Publications by authors named "Nelita du Plessis"

34 Publications

Mycobacterium tuberculosis-stimulated whole blood culture to detect host biosignatures for tuberculosis treatment response.

Tuberculosis (Edinb) 2021 Apr 10;128:102082. Epub 2021 Apr 10.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Host markers to monitor the response to tuberculosis (TB) therapy hold some promise. We evaluated the changes in concentration of Mycobacterium tuberculosis (M.tb)-induced soluble biomarkers during early treatment for predicting short- and long-term treatment outcomes. Whole blood samples from 30 cured and 12 relapsed TB patients from diagnosis, week 1, 2, and 4 of treatment were cultured in the presence of live M.tb for seven days and patients followed up for 24 weeks after the end of treatment. 57 markers were measured in unstimulated and antigen-stimulated culture supernatants using Luminex assays. Top performing multi-variable models at diagnosis using unstimulated values predicted outcome at 24 months after treatment completion with a sensitivity of 75.0% (95% CI, 42.8-94.5%) and specificity of 72.4% (95% CI, 52.8-87.3%) in leave-one-out cross validation. Month two treatment responder classification was correctly predicted with a sensitivity of 79.2% (95% CI, 57.8-92.9%) and specificity of 92.3% (95% CI, 64.0-99.8%). This study provides evidence of the early M.tb-specific treatment response in TB patients but shows that the observed unstimulated marker models are not outperformed by stimulated marker models. Performance of unstimulated predictive host marker signatures is promising and requires validation in larger studies.
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http://dx.doi.org/10.1016/j.tube.2021.102082DOI Listing
April 2021

Targeting of myeloid-derived suppressor cells by all-trans retinoic acid as host-directed therapy for human tuberculosis.

Cell Immunol 2021 Jun 8;364:104359. Epub 2021 Apr 8.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medical and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.
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http://dx.doi.org/10.1016/j.cellimm.2021.104359DOI Listing
June 2021

The Peripheral Blood Transcriptome Is Correlated With PET Measures of Lung Inflammation During Successful Tuberculosis Treatment.

Front Immunol 2020 10;11:596173. Epub 2021 Feb 10.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.

Pulmonary tuberculosis (PTB) is characterized by lung granulomas, inflammation and tissue destruction. Here we used within-subject peripheral blood gene expression over time to correlate with the within-subject lung metabolic activity, as measured by positron emission tomography (PET) to identify biological processes and pathways underlying overall resolution of lung inflammation. We used next-generation RNA sequencing and [F]FDG PET-CT data, collected at diagnosis, week 4, and week 24, from 75 successfully cured PTB patients, with the [F]FDG activity as a surrogate for lung inflammation. Our linear mixed-effects models required that for each individual the slope of the line of [F]FDG data in the outcome and the slope of the peripheral blood transcript expression data correlate, i.e., the slopes of the outcome and explanatory variables had to be similar. Of 10,295 genes that changed as a function of time, we identified 639 genes whose expression profiles correlated with decreasing [F]FDG uptake levels in the lungs. Gene enrichment over-representation analysis revealed that numerous biological processes were significantly enriched in the 639 genes, including several well known in TB transcriptomics such as platelet degranulation and response to interferon gamma, thus validating our novel approach. Others not previously associated with TB pathobiology included smooth muscle contraction, a set of pathways related to mitochondrial function and cell death, as well as a set of pathways connecting transcription, translation and vesicle formation. We observed up-regulation in genes associated with B cells, and down-regulation in genes associated with platelet activation. We found 254 transcription factor binding sites to be enriched among the 639 gene promoters. In conclusion, we demonstrated that of the 10,295 gene expression changes in peripheral blood, only a subset of 639 genes correlated with inflammation in the lungs, and the enriched pathways provide a description of the biology of resolution of lung inflammation as detectable in peripheral blood. Surprisingly, resolution of PTB inflammation is positively correlated with smooth muscle contraction and, extending our previous observation on mitochondrial genes, shows the presence of mitochondrial stress. We focused on pathway analysis which can enable therapeutic target discovery and potential modulation of the host response to TB.
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http://dx.doi.org/10.3389/fimmu.2020.596173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902901PMC
February 2021

Higher SARS-CoV-2 seroprevalence in workers with lower socioeconomic status in Cape Town, South Africa.

PLoS One 2021 25;16(2):e0247852. Epub 2021 Feb 25.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Department of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: Inequality is rife throughout South Africa. The first wave of COVID-19 may have affected people in lower socioeconomic groups worse than the affluent. The SARS-CoV-2 seroprevalence and the specificity of anti-SARS-CoV-2 antibody tests in South Africa is not known.

Methods: We tested 405 volunteers representing all socioeconomic strata from the workforce of a popular shopping and tourist complex in central Cape Town with the Abbott SARS-CoV-2 IgG assay. We assessed the association between antibody positivity and COVID-19 symptom status, medical history, and sociodemographic variables. We tested 137 serum samples from healthy controls collected in Cape Town prior to the COVID-19 pandemic, to confirm the specificity of the assay in the local population.

Results: Of the 405 volunteers tested one month after the first peak of the epidemic in Cape Town, 96(23.7%) were SARS-CoV-2 IgG positive. Of those who tested positive, 46(47.9%) reported no symptoms of COVID-19 in the previous 6 months. Seropositivity was significantly associated with living in informal housing, residing in a subdistrict with low income-per household, and having a low-earning occupation. The specificity of the assay was 98.54%(95%CI 94.82%-99.82%) in the pre-COVID controls.

Conclusions: There is a high background seroprevalence in Cape Town, particularly in people of lower socioeconomic status. Almost half of cases are asymptomatic, and therefore undiagnosed by local testing strategies. These results cannot be explained by low assay specificity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247852PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906413PMC
March 2021

Safety and immunogenicity of the adjunct therapeutic vaccine ID93 + GLA-SE in adults who have completed treatment for tuberculosis: a randomised, double-blind, placebo-controlled, phase 2a trial.

Lancet Respir Med 2021 04 8;9(4):373-386. Epub 2020 Dec 8.

South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa. Electronic address:

Background: A therapeutic vaccine that prevents recurrent tuberculosis would be a major advance in the development of shorter treatment regimens. We aimed to assess the safety and immunogenicity of the ID93 + GLA-SE vaccine at various doses and injection schedules in patients with previously treated tuberculosis.

Methods: This randomised, double-blind, placebo-controlled, phase 2a trial was conducted at three clinical sites near Cape Town, South Africa. Patients were recruited at local clinics after receiving 4 months of tuberculosis treatment, and screened for eligibility after providing written informed consent. Participants were aged 18-60 years, BCG-vaccinated, HIV-uninfected, and diagnosed with drug-sensitive pulmonary tuberculosis. Eligible patients had completed standard treatment for pulmonary tuberculosis in the past 28 days. Participants were enrolled after completing standard treatment and randomly assigned sequentially to receive vaccine or placebo in three cohorts: 2 μg intramuscular ID93 + 2 μg GLA-SE on days 0 and 56 (cohort 1); 10 μg ID93 + 2 μg GLA-SE on days 0 and 56 (cohort 2); 2 μg ID93 + 5 μg GLA-SE on days 0 and 56 and placebo on day 28 (cohort 3); 2 μg ID93 + 5 μg GLA-SE on days 0, 28, and 56 (cohort 3); or placebo on days 0 and 56 (cohorts 1 and 2), with the placebo group for cohort 3 receiving an additional injection on day 28. Randomisation was in a ratio of 3:1 for ID93 + GLA-SE and saline placebo in cohorts 1 and 2, and in a ratio of 3:3:1 for (2 ×) ID93 + GLA-SE, (3 ×) ID93 + GLA-SE, and placebo in cohort 3. The primary outcomes were safety and immunogenicity (vaccine-specific antibody response and T-cell response). For the safety outcome, participants were observed for 30 min after each injection, injection site reactions and systemic adverse events were monitored until day 84, and serious adverse events and adverse events of special interest were monitored for 6 months after the last injection. Vaccine-specific antibody responses were measured by serum ELISA, and T-cell responses after stimulation with vaccine antigens were measured in cryopreserved peripheral blood mononuclear cells specimens using intracellular cytokine staining followed by flow cytometry. This study is registered with ClinicalTrials.gov, number NCT02465216.

Findings: Between June 17, 2015, and May 30, 2016, we assessed 177 patients for inclusion. 61 eligible patients were randomly assigned to receive: saline placebo (n=5) or (2 ×) 2 μg ID93 + 2 μg GLA-SE (n=15) on days 0 and 56 (cohort 1); saline placebo (n=2) or (2 ×) 10 μg ID93 + 2 μg GLA-SE (n=5) on days 0 and 56 (cohort 2); saline placebo (n=5) on days 0, 28 and 56, or 2 μg ID93 + 5 μg GLA-SE (n=15) on days 0 and 56 and placebo injection on day 28, or (3 ×) 2 μg ID93 + 5 μg GLA-SE (n=14) on days 0, 28, and 56 (cohort 3). ID93 + GLA-SE induced robust and durable antibody responses and specific, polyfunctional CD4 T-cell responses to vaccine antigens. Two injections of the 2 μg ID93 + 5 μg GLA-SE dose induced antigen-specific IgG and CD4 T-cell responses that were significantly higher than those with placebo and persisted for the 6-month study duration. Mild to moderate injection site pain was reported after vaccination across all dose combinations, and induration and erythema in patients given 2 μg ID93 + 5 μg GLA-SE in two or three doses. One participant had grade 3 erythema and induration at the injection site. No vaccine-related serious adverse events were observed.

Interpretation: Vaccination with ID93 + GLA-SE was safe and immunogenic for all tested regimens. These data support further evaluation of ID93 + GLA-SE in therapeutic vaccination strategies to improve tuberculosis treatment outcomes.

Funding: Wellcome Trust (102028/Z/13/Z).
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http://dx.doi.org/10.1016/S2213-2600(20)30319-2DOI Listing
April 2021

Isolation and Functional Characterization of Myeloid-Derived Suppressor Cells in Infections Under High Containment.

Methods Mol Biol 2021 ;2236:129-156

Division of Molecular Biology and Human Genetics, Faculty of Medical and Health Sciences, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.

The current absence of markers unique to MDSC, particularly those expanded during human infection, necessitate concurrent demonstration of their suppressive capacity to ensure unequivocal identification. This is further complicated by the array of heterogeneous markers used to characterize MDSC in various conditions and models. Standardization of phenotypic and functional characterization, as well as isolation, from infectious biological samples of patients, are critical for accurately reporting MDSC dynamics, function, organ abundance, and establishment of their therapeutic value in infectious diseases. To illustrate, we report on our established method for MDSC isolation from bronchoalveolar lavage fluid and peripheral blood of pulmonary TB patients, as well as functional impact on T cells by measuring T cell activation, proliferation, and cytokine production.
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http://dx.doi.org/10.1007/978-1-0716-1060-2_12DOI Listing
March 2021

Monocytic myeloid-derived suppressor cells reflect tuberculosis severity and are influenced by cyclooxygenase-2 inhibitors.

J Leukoc Biol 2020 Nov 6. Epub 2020 Nov 6.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

Myeloid-derived suppressor cells (MDSCs) increase in tuberculosis (TB) and may be targets for host-directed therapy (HDT). In this study, we use flow cytometry to analyze the effects of cyclooxygenase-2 inhibitors (COX-2i) on monocytic (M)-MDSCs in blood from TB patients attending a clinical trial of COX-2i. The effects of COX-2i on M-MDSCs and mycobacterial uptake were also studied by an in vitro mycobacterial infection model. We found that M-MDSC frequencies correlated with TB disease severity. Reduced M-MDSC (P = 0.05) and IDO (P = 0.03) expression was observed in the COX-2i group. We show that peripheral blood-derived M-MDSCs successfully internalized Mycobacterium bovis and that in vitro mycobacterial infection increased COX-2 (P = 0.002), PD-L1 (P = 0.01), and Arginase-1 (P = 0.002) expression in M-MDSCs. Soluble IL-1β, IL-10, and S100A9 were reduced in COX-2i-treated M-MDSCs cultures (P < 0.05). We show novel data that COX-2i had limited effect in vivo but reduced M-MDSC cytokine production in vitro. The relevance of COX-2i in a HDT strategy needs to be further explored.
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http://dx.doi.org/10.1002/JLB.4A0720-409RRDOI Listing
November 2020

Investigating Non-sterilizing Cure in TB Patients at the End of Successful Anti-TB Therapy.

Front Cell Infect Microbiol 2020 25;10:443. Epub 2020 Aug 25.

Department of Science and Technology/National Research Foundation, Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Council Centre for Tuberculosis Research, Cape Town, South Africa.

(Mtb) is extremely recalcitrant to antimicrobial chemotherapy requiring 6 months to treat drug-sensitive tuberculosis (TB). Despite this, 4-10% of cured patients will develop recurrent disease within 12 months after completing therapy. Reasons for relapse in cured TB patients remains speculative, attributed to both pathogen and host factors. Populations of dormant bacilli are hypothesized to cause relapse in initially cured TB patients however, development of tests to convincingly demonstrate their presence at the end of anti-TB treatment has been challenging. Previous studies have indicated the utility of culture filtrate supplemented media (CFSM) to detect differentially culturable tubercle bacilli (DCTB). Here, we show that 3/22 of clinically cured patients retained DCTB in induced sputum and bronchoalveolar lavage fluid (BALF), with one DCTB positive patient relapsing within the first year of completing therapy. We also show a correlation of DCTB status with "unresolved" end of treatment FDG PET-CT imaging. Additionally, 19 end of treatment induced sputum samples from patients not undergoing bronchoscopy were assessed for DCTB, identifying a further relapse case with DCTB. We further show that induced sputum is a less reliable source for the DCTB assay at the end of treatment, limiting the utility of this assay in a clinical setting. We next investigated the host proteome at the site of disease (BALF) using multiplexed proteomic analysis and compared these to active TB cases to identify host-specific factors indicative of cure. Distinct signatures stratified active from cured TB patients into distinct groups, with a DCTB positive, subsequently relapsing, end of treatment patient showing a proteomic signature closer to active TB disease than cure. This exploratory study offers evidence of live Mtb, undetectable with conventional culture methods, at the end of clinically successful treatment and putative host protein biomarkers of active disease and cure. These findings have implications for the assessment of true sterilizing cure in TB patients and opens new avenues for targeted approaches to monitor treatment response.
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http://dx.doi.org/10.3389/fcimb.2020.00443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477326PMC
August 2020

Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus.

J Clin Invest 2020 06;130(6):2789-2799

Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.

The critical role of suppressive myeloid cells in immune regulation has come to the forefront in cancer research, with myeloid-derived suppressor cells (MDSCs) as a main oncology immunotherapeutic target. Recent improvement and standardization of criteria classifying tumor-induced MDSCs have led to unified descriptions and also promoted MDSC research in tuberculosis (TB) and AIDS. Despite convincing evidence on the induction of MDSCs by pathogen-derived molecules and inflammatory mediators in TB and AIDS, very little attention has been given to their therapeutic modulation or roles in vaccination in these diseases. Clinical manifestations in TB are consequences of complex host-pathogen interactions and are substantially affected by HIV infection. Here we summarize the current understanding and knowledge gaps regarding the role of MDSCs in HIV and Mycobacterium tuberculosis (co)infections. We discuss key scientific priorities to enable application of this knowledge to the development of novel strategies to improve vaccine efficacy and/or implementation of enhanced treatment approaches. Building on recent findings and potential for cross-fertilization between oncology and infection biology, we highlight current challenges and untapped opportunities for translating new advances in MDSC research into clinical applications for TB and AIDS.
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http://dx.doi.org/10.1172/JCI136288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260010PMC
June 2020

Interrogating Fractionation and Other Sources of Variability in Shotgun Proteomes Using Quality Metrics.

Proteomics 2020 11 23;20(21-22):e1900382. Epub 2020 Aug 23.

SATBBI (South African Tuberculosis Bioinformatics Initiative), Centre for Bioinformatics and Computational Biology, Stellenbosch University, Cape Town, 7505, South Africa.

The increasing amount of publicly available proteomics data creates opportunities for data scientists to investigate quality metrics in novel ways. QuaMeter IDFree is used to generate quality metrics from 665 RAW files and 97 WIFF files representing publicly available "shotgun" mass spectrometry datasets. These experiments are selected to represent Mycobacterium tuberculosis lysates, mouse MDSCs, and exosomes derived from human cell lines. Machine learning techniques are demonstrated to detect outliers within experiments and it is shown that quality metrics may be used to distinguish sources of variability among these experiments. In particular, the findings demonstrate that according to nested ANOVA performed on an SDS-PAGE shotgun principal component analysis, runs of fractions from the same gel regions cluster together rather than technical replicates, close temporal proximity, or even biological samples. This indicates that the individual fraction may have had a higher impact on the quality metrics than other factors. In addition, sample type, instrument type, mass analyzer, fragmentation technique, and digestion enzyme are identified as sources of variability. From a quality control perspective, the importance of study design and in particular, the run order, is illustrated in seeking ways to limit the impact of technical variability.
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http://dx.doi.org/10.1002/pmic.201900382DOI Listing
November 2020

Myeloid-Derived Suppressor Cells as Target of Phosphodiesterase-5 Inhibitors in Host-Directed Therapeutics for Tuberculosis.

Front Immunol 2020 25;11:451. Epub 2020 Mar 25.

Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.

Resistance toward current and new classes of anti-tuberculosis (anti-TB) antibiotics are rapidly emerging; thus, innovative therapies focused on host processes, termed host-directed therapies (HDTs), are promising novel approaches for shortening therapy regimens without inducing drug resistance. Development of new TB drugs is lengthy and expensive, and success is not guaranteed; thus, alternatives are needed. Repurposed drugs have already passed Food and Drug Administration (FDA) as well as European Medicines Agency (EMA) safety requirements and may only need to prove efficacy against (). Phosphodiesterases (PDEs) hydrolyze the catalytic breakdown of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to their inactive mononucleotides. Advances in molecular pharmacology have identified 11 PDE families; and the success of sildenafil, a PDE-5 selective inhibitor (PDE-5i), in treating pulmonary hypertension and erectile dysfunction has invigorated research into the therapeutic potential of selective PDE inhibitors in other conditions. Myeloid-derived suppressor cells (MDSCs) suppress anti-TB T-cell responses, likely contributing to TB disease progression. PDE-5i increases cGMP within MDSC resulting in the downregulation of arginase-1 (ARG1) and nitric oxide synthase 2 (NOS2), reducing MDSC's suppressive potential. The effect of this reduction decreases MDSC-induced T-cell-suppressive mechanisms. This review highlights the possibility of HDT targeting of MDSC, using a PDE-5i in combination with the current TB regimen, resulting in improved TB treatment efficacy.
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http://dx.doi.org/10.3389/fimmu.2020.00451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109258PMC
March 2021

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis.

J Clin Invest 2020 06;130(6):3098-3112

Department of Molecular Microbiology and.

Neutrophil accumulation is associated with lung pathology during active tuberculosis (ATB). However, the molecular mechanism or mechanisms by which neutrophils accumulate in the lung and contribute to TB immunopathology are not fully delineated. Using the well-established mouse model of TB, our new data provide evidence that the alarmin S100A8/A9 mediates neutrophil accumulation during progression to chronic TB. Depletion of neutrophils or S100A8/A9 deficiency resulted in improved Mycobacterium tuberculosis (Mtb) control during chronic but not acute TB. Mechanistically, we demonstrate that, following Mtb infection, S100A8/A9 expression is required for upregulation of the integrin molecule CD11b specifically on neutrophils, mediating their accumulation during chronic TB disease. These findings are further substantiated by increased expression of S100A8 and S100A9 mRNA in whole blood in human TB progressors when compared with nonprogressors and rapidly decreased S100A8/A9 protein levels in the serum upon TB treatment. Furthermore, we demonstrate that S100A8/A9 serum levels along with chemokines are useful in distinguishing between ATB and asymptomatic Mtb-infected latent individuals. Thus, our results support targeting S100A8/A9 pathways as host-directed therapy for TB.
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http://dx.doi.org/10.1172/JCI130546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259997PMC
June 2020

Mycobacterium tuberculosis and myeloid-derived suppressor cells: Insights into caveolin rich lipid rafts.

EBioMedicine 2020 Mar 26;53:102670. Epub 2020 Feb 26.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medical and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Mycobacterium tuberculosis (M.tb) is likely the most successful human pathogen, capable of evading protective host immune responses and driving metabolic changes to support its own survival and growth. Ineffective innate and adaptive immune responses inhibit effective clearance of the bacteria from the human host, resulting in the progression to active TB disease. Many regulatory mechanisms exist to prevent immunopathology, however, chronic infections result in the overproduction of regulatory myeloid cells, like myeloid-derived suppressor cells (MDSC), which actively suppress protective host T lymphocyte responses among other immunosuppressive mechanisms. The mechanisms of M.tb internalization by MDSC and the involvement of host-derived lipid acquisition, have not been fully elucidated. Targeted research aimed at investigating MDSC impact on phagocytic control of M.tb, would be advantageous to our collective anti-TB arsenal. In this review we propose a mechanism by which M.tb may be internalized by MDSC and survive via the manipulation of host-derived lipid sources.
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http://dx.doi.org/10.1016/j.ebiom.2020.102670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047144PMC
March 2020

Caveolin-1 Controls Vesicular TLR2 Expression, p38 Signaling and T Cell Suppression in BCG Infected Murine Monocytic Myeloid-Derived Suppressor Cells.

Front Immunol 2019 3;10:2826. Epub 2019 Dec 3.

Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.

Monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic MDSCs (G-MDSCs) have been found to be massively induced in TB patients as well in murine Mtb infection models. However, the interaction of mycobacteria with MDSCs and its role in TB infection is not well studied. Here, we investigated the role of Cav-1 for MDSCs infected with Bacille-Calmette-Guerín (BCG). MDSCs that were generated from murine bone marrow (MDSCs) of wild-type (WT) or mice upregulated Cav-1, TLR4 and TLR2 expression after BCG infection on the cell surface. However, Cav-1 deficiency resulted in a selective defect of intracellular TLR2 levels predominantly in the M-MDSC subset. Further analysis indicated no difference in the phagocytosis of BCG by M-MDSCs from WT and mice or caveosome formation, but a reduced capacity to up-regulate surface markers, to secrete various cytokines, to induce iNOS and NO production required for suppression of T cell proliferation, whereas Arg-1 was not affected. Among the signaling pathways affected by Cav-1 deficiency, we found lower phosphorylation of the p38 mitogen-activated protein kinase (MAPK). Together, our findings implicate that (i) Cav-1 is dispensable for the internalization of BCG, (ii) vesicular TLR2 signaling in M-MDSCs is a major signaling pathway induced by BCG, (iii) vesicular TLR2 signals are controlled by Cav-1, (iv) vesicular TLR2/Cav-1 signaling is required for T cell suppressor functions.
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http://dx.doi.org/10.3389/fimmu.2019.02826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901706PMC
November 2020

The gut microbiome in tuberculosis susceptibility and treatment response: guilty or not guilty?

Cell Mol Life Sci 2020 Apr 15;77(8):1497-1509. Epub 2019 Nov 15.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, P.O. Box 241, Cape Town, 8000, South Africa.

Although tuberculosis (TB) is a curable disease, it remains the foremost cause of death from a single pathogen. Globally, approximately 1.6 million people died of TB in 2017. Many predisposing factors related to host immunity, genetics and the environment have been linked to TB. However, recent evidence suggests a relationship between dysbiosis in the gut microbiome and TB disease development. The underlying mechanism(s) whereby dysbiosis in the gut microbiota may impact the different stages in TB disease progression, are, however, not fully explained. In the wake of recently emerging literature, the gut microbiome could represent a potential modifiable host factor to improve TB immunity and treatment response. Herein, we summarize early data detailing (1) possible association between gut microbiome dysbiosis and TB (2) the potential for the use of microbiota biosignatures to discriminate active TB disease from healthy individuals (3) the adverse effect of protracted anti-TB antibiotics treatment on gut microbiota balance, and possible link to increased susceptibility to Mycobacterium tuberculosis re-infection or TB recrudescence following successful cure. We also discuss immune pathways whereby the gut microbiome could impact TB disease and serve as target for clinical manipulation.
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http://dx.doi.org/10.1007/s00018-019-03370-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162824PMC
April 2020

Distinct serum biosignatures are associated with different tuberculosis treatment outcomes.

Tuberculosis (Edinb) 2019 09 12;118:101859. Epub 2019 Aug 12.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Biomarkers for TB treatment response and outcome are needed. This study characterize changes in immune profiles during TB treatment, define biosignatures associated with treatment outcomes, and explore the feasibility of predictive models for relapse. Seventy-two markers were measured by multiplex cytokine array in serum samples from 78 cured, 12 relapsed and 15 failed treatment patients from South Africa before and during therapy for pulmonary TB. Promising biosignatures were evaluated in a second cohort from Uganda/Brazil consisting of 17 relapse and 23 cured patients. Thirty markers changed significantly with different response patterns during TB treatment in cured patients. The serum biosignature distinguished cured from relapse patients and a combination of two clinical (time to positivity in liquid culture and BMI) and four immunological parameters (TNF-β, sIL-6R, IL-12p40 and IP-10) at diagnosis predicted relapse with a 75% sensitivity (95%CI 0.38-1) and 85% specificity (95%CI 0.75-0.93). This biosignature was validated in an independent Uganda/Brazil cohort correctly classifying relapse patients with 83% (95%CI 0.58-1) sensitivity and 61% (95%CI 0.39-0.83) specificity. A characteristic biosignature with value as predictor of TB relapse was identified. The repeatability and robustness of these biomarkers require further validation in well-characterized cohorts.
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http://dx.doi.org/10.1016/j.tube.2019.101859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839616PMC
September 2019

Corrigendum: The Emerging Role of Myeloid-Derived Suppressor Cells in Tuberculosis.

Front Immunol 2019;10:1528. Epub 2019 Jul 2.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, South African MRC Centre for Tuberculosis Research, DST and NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Stellenbosch, South Africa.

[This corrects the article DOI: 10.3389/fimmu.2019.00917.].
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http://dx.doi.org/10.3389/fimmu.2019.01528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614722PMC
July 2019

Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell-killing capability.

JCI Insight 2019 06 4;5. Epub 2019 Jun 4.

Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany.

Tuberculosis patients and mice infected with live Mycobacterium tuberculosis (Mtb) accumulate high numbers of myeloid-derived suppressor cells (MDSCs). Here, we hypothesized that also dead Mtb vaccines may induce MDSCs that could impair the efficacy of vaccination. We found that repeated injections of Mtb vaccines (heat-killed Mtb in Incomplete Freund's Adjuvant, like Montanide) but not single or control vaccines without Mtb strongly expanded CD11b+ myeloid cells in the spleen, that suppressed T cell proliferation and killing ex vivo. Dead Mtb vaccination induced the generation of CD11b+ Ly-6Chigh CD115+ iNOS/Nos2+ monocytic MDSCs (M-MDSCs) upon application of inflammatory or microbial activation signals. In vivo these M-MDSCs positioned strategically in the spleen by infiltrating the splenic bridging channels and white pulp areas. Notably, within 6 to 24 hours in a Nos2-dependent fashion they produced NO to rapidly kill conventional and plasmacytoid dendritic cells (cDCs, pDCs) while, surprisingly, sparing T cells in vivo. Thus, we demonstrate that Mtb vaccine induced M-MDSCs to not directly suppress T cell in vivo but, instead, M-MDSCs directly target DC subpopulations thereby indirectly suppressing effector T cell responses. Collectively, we demonstrate that Mtb booster vaccines induce M-MDSCs in the spleen that can be activated to kill DCs cautioning to thoroughly investigate MDSC formation in individuals after Mtb vaccination in clinical trials.
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http://dx.doi.org/10.1172/jci.insight.128664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629241PMC
June 2019

The Emerging Role of Myeloid-Derived Suppressor Cells in Tuberculosis.

Front Immunol 2019 30;10:917. Epub 2019 Apr 30.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, South African MRC Centre for Tuberculosis Research, DST and NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Stellenbosch, South Africa.

Myeloid cells are crucial for the host control of a () infection, however the adverse role of specific myeloid subsets has increasingly been appreciated. The relevance of such cells in therapeutic strategies and predictive/prognostic algorithms is to promote interest in regulatory myeloid cells in tuberculosis (TB). Myeloid-derived suppressor cells (MDSC) are a heterogeneous collection of phagocytes comprised of monocytic- and polymorphonuclear cells that exhibit a potent suppression of innate- and adaptive immune responses. Accumulation of MDSC under pathological conditions associated with chronic inflammation, most notably cancer, has been well-described. Evidence supporting the involvement of MDSC in TB is increasing, yet their significance in this infection continues to be viewed with skepticism, primarily due to their complex nature and the lack of genetic evidence unequivocally discriminating these cells from other terminally differentiated myeloid populations. Here we highlight recent advances in MDSC characterization and summarize findings on the TB-induced hematopoietic shift associated with MDSC expansion. Lastly, the mechanisms of MDSC-mediated disease progression and future research avenues in the context of TB therapy and prophylaxis are discussed.
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http://dx.doi.org/10.3389/fimmu.2019.00917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502992PMC
September 2020

Isolation of B-cells using Miltenyi MACS bead isolation kits.

PLoS One 2019 20;14(3):e0213832. Epub 2019 Mar 20.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; Stellenbosch University, Cape Town, South Africa.

This article describes the procedures used to isolate pure B-cell populations from whole blood using various Miltenyi magnetic-activated cell sorting (MACS) bead Isolation kits. Such populations are vital for studies investigating the functional capacity of B-cells, as the presence of other cell types may have indirect effects on B-cell function through cell-cell interactions or by secretion of several soluble molecules. B-cells can be isolated by two main approaches: 1) Negative selection-in which B-cells remain "untouched" in their native state; this is advantageous as it is likely that B-cells remain functionally unaltered by this process. 2) Positive selection-in which B-cells are labelled and actively removed from the sample. We used three Negative B-cell isolation kits as well as the Positive B-cell isolation kit from Miltenyi and compared the purity of each of the resulting B-cells fractions. Contamination of isolated B-cell fractions with platelets was the conclusive finding for all of the isolation techniques tested. These results illustrate the inefficiency of current available MACS B-cell isolation kits to produce pure B-cell populations, from which concrete findings can be made. As such we suggest cell sorting as the preferred method for isolating pure B-cells to be used for downstream functional assays.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213832PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426237PMC
December 2019

Human Monocytic Suppressive Cells Promote Replication of and Alter Stability of Generated Granulomas.

Front Immunol 2018 23;9:2417. Epub 2018 Oct 23.

Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.

Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with () and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon infection. We employed an granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
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http://dx.doi.org/10.3389/fimmu.2018.02417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205994PMC
September 2019

Translational Potential of Therapeutics Targeting Regulatory Myeloid Cells in Tuberculosis.

Front Cell Infect Microbiol 2018 21;8:332. Epub 2018 Sep 21.

Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.

Despite recent advances in tuberculosis (TB) drug development and availability, successful antibiotic treatment is challenged by the parallel development of antimicrobial resistance. As a result, new approaches toward improving TB treatment have been proposed in an attempt to reduce the high TB morbidity and mortality rates. Host-directed therapies (HDTs), designed to modulate host immune components, provide an alternative approach for improving treatment outcome in both non-communicable and infectious diseases. Many candidate immunotherapeutics, designed to target regulatory myeloid immune components in cancer, have so far proven to be of value as repurposed HDT in TB. Several of these studies do however lack detailed description of the mechanism or host pathway affected by TB HDT treatment. In this review, we present an argument for greater appreciation of the role of regulatory myeloid cells, such as myeloid-derived suppressor cells (MDSC), as potential targets for the development of candidate TB HDT compounds. We discuss the role of MDSC in the context of Mycobacterium tuberculosis infection and disease, focussing primarily on their specific cellular functions and highlight the impact of HDTs on MDSC frequency and function.
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http://dx.doi.org/10.3389/fcimb.2018.00332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160538PMC
September 2019

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies.

Lancet Infect Dis 2018 07 23;18(7):e183-e198. Epub 2018 Mar 23.

Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK; National Institute of Health and Research Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK. Electronic address:

Tuberculosis remains the world's leading cause of death from an infectious disease, responsible for an estimated 1 674 000 deaths annually. WHO estimated 600 000 cases of rifampicin-resistant tuberculosis in 2016-of which 490 000 were multidrug resistant (MDR), with less than 50% survival after receiving recommended treatment regimens. Concerted efforts of stakeholders, advocates, and researchers are advancing further development of shorter course, more effective, safer, and better tolerated treatment regimens. We review the developmental pipeline and landscape of new and repurposed tuberculosis drugs, treatment regimens, and host-directed therapies (HDTs) for drug-sensitive and drug-resistant tuberculosis. 14 candidate drugs for drug-susceptible, drug-resistant, and latent tuberculosis are in clinical stages of drug development; nine are novel in phase 1 and 2 trials, and three new drugs are in advanced stages of development for MDR tuberculosis. Specific updates are provided on clinical trials of bedaquiline, delamanid, pretomanid, and other licensed or repurposed drugs that are undergoing investigation, including trials aimed at shortening duration of tuberculosis treatment, improving treatment outcomes and patient adherence, and reducing toxic effects. Ongoing clinical trials for shortening tuberculosis treatment duration, improving treatment outcomes in MDR tuberculosis, and preventing disease in people with latent tuberculosis infection are reviewed. A range of HDTs and immune-based treatments are under investigation as adjunctive therapy for shortening duration of therapy, preventing permanent lung injury, and improving treatment outcomes of MDR tuberculosis. We discuss the HDT development pipeline, ongoing clinical trials, and translational research efforts for adjunct tuberculosis treatment.
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http://dx.doi.org/10.1016/S1473-3099(18)30110-5DOI Listing
July 2018

Tuberculosis: advances and challenges in development of new diagnostics and biomarkers.

Lancet Infect Dis 2018 07 23;18(7):e199-e210. Epub 2018 Mar 23.

Centre for Clinical Microbiology, Division of Infection and Immunity, University College London (UCL), London, UK; National Institute of Health and Research Biomedical Research Centre, UCL Hospitals National Health Service Foundation Trust, London, UK; University of Zambia-University College London Medical School Research and Training Programme, University Teaching Hospital, Lusaka, Zambia. Electronic address:

Tuberculosis remains the leading cause of death from an infectious disease worldwide. Early and accurate diagnosis and detection of drug-sensitive and drug-resistant tuberculosis is essential for achieving global tuberculosis control. Despite the introduction of the Xpert MTB/RIF assay as the first-line rapid tuberculosis diagnostic test, the gap between global estimates of incidence and new case notifications is 4·1 million people. More accurate, rapid, and cost-effective screening tests are needed to improve case detection. Diagnosis of extrapulmonary tuberculosis and tuberculosis in children, people living with HIV, and pregnant women remains particularly problematic. The diagnostic molecular technology landscape has continued to expand, including the development of tests for resistance to several antituberculosis drugs. Biomarkers are urgently needed to indicate progression from latent infection to clinical disease, to predict risk of reactivation after cure, and to provide accurate endpoints for drug and vaccine trials. Sophisticated bioinformatic computational tools and systems biology approaches are being applied to the discovery and validation of biomarkers, with substantial progress taking place. New data have been generated from the study of T-cell responses and T-cell function, serological studies, flow cytometric-based assays, and protein and gene expression studies. Alternative diagnostic strategies under investigation as potential screening and triaging tools include non-sputum-based detection with breath-based tests and automated digital radiography. We review developments and key achievements in the search for new tuberculosis diagnostics and biomarkers. We highlight gaps and challenges in evaluation and rollout of new diagnostics and biomarkers, and prioritise areas needing further investment, including impact assessment and cost-benefit studies.
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http://dx.doi.org/10.1016/S1473-3099(18)30111-7DOI Listing
July 2018

Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections.

Front Immunol 2017 4;8:1895. Epub 2018 Jan 4.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, SAMRC Centre for Tuberculosis Research, DST and NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Tygerberg, South Africa.

Heterogeneous populations of myeloid regulatory cells (MRC), including monocytes, macrophages, dendritic cells, and neutrophils, are found in cancer and infectious diseases. The inflammatory environment in solid tumors as well as infectious foci with persistent pathogens promotes the development and recruitment of MRC. These cells help to resolve inflammation and establish host immune homeostasis by restricting T lymphocyte function, inducing regulatory T cells and releasing immune suppressive cytokines and enzyme products. Monocytic MRC, also termed monocytic myeloid-derived suppressor cells (M-MDSC), are phagocytes, capable of pathogen internalization and persistence, while exerting localized suppressive activity. Here, we summarize molecular pathways controlling M-MDSC genesis and functions in microbial-induced non-resolved inflammation and immunopathology. We focus on the roles of M-MDSC in infections, including opportunistic extracellular bacteria and fungi as well as persistent intracellular pathogens, such as mycobacteria and certain viruses. Better understanding of M-MDSC biology in chronic infections and their role in antimicrobial immunity, will advance development of novel, more effective and broad-range anti-infective therapies.
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http://dx.doi.org/10.3389/fimmu.2017.01895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758551PMC
January 2018

Phenotypically resembling myeloid derived suppressor cells are increased in children with HIV and exposed/infected with Mycobacterium tuberculosis.

Eur J Immunol 2017 01 16;47(1):107-118. Epub 2016 Dec 16.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences/SAMRC Centre for Tuberculosis Research/DST and NRF Centre of Excellence for Biomedical TB Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.

Increased disease susceptibility during early life has been linked to immune immaturity, regulatory T-cell/TH2 immune biasing and hyporesponsiveness. The contribution of myeloid derived suppressor cells (MDSCs) remains uninvestigated. Here, we assessed peripheral MDSC in HIV-infected and -uninfected children with tuberculosis (TB) disease before, during and after TB treatment, along with matched household contacts (HHCs), HIV-exposed, -infected and -uninfected children without recent TB exposure. Serum analytes and enzymes associated with MDSC accumulation/activation/function were measured by colorimetric- and fluorescence arrays. Peripheral frequencies of cells phenotypically resembling MDSCs were significantly increased in HIV-exposed uninfected (HEU) and M.tb-infected children, but peaked in children with TB disease and remained high following treatment. MDSC in HIV-infected (HI) children were similar to unexposed uninfected controls; however, HAART-mediated MDSC restoration to control levels could not be disregarded. Increased MDSC frequencies in HHC coincided with enhanced indoleamine-pyrrole-2,3-dioxygenase (IDO), whereas increased MDSC in TB cases were linked to heightened IDO and arginase-1. Increased MDSC were paralleled by reduced plasma IP-10 and thrombospondin-2 levels in HEU and significantly increased plasma IL-6 in HI HHC. Current investigations into MDSC-targeted treatment strategies, together with functional analyses of MDSCs, could endorse these cells as novel innate immune regulatory mechanism of infant HIV/TB susceptibility.
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http://dx.doi.org/10.1002/eji.201646658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233566PMC
January 2017

Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure.

Nat Med 2016 10 5;22(10):1094-1100. Epub 2016 Sep 5.

National Medical Center, Seoul, South Korea.

The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET-CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET-CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053881PMC
http://dx.doi.org/10.1038/nm.4177DOI Listing
October 2016

The Functional Response of B Cells to Antigenic Stimulation: A Preliminary Report of Latent Tuberculosis.

PLoS One 2016 6;11(4):e0152710. Epub 2016 Apr 6.

SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Mycobacterium tuberculosis (M.tb) remains a successful pathogen, causing tuberculosis disease numbers to constantly increase. Although great progress has been made in delineating the disease, the host-pathogen interaction is incompletely described. B cells have shown to function as both effectors and regulators of immunity via non-humoral methods in both innate and adaptive immune settings. Here we assessed specific B cell functional interaction following stimulation with a broad range of antigens within the LTBI milieu. Our results indicate that B cells readily produce pro- and anti-inflammatory cytokines (including IL-1β, IL-10, IL-17, IL-21 and TNF-α) in response to stimulation. TLR4 and TLR9 based stimulations achieved the greatest secreted cytokine-production response and BCG stimulation displayed a clear preference for inducing IL-1β production. We also show that the cytokines produced by B cells are implicated strongly in cell-mediated communication and that plasma (memory) B cells (CD19+CD27+CD138+) is the subset with the greatest contribution to cytokine production. Collectively our data provides insight into B cell responses, where they are implicated in and quantifies responses from specific B cell phenotypes. These findings warrant further functional B cell research with a focus on specific B cell phenotypes under conditions of active TB disease to further our knowledge about the contribution of various cell subsets which could have implications for future vaccine development or refined B cell orientated treatment in the health setting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152710PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822853PMC
August 2016

Helminth-M. tb co-infection.

Adv Exp Med Biol 2014 ;828:49-74

Biomedical Sciences, Division Molecular Biology and Human Genetics, DST/NRF, Centre of Excellence in Biomedical TB Research, Stellenbosch University, Cape Town, Western Cape, South Africa,

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http://dx.doi.org/10.1007/978-1-4939-1489-0_3DOI Listing
February 2015

Mycobacterium bovis BCG infection severely delays Trichuris muris expulsion and co-infection suppresses immune responsiveness to both pathogens.

BMC Microbiol 2014 Jan 17;14. Epub 2014 Jan 17.

Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, NRF/DST Centre of Excellence in Biomedical TB Research, Faculty Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: The global epidemiology of parasitic helminths and mycobacterial infections display extensive geographical overlap, especially in the rural and urban communities of developing countries. We investigated whether co-infection with the gastrointestinal tract-restricted helminth, Trichuris muris, and the intracellular bacterium, Mycobacterium bovis (M. bovis) BCG, would alter host immune responses to, or the pathological effect of, either infection.

Results: We demonstrate that both pathogens are capable of negatively affecting local and systemic immune responses towards each other by modifying cytokine phenotypes and by inducing general immune suppression. T. muris infection influenced non-specific and pathogen-specific immunity to M. bovis BCG by down-regulating pulmonary TH1 and Treg responses and inducing systemic TH2 responses. However, co-infection did not alter mycobacterial multiplication or dissemination and host pulmonary histopathology remained unaffected compared to BCG-only infected mice. Interestingly, prior M. bovis BCG infection significantly delayed helminth clearance and increased intestinal crypt cell proliferation in BALB/c mice. This was accompanied by a significant reduction in systemic helminth-specific TH1 and TH2 cytokine responses and significantly reduced local TH1 and TH2 responses in comparison to T. muris-only infected mice.

Conclusion: Our data demonstrate that co-infection with pathogens inducing opposing immune phenotypes, can have differential effects on compartmentalized host immune protection to either pathogen. In spite of local and systemic decreases in TH1 and increases in TH2 responses co-infected mice clear M. bovis BCG at the same rate as BCG only infected animals, whereas prior mycobacterial infection initiates prolonged worm infestation in parallel to decreased pathogen-specific TH2 cytokine production.
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http://dx.doi.org/10.1186/1471-2180-14-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898725PMC
January 2014