented by the balance achieved between proinflammatory and anti-inflammatory responses. The novel mechanism employed by conventional DCs during CNS-TB is modulating CD4+ and CD8+ T cell cytokine responses to Th1 and Treg polarization that achieved M. tuberculosis control in the brain. We demonstrated that DCs can be targeted for strategic therapeutic intervention against CNS-TB. Therefore; we support ongoing research that focuses on DCs for the development of tuberculosis vaccines and host-directed therapy. This study provided new knowledge on immune mechanisms and pathogenesis experienced during TBM, thus adding to the current gap of advancing basic and translational TBM research that will inform clinical interventions. These new insights have the potential to help reduce the high death and disability associated with CNS-TB.
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- 2022
8. The impact of malaria on the immunogenicity and efficacy of mycobacterium bovis BCG vaccination against mycobacterium tuberculosis in mice
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Tangie, Emily Nchangnwie, Jacobs, Muazzam, and Keeton, Roanne
- Subjects
parasitic diseases ,clinical laboratory ,complex mixtures - Abstract
Background Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine for use against tuberculosis (TB), however, it is poorly efficacious against pulmonary TB in adults. The poor efficacy has been attributed in part to coinfections with many other unrelated pathogens that overlap geographically with Mycobacterium tuberculosis (M. tuberculosis). In this study, we used a murine model to investigate the effect of Plasmodium species virulence and the timing of infection on BCG-induced immune responses and efficacy against M. tuberculosis both in vivo by aerosol challenge and ex vivo by Mycobacterial Growth Inhibition Assay (MGIA). Methods and Results To assess the impact of malaria parasite virulence on BCG, wild-type C57BL/6 mice were vaccinated intraperitoneally with BCG Pasteur and 6 weeks later, they were infected with either virulent Plasmodium berghei (P. berghei) or less-virulent Plasmodium chabaudi chabaudi AS (P. chabaudi) infected red blood cells with appropriate controls. The mice were euthanased at 7, 10, 17, 26 days after malaria infection for multiparameter flow cytometry analysis. We compared P. berghei and P. chabaudi, their effects on B cells, effector and memory T cells and the outcome on BCG-induced protective efficacy against M. tuberculosis H37Rv infection by subsequent aerosol challenge. P. berghei induced a significant decrease in the frequency of central memory T cell (CD44hiCD62Lhi), marginal zone B cell (B220+AA4.1-CD1dlo), and follicular B cell (B220+AA4.1-CD1dhi ) populations. In contrast, infection with the less virulent P. chabaudi induced depletion in the marginal zone B cells but not the follicular B cells or the central memory T cells. A strong effector T cell/effector memory T cell (CD44hiCD62Lo) response enhanced by BCG vaccination was observed in both species. The reduction in the central memory T cells observed during P. berghei infection was attributed to T cell apoptosis. It should be noted that the observed changes in T cell and B cell populations described above are relative proportions of these cells among splenocytes. Surprisingly, BCG-mediated protection against M. tuberculosis H37Rv by aerosol challenge was retained in both the virulent P. berghei and less virulent P. chabaudi species despite modulations in the immune responses. We also investigated the effect of malaria infection post BCG vaccination and malaria infection prior to BCG vaccination on the cytokine responses and the efficacy of BCG vaccine both in vivo and ex vivo. Splenocytes from wild type C57BL/6 mice infected with P. yoelii 17XNL 4 weeks post BCG vaccination were analysed 13 days after P. yoelii 17XNL infection. We compared the cytokine responses and growth inhibition by MGIA in four groups of 6 mice each: naïve, BCG, BCG-malaria, and malaria control. BCG Pasteur Aeras was used as a surrogate for M. tuberculosis in the MGIA. Restimulation with PPD-T induced a significant increase in both the proportion and absolute cell numbers of CD4+ IFNγ+ and CD4+ TNF+ T cells in the BCG vaccinated compared to the naïve control. No significant differences in the proportion and cell numbers of CD4+ IFNγ+ T cells were observed between the BCG and BCGmalaria groups restimulated with PPD-T. This indicates that the presence of malaria did not significantly hamper the IFNγ response to BCG. In contrast, a significant (p
- Published
- 2022
9. Cell type-specific gene expression dynamics during human brain maturation.
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Steyn C, Mishi R, Fillmore S, Verhoog MB, More J, Rohlwink UK, Melvill R, Butler J, Enslin JMN, Jacobs M, Sauka-Spengler T, Greco M, Quiñones S, Dulla CG, Raimondo JV, Figaji A, and Hockman D
- Abstract
The human brain undergoes protracted post-natal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell type-specific gene expression dynamics. Here, using single nucleus (sn)RNA-seq on temporal lobe tissue, including samples of African ancestry, we build a joint paediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between paediatric and adult cell types, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including the LTK and FREM subtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in paediatric tissue. The new resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map.
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- 2024
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