Robert J Wilkinson

The Francis Crick Institute, Londinium, England, United Kingdom

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Publications (250)1860.3 Total impact

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    ABSTRACT: Background Identifying those at increased risk of death during TB treatment is a priority in resource-constrained settings. We performed this study to determine predictors of mortality during TB treatment. Methods We performed a retrospective analysis of a TB surveillance population in a high HIV prevalence area that was recorded in (Electronic Tuberculosis Register). Adult TB cases initiated TB treatment from 2007 through 2009 in Khayelitsha, South Africa. Cox proportional hazards models were used to identify risk factors for death (after multiple imputations for missing data). Model selection was performed using Akaike’s Information Criterion to obtain the most relevant predictors of death. Results Of 16,209 adult TB cases, 851 (5.3 %) died during TB treatment. In all TB cases, advancing age, co-infection with HIV, a prior history of TB and the presence of both pulmonary and extra-pulmonary TB were independently associated with an increasing hazard of death. In HIV-infected TB cases, advancing age and female gender were independently associated with an increasing hazard of death. Increasing CD4 counts and antiretroviral treatment during TB treatment were protective against death. In HIV-uninfected TB cases, advancing age was independently associated with death, whereas smear-positive disease was protective. Conclusion We identified several independent predictors of death during TB treatment in resource-constrained settings. Our findings inform resource-constrained settings about certain subgroups of TB patients that should be targeted to improve mortality during TB treatment.
    AIDS Research and Therapy 10/2015; 12(1). DOI:10.1186/s12981-015-0076-5 · 1.46 Impact Factor
  • Suzaan Marais · Graeme Meintjes · Maia Lesosky · Katalin A. Wilkinson · Robert J. Wilkinson ·

    AIDS 10/2015; DOI:10.1097/QAD.0000000000000904 · 5.55 Impact Factor
  • Suzaan Marais · Robert J. Wilkinson ·

    10/2015; DOI:10.1016/j.ebiom.2015.10.013
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    Rachel P J Lai · Graeme Meintjes · Robert J Wilkinson ·
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    ABSTRACT: Patients co-infected with HIV-1 and tuberculosis (TB) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) following commencement of antiretroviral therapy (ART). TB-IRIS is characterized by transient but severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. Here, we review the risk factors and clinical management of TB-IRIS, as well as the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis.
    Seminars in Immunopathology 10/2015; DOI:10.1007/s00281-015-0532-2 · 7.75 Impact Factor
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    Neesha Rockwood · Leila H. Abdullahi · Robert J. Wilkinson · Graeme Meintjes ·

    PLoS ONE 09/2015; 10(9):e0139017. DOI:10.1371/journal.pone.0139017 · 3.23 Impact Factor
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    ABSTRACT: Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.
    European Respiratory Journal 09/2015; DOI:10.1183/13993003.01245-2015 · 7.64 Impact Factor
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    ABSTRACT: Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.
    Nature Communications 09/2015; 6:8451. DOI:10.1038/ncomms9451 · 11.47 Impact Factor
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    ABSTRACT: Rationale: Experimental and epidemiological evidence suggests that neutrophils are important in the host response to tuberculosis. HIV infection, which increases the risk of tuberculosis, adversely affects neutrophil function. Objectives: To determine the impact of HIV and antiretroviral therapy on neutrophil antimycobacterial activity. Methods: We performed a cross-sectional comparison of neutrophil functions in 20 antiretroviral-naïve HIV-infected and 20 HIV-uninfected individuals utilising luminescence-, flow cytometry- and ELISA-based assays. We then conducted a prospective study in the HIV-infected individuals investigating these parameters during the first 6 months of antiretroviral therapy. Surface markers of neutrophil activation were investigated in a separate cohort using flow cytometry. Measurements and main results: HIV infection impaired control of M.tuberculosis by neutrophils (mean ratio of mycobacterial luminescence in neutrophil samples vs. serum controls at one hour in HIV-infected participants 0.88 ±0.13 versus HIV-uninfected participants 0.76 ±0.14, p=0.01; at 24 hours 0.82 ±0.13 vs. 0.71 ±0.13, p=0.01). The extent of impairment correlated with log[HIV viral load]. Neutrophil cell death after 24 hours' incubation with M.tuberculosis was higher in the HIV-infected cohort (85.3 ±11.8% vs. 57.9 ±22.4% necrotic cells, p<0.0001). Neutrophils from HIV-infected participants demonstrated significantly more CD62L-negative cells (median 23.0% vs. 8.5%, p=0.008) and CD16-negative cells (3.2% vs. 1.3%, p=0.03). Antiretroviral therapy restored mycobacterial restriction and pattern of neutrophil death towards levels seen in HIV-uninfected persons. Conclusions: Neutrophils in antiretroviral-naïve HIV-infected persons are hyperactivated, eliminate M.tuberculosis less effectively than in HIV-uninfected individuals and progress rapidly to necrotic cell death. These factors are ameliorated by antiretroviral therapy.
    Annals of the American Thoracic Society 09/2015; DOI:10.1513/AnnalsATS.201507-463OC
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    ABSTRACT: CD4(+) T cells mediate protection against Mycobacterium tuberculosis (Mtb); however, the phenotype of protective T cells is undefined, thereby confounding vaccination efforts. IL-27 is highly expressed during human tuberculosis (TB), and absence of IL-27R (Il27ra) specifically on T cells results in increased protection. IL-27R deficiency during chronic Mtb infection does not impact antigen-specific CD4(+) T cell number but maintains programmed death-1 (PD-1), CD69, and CD127 expression while reducing T-bet and killer cell lectin-like receptor G1 (KLRG1) expression. Furthermore, T-bet haploinsufficiency results in failure to generate KLRG1(+), antigen-specific CD4(+) T cells, and in improved protection. T cells in Il27ra(-/-) mice accumulate preferentially in the lung parenchyma within close proximity to Mtb, and antigen-specific CD4(+) T cells lacking IL-27R are intrinsically more fit than intact T cells and maintain IL-2 production. Improved fitness of IL-27R-deficient T cells is not associated with increased proliferation but with decreased expression of cell death-associated markers. Therefore, during Mtb infection, IL-27R acts intrinsically on T cells to limit protection and reduce fitness, whereas the IL-27R-deficient environment alters the phenotype and location of T cells. The significant expression of IL-27 in TB and the negative influence of IL-27R on T cell function demonstrate the pathway by which this cytokine/receptor pair is detrimental in TB. © 2015 Torrado et al.
    Journal of Experimental Medicine 08/2015; 212(9). DOI:10.1084/jem.20141520 · 12.52 Impact Factor
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    ABSTRACT: The treatment of tuberculosis is based on combinations of drugs that directly target Mycobacterium tuberculosis. A new global initiative is now focusing on a complementary approach of developing adjunct host-directed therapies.
    Nature Reviews Drug Discovery 07/2015; 14(8). DOI:10.1038/nrd4696 · 41.91 Impact Factor
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    ABSTRACT: Case fatality among inpatients with HIV-associated tuberculosis (HIV-TB) in Africa is high. We investigated the factors associated with mortality in a rural South African hospital. This was a prospective observational study of HIV-TB inpatients, with death by eight weeks the endpoint. Of ninety-nine patients (median CD4 count 72 cells/mm), thirty-two (32%) died, after median 8 days TB treatment. TB was diagnosed microbiologically in 75/99 and clinico-radiologically in 24, with no mortality difference between these groups (31% vs. 38% (p=0.53)). Median venous lactate was 5.5 mmol/l (IQR 3.9, 6.2) in those who died, 3.1 mmol/l (IQR 2.2, 4.1) in survivors (p<0.001). In multivariable analysis lactate ≥4 mmol/L (adjusted odds ratio [aOR] 9.8, 95% confidence interval [CI] 3.0-32.2), Glasgow Coma Score <15 (aOR 6.6, 95% CI 1.5-29.6), CD4 count <50 cells/mm (aOR 5.5, 95% CI 1.6-18.5) and age ≥50 (aOR 7.7, 95% CI 1.2-46.9) independently predicted death. In a nested case-control study, comparing those who died versus CD4-matched survivors, median plasma lipopolysaccharide concentrations were 93 and 57 pg/mL (p=0.026) and intestinal fatty acid binding protein 132 and 0 pg/mL (p=0.002). Mortality was high and predicted by elevated lactate, likely reflecting a sepsis-syndrome secondary to TB or bacterial co-infection with intestinal barrier dysfunction appearing to contribute.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 07/2015; 70(4). DOI:10.1097/QAI.0000000000000763 · 4.56 Impact Factor
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    ABSTRACT: Host-range restricted poxviruses make promising vaccine vectors due to their safety profile and immunogenicity. An understanding of the host innate immune responses produced by different poxvirus vectors would aid in the assessment, selection and rational design of improved vaccines for human and veterinary applications. Novel avipoxviruses are being assessed to determine if they are different from other poxvirus vectors. Analysis of the transcriptome induced in a mouse model would aid in determining if there were significant differences between different poxvirus vectors which may reflect different adjuvant potential as well as establish if they should be further evaluated as vaccine vectors. We compared host transcript abundance in the spleens of BALB/c mice twenty four hours after intravenous infection (10(5) pfu/mouse) with six host-restricted poxvirus species from three genera, namely Lumpy Skin Disease virus (LSDV), Canarypox virus (CNPV), Fowlpox virus (FWPV), modified vaccinia Ankara (MVA) and two novel South African avipoxviruses, Feral Pigeonpox virus (FeP2) and Penguinpox virus (PEPV). These six viruses produced qualitatively and quantitatively distinct host responses with LSDV, followed by MVA, inducing the greatest interferon (IFN) response. FeP2 and PEPV caused very little change to host transcript abundance compared to the other 4 viruses tested. CNPV and FWPV induced the up regulation of two immunoglobulin genes (Ighg and Ighg3 (IgG3)) with CNPV inducing a third, Ighm (IgM). HIV-1-specific IgG3 antibodies have been correlated with decreased risk of HIV-1 infection in the RV144 trial, which included a CNPV-based vector (Yates et al. (Sci Transl Med, 6(228) p228, 2014). Up regulation of IgG3 by CNPV and FWPV but not the other poxviruses tested in vivo, implies that these two avipoxvirus-vector backbones may be involved in stimulation of the clinically important IgG3 antibody subclass. Differential transcript abundance associated with the different poxviruses is further discussed with particular emphasis on responses related to immune responses. Six, genetically diverse host-restricted poxviruses produce different responses in a mouse model early after infection. These differences may affect the immune response induced to vaccine antigen in vectors based on these viruses. The two novel avipoxviruses were clearly distinguishable from the other viruses.
    BMC Genomics 07/2015; 16(1):510. DOI:10.1186/s12864-015-1659-1 · 3.99 Impact Factor
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    Anna K Coussens · Robert J Wilkinson · Adrian R Martineau ·
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    ABSTRACT: Adjunctive vitamin D treatment for pulmonary tuberculosis enhances resolution of inflammation but has modest effects on bacterial clearance. Sodium 4-phenylbutyrate (PBA) is in clinical use for a range of conditions and has been shown to synergise with vitamin D metabolites to upregulate cathelicidin antimicrobial peptide (CAMP) expression. We investigated whether clinically attainable plasma concentrations of PBA (0.4-4mM) directly affect Mycobacterium tuberculosis (Mtb) growth and human macrophage and PBMC response to infection. We also tested the ability of PBA to enhance the immunomodulatory actions of the vitamin D metabolite 25(OH)D3 during infection and synergistically inhibit intracellular Mtb growth. PBA inhibited Mtb growth in broth with an MIC99 of 1mM, which was reduced to 0.25mM by lowering pH. During human macrophage infection, PBA treatment restricted Mtb uptake, phagocytic receptor expression and intracellular growth in a dose-dependent manner. PBA independently regulated CCL chemokine secretion and induced expression of the antimicrobial LTF (lactoferrin), the anti-inflammatory PROC (protein C) and multiple genes within the NLRP3 inflammasome pathway. PBA co-treatment with 25(OH)D3 synergistically modulated expression of numerous vitamin D-response genes, including CAMP, CYP24A1, CXCL10 and IL-37. This synergistic effect was dependent on MAPK signalling, while the effect of PBA on LTF, PROC and NLRP3 was MAPK-independent. During PBA and 25(OH)D3 co-treatment of human macrophages, in the absence of exogenous proteinase 3 (PR3) to activate cathelicidin, Mtb growth restriction was dominated by the effect of PBA, while the addition of PR3 enhanced growth restriction by 25(OH)D3 and PBA co-treatment. This suggests that PBA augments vitamin D-mediated cathelicidin-dependent Mtb growth restriction by human macrophages and independently induces antimicrobial and anti-inflammatory action. Therefore through both host-directed and bacterial-directed mechanisms PBA and vitamin D may prove an effective combinatorial adjunct therapy for tuberculosis to both resolve immunopathology and enhance bacterial clearance.
    PLoS Pathogens 07/2015; 11(7):e1005007. DOI:10.1371/journal.ppat.1005007 · 7.56 Impact Factor
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    ABSTRACT: Tuberculosis (TB) remains a global pandemic and drug resistance is rising. Multicellular granuloma formation is the pathological hallmark of Mycobacterium tuberculosis infection. The membrane type 1 matrix metalloproteinase (MT1-MMP or MMP-14) is a collagenase that is key in leukocyte migration and collagen destruction. In patients with TB, induced sputum MT1-MMP mRNA levels were increased 5.1-fold compared with matched controls and correlated positively with extent of lung infiltration on chest radiographs (r = 0.483; p < 0.05). M. tuberculosis infection of primary human monocytes increased MT1-MMP surface expression 31.7-fold and gene expression 24.5-fold. M. tuberculosis-infected monocytes degraded collagen matrix in an MT1-MMP-dependent manner, and MT1-MMP neutralization decreased collagen degradation by 73%. In human TB granulomas, MT1-MMP immunoreactivity was observed in macrophages throughout the granuloma. Monocyte-monocyte networks caused a 17.5-fold increase in MT1-MMP surface expression dependent on p38 MAPK and G protein-coupled receptor-dependent signaling. Monocytes migrating toward agarose beads impregnated with conditioned media from M. tuberculosis-infected monocytes expressed MT1-MMP. Neutralization of MT1-MMP activity decreased this M. tuberculosis network-dependent monocyte migration by 44%. Taken together, we demonstrate that MT1-MMP is central to two key elements of TB pathogenesis, causing collagen degradation and regulating monocyte migration. Copyright © 2015 The Authors.
    The Journal of Immunology 06/2015; 195(3). DOI:10.4049/jimmunol.1403110 · 4.92 Impact Factor
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    ABSTRACT: Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. We conducted a longitudinal study in two ethnically distinct groups of healthy young adults in Cape Town, supplemented with vitamin D3 in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.
    Proceedings of the National Academy of Sciences 06/2015; DOI:10.1073/pnas.1500909112 · 9.67 Impact Factor
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    ABSTRACT: ABSTRACT Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) was first described almost two decades ago. We undertook this systematic review and meta-analysis to collate findings across studies that have reported the incidence, clinical features, management and outcomes of paradoxical TB-IRIS. Forty studies that cumulatively reported 1048 paradoxical TB-IRIS cases were included. The pooled estimated incidence among patients with HIV-associated TB initiating antiretroviral therapy was 18% (95% CI: 16-21%). Frequent features were pulmonary and lymph node involvement. Hospitalization occurred in 25% (95% CI: 19-30%). In studies that reported treatment, corticosteroids were prescribed more frequently (38%; 95% CI: 27-48%) than nonsteroidal anti-inflammatory drugs (28%; 95% CI: 2-53%). Case fatality was 7% (95% CI: 4-11%), but death attributed to TB-IRIS occurred in 2% of cases (95% CI: 1-3%).
    Future Microbiology 06/2015; 10(6):1077-99. DOI:10.2217/fmb.15.9 · 4.28 Impact Factor
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    ABSTRACT: In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Tuberculosis (Edinburgh, Scotland) 05/2015; 190(4). DOI:10.1016/ · 2.71 Impact Factor

Publication Stats

10k Citations
1,860.30 Total Impact Points


  • 2015
    • The Francis Crick Institute
      Londinium, England, United Kingdom
  • 1996-2015
    • Imperial College London
      • • Department of Medicine
      • • Centre for Molecular Microbiology and Infection
      Londinium, England, United Kingdom
    • St. Mary’s Hospital for Children
      New York City, New York, United States
  • 2013-2014
    • Clinical Infectious Diseases Research Initiative IDM
      Kaapstad, Western Cape, South Africa
  • 2005-2014
    • University of Cape Town
      • • Institute of Infectious Disease & Molecular Medicine (IIDMM)
      • • Department of Medicine
      Kaapstad, Western Cape, South Africa
  • 2011-2013
    • MRC National Institute for Medical Research
      • • Division of Immunoregulation
      • • Division of Mycobacterial Research
      London, ENG, United Kingdom
  • 2012
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 2009
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 2007
    • North West London Hospitals NHS Trust
      Harrow, England, United Kingdom
  • 2006-2007
    • University of Melbourne
      • Department of Paediatrics
      Melbourne, Victoria, Australia
  • 2001
    • University of Iowa
      • Department of Internal Medicine
      Iowa City, Iowa, United States
  • 1999-2000
    • Case Western Reserve University
      • Division of Infectious Diseases and HIV Medicine
      Cleveland, Ohio, United States
    • National Institute of Immunology
      New Dilli, NCT, India
  • 1997
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
  • 1996-1997
    • MRC Clinical Sciences Centre
      London Borough of Harrow, England, United Kingdom