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Article ; Online: Biomarkers for Identifying Risk of Immune Reconstitution Inflammatory Syndrome.

Wilkinson, Katalin Andrea / Walker, Naomi

2016 Volume 4, Page(s) 9–10

MeSH term(s)	Biomarkers ; HIV Infections/immunology ; Humans ; Immune Reconstitution Inflammatory Syndrome/immunology
Chemical Substances	Biomarkers
Language	English
Publishing date	2016-02-06
Publishing country	Netherlands
Document type	Journal Article ; Comment
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2016.02.013
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Article ; Online: Mycobacterial-specific secretion of cytokines and chemokines in healthcare workers with apparent resistance to infection with

Shey, Muki Shehu / Balfour, Avuyonke / Masina, Nomawethu / Bekiswa, Abulele / Schutz, Charlotte / Goliath, Rene / Dielle, Rachel / Katoto, Patrick Dmc / Wilkinson, Katalin Andrea / Lewinsohn, David / Lewinsohn, Deborah Anne / Meintjes, Graeme

Frontiers in immunology

2023 Volume 14, Page(s) 1176615

Abstract: Background: Currently, diagnosis of latent TB infection (LTBI) is based on the secretion of IFN-γ in response to : Methods: We enrolled HIV-uninfected healthcare workers who had worked in high TB-exposure environments for 5 years or longer. We ... ...

Abstract	Background: Currently, diagnosis of latent TB infection (LTBI) is based on the secretion of IFN-γ in response to Methods: We enrolled HIV-uninfected healthcare workers who had worked in high TB-exposure environments for 5 years or longer. We screened them for LTBI using the tuberculin skin test and the QuantiFERON-TB Gold Plus assay. We performed multiplex Luminex to measure concentrations of T cell-associated cytokines and chemokines as well as total antibodies in plasma collected from unstimulated fresh whole blood and supernatants from QuantiFERON-TB Gold Plus tubes following incubation of whole blood for 16-24 hours with ESAT6/CFP10 peptides. Results: Samples from 78 individuals were analyzed: 33 resisters (TST<10mm; IGRA<0.35 IU/mL), 33 with LTBI (TST≥10mm and IGRA≥0.35 IU/mL) and 12 discordant (TST=0mm; IGRA≥1.0 IU/mL). There were no differences in concentrations of cytokines and chemokines in plasma between the different groups. Resisters had significantly lower concentrations of IFN-γ, IL-2, TNF-α, MIP-1α, MIP-1β, ITAC, IL-13 and GM-CSF in supernatants compared with LTBI group. There were no significant differences in the concentrations in supernatants of IL-10, IL-1β, IL-17A, IL-21, IL-23, MIP-3α, IL-4, IL-5, IL-6, IL-7, IL-8, Fractalkine and IL-12p70 between the groups. We observed that resisters had similar concentrations of total antibodies (IgG1, IgG2, IgG3, IgG4, IgA, and IgM) in plasma and supernatants compared to the LTBI and discordant groups. Conclusion: Resistance to Mtb infection despite sustained exposure is associated with lower Mtb-specific secretion of Th1-associated cytokines and chemokines. However, resisters showed secreted concentrations after Mtb stimulation of total antibodies and cytokines/chemokines associated with innate and Th17 immune responses similar to those with Mtb infection. This suggests an ability to mount non-IFN-γ immune responses to Mtb in apparent resisters.
MeSH term(s)	Humans ; Mycobacterium tuberculosis ; Cytokines ; Tuberculosis ; Latent Tuberculosis ; Tuberculin Test ; Latent Infection
Chemical Substances	Cytokines
Language	English
Publishing date	2023-05-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1176615
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Article ; Online: Contribution of APCs to mucosal-associated invariant T cell activation in infectious disease and cancer.

Shey, Muki Shehu / Balfour, Avuyonke / Wilkinson, Katalin Andrea / Meintjes, Graeme

Innate immunity

2018 Volume 24, Issue 4, Page(s) 192–202

Abstract: APCs such as monocytes and dendritic cells are among the first cells to recognize invading pathogens and initiate an immune response. The innate response can either eliminate the pathogen directly, or through presentation of Ags to T cells, which can ... ...

Abstract	APCs such as monocytes and dendritic cells are among the first cells to recognize invading pathogens and initiate an immune response. The innate response can either eliminate the pathogen directly, or through presentation of Ags to T cells, which can help to clear the infection. Mucosal-associated invariant T (MAIT) cells are among the unconventional T cells whose activation does not involve the classical co-stimulation during Ag presentation. MAIT cells can be activated either via presentation of unconventional Ags (such as riboflavin metabolites) through the evolutionarily conserved major histocompatibility class I-like molecule, MR1, or directly by cytokines such as IL-12 and IL-18. Given that APCs produce cytokines and can express MR1, these cells can play an important role in both pathways of MAIT cell activation. In this review, we summarize evidence on the role of APCs in MAIT cell activation in infectious disease and cancer. A better understanding of the interactions between APCs and MAIT cells is important in further elucidating the role of MAIT cells in infectious diseases, which may facilitate the design of novel interventions such as vaccines.
MeSH term(s)	Antigen Presentation ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Communicable Diseases/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Interleukin-12/metabolism ; Interleukin-18/metabolism ; Lymphocyte Activation ; Mucosal-Associated Invariant T Cells/immunology ; Mucosal-Associated Invariant T Cells/metabolism ; Neoplasms/immunology ; Receptors, Antigen, T-Cell, alpha-beta/metabolism
Chemical Substances	Histocompatibility Antigens Class I ; Interleukin-18 ; Receptors, Antigen, T-Cell, alpha-beta ; Interleukin-12 (187348-17-0)
Language	English
Publishing date	2018-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1753-4267
ISSN (online)	1753-4267
DOI	10.1177/1753425918768695
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Article ; Online: The effect of antiretroviral treatment on selected genes in whole blood from HIV-infected adults sensitised by Mycobacterium tuberculosis.

Jhilmeet, Nishtha / Lowe, David M / Riou, Catherine / Scriba, Thomas J / Coussens, Anna / Goliath, Rene / Wilkinson, Robert J / Wilkinson, Katalin Andrea

PloS one

2018 Volume 13, Issue 12, Page(s) e0209516

Abstract: HIV-1 co-infection is a leading cause of susceptibility to tuberculosis (TB), with the risk of TB being increased at all stages of HIV-1 infection. Antiretroviral treatment (ART) is the most effective way to reduce the risk of TB in HIV-1 co-infected ... ...

Abstract	HIV-1 co-infection is a leading cause of susceptibility to tuberculosis (TB), with the risk of TB being increased at all stages of HIV-1 infection. Antiretroviral treatment (ART) is the most effective way to reduce the risk of TB in HIV-1 co-infected people. Studying protective, ART-induced, immune restoration in HIV-1 infected individuals sensitised by Mycobacterium tuberculosis (Mtb) can thus help identify mechanisms of protection against TB. In order to understand ART-mediated prevention of TB in HIV-1 infected adults, we investigated the expression of 30 genes in whole blood from HIV-1 infected patients during the first 6 months of ART-induced immune reconstitution. The 30 selected genes were previously described to be differentially expressed between sorted Mtb specific central and effector memory CD4 T cells. HIV-1 infected persons sensitised by Mtb were recruited in Khayelitsha, South Africa, when initiating ART. RNA was extracted from whole blood at initiation and 1, 3 and 6 months of ART. qRT-PCR was used to determine gene expression and three reference 'housekeeping' genes were used to calculate the fold change in the expression of each gene relative to day 0 of ART. Results were assessed longitudinally. We observed a decrease in the expression of a number of genes at 6 months of ART, reflecting a decrease in immune activation. However, following correction for multiple comparisons and increasing CD4 counts, only the decrease in CD27 gene expression remained statistically significant. While not statistically significant, a number of genes also showed increased expression at various timepoints, illustrating the broad regeneration of the T cell pool in HIV-1 infected adults on ART. Our findings generate hypotheses underlying ART- induced protective immune reconstitution and may pave the way for future studies to evaluate ART mediated prevention of TB in HIV-1 infected persons.
MeSH term(s)	Antiretroviral Therapy, Highly Active ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/virology ; Coinfection ; Female ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/physiology ; Humans ; Immunization ; Interferon-gamma Release Tests ; Male ; Mycobacterium tuberculosis/immunology ; Treatment Outcome ; Tuberculosis/immunology ; Tuberculosis/metabolism ; Tuberculosis/microbiology ; Viral Load
Language	English
Publishing date	2018-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0209516
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Article ; Online: Rapid, simplified whole blood-based multiparameter assay to quantify and phenotype SARS-CoV-2 specific T cells

Riou, Catherine / Schafer, Georgia / Du Bruyn, Elsa / Goliath, Rene / Stek, Cari / Mou, Huihui / Hung, Deli / Wilkinson, Katalin Andrea / Wilkinson, Robert John

medRxiv

Keywords	covid19
Language	English
Publishing date	2020-11-03
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.10.30.20223099
Database	COVID19

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Article ; Online: Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus-1.

Lesosky, Maia / Rangaka, Molebogeng X / Pienaar, Cara / Coussens, Anna K / Goliath, Rene / Mathee, Shaheed / Mwansa-Kambafwile, Judith / Maartens, Gary / Wilkinson, Robert J / Wilkinson, Katalin Andrea

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2018 Volume 69, Issue 2, Page(s) 295–305

Abstract: Background: The risk of individuals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1- ... ...

Abstract	Background: The risk of individuals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1-infected individuals are likely to progress to active disease is unknown. Methods: Thirteen analytes were measured from QuantiFERON Gold in-tube (QFT) plasma samples in 421 HIV-1-infected persons recruited within the screening and enrollment phases of a randomized, controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomization. Individuals were classified into prevalent TB, incident TB, and control groups. Comparisons between groups, supervised learning methods, and weighted correlation network analyses were applied utilizing the unstimulated and background-corrected plasma analyte concentrations. Results: Unstimulated samples showed higher analyte concentrations in the prevalent and incident TB groups compared to the control group. The largest differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2 (IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis using unstimulated analytes discriminated best between the control and prevalent TB groups (area under the curve [AUC] = 0.9), reasonably well between the incident and prevalent TB groups (AUC > 0.8), and poorly between the control and incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons, except the comparison between the control vs incident TB groups. Models using background-adjusted values performed poorly. Conclusions: Single plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected individuals, and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has been suggested as having the utility to detect prevalent TB amongst HIV-1 co-infected persons.
MeSH term(s)	Adult ; Biomarkers/blood ; Clinical Decision Rules ; Diagnostic Tests, Routine/methods ; Female ; HIV Infections/complications ; Humans ; Male ; Plasma/chemistry ; Tuberculosis/diagnosis
Chemical Substances	Biomarkers
Language	English
Publishing date	2018-09-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciy823
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Article ; Online: Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α.

Tezera, Liku B / Bielecka, Magdalena K / Ogongo, Paul / Walker, Naomi F / Ellis, Matthew / Garay-Baquero, Diana J / Thomas, Kristian / Reichmann, Michaela T / Johnston, David A / Wilkinson, Katalin Andrea / Ahmed, Mohamed / Jogai, Sanjay / Jayasinghe, Suwan N / Wilkinson, Robert J / Mansour, Salah / Thomas, Gareth J / Ottensmeier, Christian H / Leslie, Alasdair / Elkington, Paul T

eLife

2020 Volume 9

Abstract: Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune ... ...

Abstract	Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Hypoxia ; Granuloma/metabolism ; Humans ; Immunotherapy/methods ; Latent Tuberculosis/immunology ; Latent Tuberculosis/pathology ; Microspheres ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/growth & development ; Mycobacterium tuberculosis/metabolism ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; Up-Regulation
Chemical Substances	PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2020-02-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.52668
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Article ; Online: Communicable and non-communicable co-morbidities and the presentation of COVID-19 in an African setting of high HIV-1 and tuberculosis prevalence

medRxiv

Abstract: Objectives To describe the presentation and outcome of SARS–CoV2 infection in an African setting of high non–communicable co–morbidity and also HIV–1 and tuberculosis prevalence. Design Case control analysis with cases stratified by HIV–1 and ... ...

Abstract	Objectives To describe the presentation and outcome of SARS–CoV2 infection in an African setting of high non–communicable co–morbidity and also HIV–1 and tuberculosis prevalence. Design Case control analysis with cases stratified by HIV–1 and tuberculosis status. Setting A single–centre observational case–control study of adults admitted to a South African hospital with proven SARS–CoV–2 infection or alternative diagnosis. Participants 104 adults with RT–PCR–proven SARS–CoV2 infection of which 55 (52.9%) were male and 31 (29.8%) HIV–1 co–infected. 40 adults (35.7% male, 30.9% HIV–1 co–infected) admitted during the same period with no RT–PCR or serological evidence of SARS–CoV2 infection and assigned alternative diagnoses. Additional in vitro data from prior studies of 72 healthy controls and 118 HIV–1 uninfected and infected persons participants enrolled to a prior study with either immune evidence of tuberculosis sensitization but no symptoms or microbiologically confirmed pulmonary tuberculosis. Results Two or more co–morbidities were present in 57.7% of 104 RT–PCR proven COVID–19 presentations, the commonest being hypertension (48%), type 2 diabetes mellitus (39%), obesity (31%) but also HIV–1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS–CoV–2, clinical features could be dominated by either SARS–CoV–2 or tuberculosis: lymphopenia was exacerbated, and some markers of inflammation (D–dimer and ferritin) elevated in singly SARS–CoV–2 infected patients were even further elevated (p less than 0.05). HIV–1 and SARS–CoV2 co–infection resulted in lower absolute number and proportion of CD4 lymphocytes, with those in the lowest peripheral CD4 percentage strata exhibiting absent or lower antibody responses against SARS–CoV2. Death occurred in 30/104 (29%) of all COVID–19 patients and in 6/15 (40%) of patients with coincident SARS–CoV–2 and tuberculosis. Conclusions In this South African setting, HIV–1 and tuberculosis are common co–morbidities in patients presenting with COVID–19. In environments in which tuberculosis is common, SARS–CoV–2 and tuberculosis may co–exist with clinical presentation being typical of either disease. Clinical suspicion of exacerbation of co–existent tuberculosis accompanying SARS–CoV–2 should be high.
Keywords	covid19
Language	English
Publishing date	2021-05-11
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.05.11.21256479
Database	COVID19

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Article: Association between tuberculin skin test reactivity, the memory CD4 cell subset, and circulating FoxP3-expressing cells in HIV-infected persons.

Sarrazin, Heike / Wilkinson, Katalin Andrea / Andersson, Jan / Rangaka, Molebogeng Xheeda / Radler, Lena / van Veen, Kerryn / Lange, Christoph / Wilkinson, Robert John

The Journal of infectious diseases

2009 Volume 199, Issue 5, Page(s) 702–710

Abstract: Background: Lack of reactivity to the tuberculin skin test (TST) is widely observed in individuals with advanced human immunodeficiency virus type 1 (HIV-1) infection.: Methods: Biopsy specimens from the TST reaction site and from skin not ... ...

Abstract	Background: Lack of reactivity to the tuberculin skin test (TST) is widely observed in individuals with advanced human immunodeficiency virus type 1 (HIV-1) infection. Methods: Biopsy specimens from the TST reaction site and from skin not infiltrated with purified protein derivative were obtained from 15 HIV-1-infected and 23 uninfected persons who did not have active tuberculosis and who were from a community in which the incidence of tuberculosis was very high. Histologic sections (size, 8 mum) were immunohistochemically stained for CD4, CD8, CD28, CD45RA, CD45RO, CD62L, CD1a, human leukocyte antigen (HLA)-DR, granulysin, interferon-gamma, and FoxP3 and were analyzed by single-cell in situ digital imaging. Peripheral blood mononuclear cells were analyzed using a fluorescence-activated cell sorter. Results: Biopsy specimens obtained from TST-reactive skin of HIV-1-infected persons demonstrated fewer CD4(+) T cells at the TST site (P = .36) but more HLA-DR(+) T cells (P = .037) than did such biopsy specimens obtained from HIV-1-uninfected persons. Among HIV-1-infected persons, the total number of cells (P = .008) and numbers of CD45RO(+) memory T cells (P = .003) were significantly higher in TST-reactive persons than in TST-unreactive persons. For HIV-1-infected persons, TST induration was inversely correlated with the numbers of FoxP3(+) T cells in the blood (P = .026) but was unrelated to the number of circulating CD4(+) T cells. Conclusions: For HIV-1 infected persons, the TST depends on memory T cells and is more strongly associated with the numbers of circulating FoxP3(+)CD4(+) T cells than with the total number of CD4(+) T cells.
MeSH term(s)	Adult ; CD4-Positive T-Lymphocytes/classification ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/physiology ; Female ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; HIV Infections/complications ; HIV Infections/immunology ; Humans ; Immunologic Memory ; Immunophenotyping ; Male ; Skin/cytology ; Skin/immunology ; Tuberculin Test ; Tuberculosis/diagnosis
Chemical Substances	FOXP3 protein, human ; Forkhead Transcription Factors
Language	English
Publishing date	2009-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1086/596735
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Article ; Online: Hypoxia induces an immunodominant target of tuberculosis specific T cells absent from common BCG vaccines.

Gideon, Hannah Priyadarshini / Wilkinson, Katalin Andrea / Rustad, Tige R / Oni, Tolu / Guio, Heinner / Kozak, Robert Andrew / Sherman, David R / Meintjes, Graeme / Behr, Marcel A / Vordermeier, Hans Martin / Young, Douglas Brownlee / Wilkinson, Robert John

PLoS pathogens

2010 Volume 6, Issue 12, Page(s) e1001237

Abstract: M. tuberculosis (MTB) species-specific antigenic determinants of the human T cell response are important for immunodiagnosis and vaccination. As hypoxia is a stimulus in chronic tuberculosis infection, we analyzed transcriptional profiles of MTB subject ... ...

Abstract	M. tuberculosis (MTB) species-specific antigenic determinants of the human T cell response are important for immunodiagnosis and vaccination. As hypoxia is a stimulus in chronic tuberculosis infection, we analyzed transcriptional profiles of MTB subject to 168 hours of hypoxia to test the hypothesis that upregulation by hypoxia might result in gene products being recognized as antigens. We identified upregulation of two region of difference (RD) 11 (Rv2658C and Rv2659c), and one RD2 (Rv1986) absent from commonly used BCG strains. In MTB infected persons, the IL-2 ELISpot response to Rv1986 peptides was several times greater than the corresponding IFN-γ response to the reference immunodominant ESAT-6 or CFP-10 antigens. The IL-2 response was confined to two epitopic regions containing residues 61-80 and 161-180. The biggest population of IL-2 secreting T cells was single cytokine positive central memory T cells. The IL-2 response to live MTB bacilli lacking Rv1986 was significantly lower than the response to wild type or mutant complemented with Rv1986. In addition, the IL-2 response to Rv1986 was significantly lower in HIV-TB co-infected persons than in HIV uninfected persons, and significantly increased during antiretroviral therapy. These findings demonstrate that Rv1986 is an immunodominant target of memory T cells and is therefore of relevance when considering the partial efficacy of currently used BCG vaccines and provide evidence for a clinical trial comparing BCG strains.
MeSH term(s)	Antigens, Bacterial/genetics ; Antigens, Bacterial/immunology ; BCG Vaccine/immunology ; Gene Expression Profiling ; Humans ; Hypoxia/immunology ; Immunodominant Epitopes/biosynthesis ; Immunodominant Epitopes/genetics ; Immunologic Memory ; T-Cell Antigen Receptor Specificity ; T-Lymphocytes/immunology ; Transcriptional Activation ; Tuberculosis/immunology
Chemical Substances	Antigens, Bacterial ; BCG Vaccine ; Immunodominant Epitopes
Language	English
Publishing date	2010-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1001237
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