Background—Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolite... more Background—Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are lacking. Methods—We conducted a multi-centre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 participants were allocated to receive 2.5 mg vitamin D3 or placebo at baseline and at 2, 4 and 6 weeks after starting standard tuberculosis treatment. The primary endpoint of the trial was time from initiation of antimicrobial therapy to sputum culture conversion. Participants were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor (VDR), and interaction analyses were conducted to determine the influence of VDR genotype on response to vitamin D. This trial is registered with ClinicalTrials.gov (NCT00419068). Findings—126 participants were included in the p...
Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacteriu... more Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacterium tuberculosis (Mtb) co-infection is an early precipitate to AIDS. We aimed to determine whether Mtb strains differentially modulate cellular susceptibility to HIV-1 infection (cis- and trans-infection), via surface receptor interaction by their cell envelope lipids. Total lipids from pathogenic (lineage 4 Mtb H37Rv, CDC1551 and lineage 2 Mtb HN878, EU127) and non-pathogenic (Mycobacterium bovis BCG and Mycobacterium smegmatis) Mycobacterium strains were integrated into liposomes mimicking the lipid distribution and antigen accessibility of the mycobacterial cell wall. The resulting liposomes were tested for modulating in vitro HIV-1 cis- and trans-infection of TZM-bl cells using single-cycle infectious virus particles. Mtb glycolipids did not affect HIV-1 direct infection however, trans-infection of both R5 and X4 tropic HIV-1 strains were impaired in the presence of glycolipids from M....
RationaleThe heterogeneity in efficacy observed in studies of BCG vaccination is not fully explai... more RationaleThe heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure.MethodsWe updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context.Main resultsOf 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings ...
Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis (Mtb)-... more Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis (Mtb)-coinfected individuals indicates the important interaction between these syndemic pathogens. The immunological interaction between HIV-1 and Mtb has been largely defined by how the virus exacerbates tuberculosis disease pathogenesis. Understanding of the mechanisms by which pre-existing or subsequent Mtb infection may favor the replication, persistence and progression of HIV, is less characterized. We present a rationale for the critical consideration of ‘latent’ Mtb infection in HIV-1 prevention and cure strategies. In support of this position, we review evidence of the effect of Mtb infection on HIV-1 acquisition, replication and persistence. We propose that ‘latent’ Mtb infection may have considerable impact on HIV-1 pathogenesis and the continuing HIV-1 epidemic in sub-Saharan Africa.
International journal of environmental research and public health, Oct 18, 2016
In this review, reports were retrieved in which vitamin D status, as assessed by serum 25-hydroxy... more In this review, reports were retrieved in which vitamin D status, as assessed by serum 25-hydroxyvitamin D [25(OH)D] levels, was measured in South African population groups with varied skin colours and ethnicities. Healthy children and adults were generally vitamin D-sufficient [25(OH)D level >50 nmol/L] but the majority of those aged above 65 years were deficient. A major role for exposure to solar ultraviolet radiation (UVR) in determining 25(OH)D levels was apparent, with the dietary contribution being minor. Limited data exist regarding the impact of recent changes in lifestyles on vitamin D status, such as urbanisation. With regard to disease susceptibility, 11 of 22 relevant publications indicated association between low 25(OH)D levels and disease, with deficiency most notably found in individuals with tuberculosis and HIV-1. Information on the relationship between vitamin D receptor variants and ethnicity, disease or treatment response in the South African population group...
Objectives To describe the presentation and outcome of SARS-CoV2 infection in an African setting ... more 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 pulmonar...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 26, 2018
The risk of HIV-1 infected individuals developing TB is high while both prognostic and diagnostic... more The risk of HIV-1 infected individuals developing TB is high while both prognostic and diagnostic tools remain insensitive. The predictive performance of plasma biomarkers to identify HIV-1 infected individuals likely to progress to active disease is unknown. Thirteen preselected analytes were determined from QuantiFERON® Gold in-tube (QFT) plasma samples in 421 HIV-1 infected persons recruited within the screening and enrolment phases of a randomised controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomisation. Individuals were classified into prevalent TB, incident TB and controls. Comparisons between groups, supervised learning methods and weighted correlation network analyses were applied utilising the unstimulated and background-corrected plasma analyte concentrations. Unstimulated samples showed higher analyte concentrations in prevalent and incident TB compared to controls. The largest differences were seen for CXCL10, IL-2, IL-1 and TGF-. ...
Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2018
The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better un... more The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better understanding of the early events in subclinical disease will facilitate the development of diagnostics and interventions that improve TB control. This is particularly relevant in the context of HIV-1 coinfection where progression of TB is more likely. In a recent study using [F]-fluoro-2-deoxy-d-glucose positron emission/computed tomography (FDG-PET/CT) on 35 asymptomatic, HIV-1-infected adults, we identified 10 participants with radiographic evidence of subclinical disease, significantly more likely to progress than the 25 participants without. To gain insight into the biological events in early disease, we performed blood-based whole genome transcriptomic analysis on these participants and 15 active patients with TB. We found transcripts representing the classical complement pathway and Fcγ receptor 1 overabundant from subclinical stages of disease. Levels of circulating immune (antibod...
During infection, certain pathogens induce host genetic instability via DNA lesions, resulting in... more During infection, certain pathogens induce host genetic instability via DNA lesions, resulting in cancer hallmarks such as apoptosis evasion. The Human Immunodeficiency Virus (HIV-1) infects both CD4+ T cells and macrophages, but largely induces apoptosis only in CD4+ T cells. Apoptosis is triggered by double-strand breaks (DSBs), and is coordinated by the p53-regulated long noncoding RNA, lincRNA-p21, with its protein binding partners. We monitored the cellular infection response to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus secures the pro-survival MAP2K1/ERK2 cellular cascade, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21 and its protein binding partners. Notably, this pro-survival cascade is unavailable for similar viral manipulation in CD4+ T cells. As inhibitors of MAP2K1 or p53 regulators restore lincRNA-p21 function and induce apoptosis in macrophages, targeting this long no...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jul 5, 2017
Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfect... more Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. MMP activity...
Individual components of solar radiation, UVA, UVB and heat generation, are linked to their downs... more Individual components of solar radiation, UVA, UVB and heat generation, are linked to their downstream immune functions, inducing vitamin D production, demonstrating a great degree of overlap between various components.
Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis ... more Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis than HIV-uninfected persons. Low peripheral CD4(+) T-cell count is not the sole cause of higher susceptibility, because HIV-infected persons with a high peripheral CD4(+) T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV-uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis-associated granulomas. We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4(+) T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas. HIV increased M. tuberculosis numbers and reduced CD4(+) ...
Tuberculosis is classically divided into states of latent infection and active disease. Using com... more Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.
Background—Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolite... more Background—Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are lacking. Methods—We conducted a multi-centre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 participants were allocated to receive 2.5 mg vitamin D3 or placebo at baseline and at 2, 4 and 6 weeks after starting standard tuberculosis treatment. The primary endpoint of the trial was time from initiation of antimicrobial therapy to sputum culture conversion. Participants were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor (VDR), and interaction analyses were conducted to determine the influence of VDR genotype on response to vitamin D. This trial is registered with ClinicalTrials.gov (NCT00419068). Findings—126 participants were included in the p...
Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacteriu... more Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacterium tuberculosis (Mtb) co-infection is an early precipitate to AIDS. We aimed to determine whether Mtb strains differentially modulate cellular susceptibility to HIV-1 infection (cis- and trans-infection), via surface receptor interaction by their cell envelope lipids. Total lipids from pathogenic (lineage 4 Mtb H37Rv, CDC1551 and lineage 2 Mtb HN878, EU127) and non-pathogenic (Mycobacterium bovis BCG and Mycobacterium smegmatis) Mycobacterium strains were integrated into liposomes mimicking the lipid distribution and antigen accessibility of the mycobacterial cell wall. The resulting liposomes were tested for modulating in vitro HIV-1 cis- and trans-infection of TZM-bl cells using single-cycle infectious virus particles. Mtb glycolipids did not affect HIV-1 direct infection however, trans-infection of both R5 and X4 tropic HIV-1 strains were impaired in the presence of glycolipids from M....
RationaleThe heterogeneity in efficacy observed in studies of BCG vaccination is not fully explai... more RationaleThe heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure.MethodsWe updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context.Main resultsOf 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings ...
Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis (Mtb)-... more Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis (Mtb)-coinfected individuals indicates the important interaction between these syndemic pathogens. The immunological interaction between HIV-1 and Mtb has been largely defined by how the virus exacerbates tuberculosis disease pathogenesis. Understanding of the mechanisms by which pre-existing or subsequent Mtb infection may favor the replication, persistence and progression of HIV, is less characterized. We present a rationale for the critical consideration of ‘latent’ Mtb infection in HIV-1 prevention and cure strategies. In support of this position, we review evidence of the effect of Mtb infection on HIV-1 acquisition, replication and persistence. We propose that ‘latent’ Mtb infection may have considerable impact on HIV-1 pathogenesis and the continuing HIV-1 epidemic in sub-Saharan Africa.
International journal of environmental research and public health, Oct 18, 2016
In this review, reports were retrieved in which vitamin D status, as assessed by serum 25-hydroxy... more In this review, reports were retrieved in which vitamin D status, as assessed by serum 25-hydroxyvitamin D [25(OH)D] levels, was measured in South African population groups with varied skin colours and ethnicities. Healthy children and adults were generally vitamin D-sufficient [25(OH)D level >50 nmol/L] but the majority of those aged above 65 years were deficient. A major role for exposure to solar ultraviolet radiation (UVR) in determining 25(OH)D levels was apparent, with the dietary contribution being minor. Limited data exist regarding the impact of recent changes in lifestyles on vitamin D status, such as urbanisation. With regard to disease susceptibility, 11 of 22 relevant publications indicated association between low 25(OH)D levels and disease, with deficiency most notably found in individuals with tuberculosis and HIV-1. Information on the relationship between vitamin D receptor variants and ethnicity, disease or treatment response in the South African population group...
Objectives To describe the presentation and outcome of SARS-CoV2 infection in an African setting ... more 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 pulmonar...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 26, 2018
The risk of HIV-1 infected individuals developing TB is high while both prognostic and diagnostic... more The risk of HIV-1 infected individuals developing TB is high while both prognostic and diagnostic tools remain insensitive. The predictive performance of plasma biomarkers to identify HIV-1 infected individuals likely to progress to active disease is unknown. Thirteen preselected analytes were determined from QuantiFERON® Gold in-tube (QFT) plasma samples in 421 HIV-1 infected persons recruited within the screening and enrolment phases of a randomised controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomisation. Individuals were classified into prevalent TB, incident TB and controls. Comparisons between groups, supervised learning methods and weighted correlation network analyses were applied utilising the unstimulated and background-corrected plasma analyte concentrations. Unstimulated samples showed higher analyte concentrations in prevalent and incident TB compared to controls. The largest differences were seen for CXCL10, IL-2, IL-1 and TGF-. ...
Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2018
The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better un... more The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better understanding of the early events in subclinical disease will facilitate the development of diagnostics and interventions that improve TB control. This is particularly relevant in the context of HIV-1 coinfection where progression of TB is more likely. In a recent study using [F]-fluoro-2-deoxy-d-glucose positron emission/computed tomography (FDG-PET/CT) on 35 asymptomatic, HIV-1-infected adults, we identified 10 participants with radiographic evidence of subclinical disease, significantly more likely to progress than the 25 participants without. To gain insight into the biological events in early disease, we performed blood-based whole genome transcriptomic analysis on these participants and 15 active patients with TB. We found transcripts representing the classical complement pathway and Fcγ receptor 1 overabundant from subclinical stages of disease. Levels of circulating immune (antibod...
During infection, certain pathogens induce host genetic instability via DNA lesions, resulting in... more During infection, certain pathogens induce host genetic instability via DNA lesions, resulting in cancer hallmarks such as apoptosis evasion. The Human Immunodeficiency Virus (HIV-1) infects both CD4+ T cells and macrophages, but largely induces apoptosis only in CD4+ T cells. Apoptosis is triggered by double-strand breaks (DSBs), and is coordinated by the p53-regulated long noncoding RNA, lincRNA-p21, with its protein binding partners. We monitored the cellular infection response to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus secures the pro-survival MAP2K1/ERK2 cellular cascade, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21 and its protein binding partners. Notably, this pro-survival cascade is unavailable for similar viral manipulation in CD4+ T cells. As inhibitors of MAP2K1 or p53 regulators restore lincRNA-p21 function and induce apoptosis in macrophages, targeting this long no...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jul 5, 2017
Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfect... more Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. MMP activity...
Individual components of solar radiation, UVA, UVB and heat generation, are linked to their downs... more Individual components of solar radiation, UVA, UVB and heat generation, are linked to their downstream immune functions, inducing vitamin D production, demonstrating a great degree of overlap between various components.
Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis ... more Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis than HIV-uninfected persons. Low peripheral CD4(+) T-cell count is not the sole cause of higher susceptibility, because HIV-infected persons with a high peripheral CD4(+) T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV-uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis-associated granulomas. We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4(+) T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas. HIV increased M. tuberculosis numbers and reduced CD4(+) ...
Tuberculosis is classically divided into states of latent infection and active disease. Using com... more Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.
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Papers by Anna K. Coussens