Publications
520 results found
Bunjun R, Riou C, Soares AP, et al., 2017, Effect of HIV on the frequency and number of Mycobacterium tuberculosis-specific CD4+ T cells in blood and the airways in latent tuberculosis infection, Journal of Infectious Diseases, Vol: 216, Pages: 1550-1560, ISSN: 0022-1899
HIV-1 infection substantially increases the risk of developing tuberculosis (TB). There is extensive depletion of Mycobacterium tuberculosis (M.tuberculosis)-specific CD4+ T cells in blood in early HIV infection, but little is known about responses in the lungs at this stage. Given that mucosal organs are a principal target for HIV-mediated CD4 destruction, we investigated M.tuberculosis-specific responses in bronchoalveolar lavage (BAL), in persons with latent TB infection and untreated HIV-1 co-infection with preserved CD4 counts. M.tuberculosis-specific CD4+ cytokine responses (IFN-, TNF- and IL-2) were discordant in frequency and function between BAL and blood. Responses in BAL were 15-fold lower in HIV-infected compared to uninfected persons (p=0.048), whilst blood responses were 2-fold lower (p=0.006). However, an increase in T cells in the airways in HIV-infected persons resulted in the overall number of M.tuberculosis-specific CD4+ cells in BAL being similar. Our study highlights the important insights gained from studying TB immunity at the site of disease during HIV infection.
Kaufmann SHE, Dockrell HM, Drager N, et al., 2017, TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel tuberculosis (TB) vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal.
Wilkinson RJ, Rohlwink U, Misra UK, et al., 2017, Tuberculous meningitis., Nat Rev Neurol, Vol: 13, Pages: 581-598
Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood-brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies - including corticosteroids, aspirin and thalidomide - has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.
du Bruyn E, Wilkinson RJ, 2017, The immune interaction between HIV-1 infection and Mycobacterium tuberculosis, Tuberculosis and the Tubercle Bacillus: Second Edition, Pages: 239-268, ISBN: 9781555819552
HIV-1-infected people are approximately 26 times more likely to develop tuberculosis (TB) than HIV-1-uninfected people (1). This increased risk of developing TB is apparent early after HIV-1 seroconversion: a large study of South African miners found that TB incidence doubled within the first year of HIV-1 infection (2). Of the 9.6 million reported TB cases in 2014, 1.2 million were coinfected with HIV-1, with 74% of reported HIV-1-infected TB cases being from Africa (1). The HIV-1 burden in sub-Saharan Africa is particularly high, where 25.8 million people were living with HIV in 2014 and only 41% had access to antiretroviral therapy (ART) (3). The relatively low ART access may arise in part from a lack of eligibility as determined by local guidelines. It is hoped that more people living with HIV might access ART as a result of the 2015 World Health Organization (WHO) recommendation that ART be initiated for everyone living with HIV at any CD4 cell count (4). ART reduces TB risk among HIV-1-infected people by 54 to 90% and halves the TB recurrence rate (5). Despite this risk reduction, HIV-1-infected people established on ART in high TB burden settings remain at higher risk than HIV-1-uninfected people, even in higher CD4 strata (6).
Riou C, Berkowitz N, Goliath R, et al., 2017, Analysis of the Phenotype of Mycobacterium tuberculosis-Specific CD4+T Cells to Discriminate Latent from Active Tuberculosis in HIV-Uninfected and HIV-Infected Individuals, FRONTIERS IN IMMUNOLOGY, Vol: 8, Pages: 1-11, ISSN: 1664-3224
Several immune-based assays have been suggested to differentiate latent from active tuberculosis (TB). However, their relative performance as well as their efficacy in HIV-infected persons, a highly at-risk population, remains unclear. In a study of 81 individuals, divided into four groups based on their HIV-1 status and TB disease activity, we compared the differentiation (CD27 and KLRG1), activation (HLA-DR), homing potential (CCR4, CCR6, CXCR3, and CD161) and functional profiles (IFNγ, IL-2, and TNFα) of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cells using flow cytometry. Active TB disease induced major changes within the Mtb-responding CD4+ T cell population, promoting memory maturation, elevated activation and increased inflammatory potential when compared to individuals with latent TB infection. Moreover, the functional profile of Mtb-specific CD4+ T cells appeared to be inherently related to their degree of differentiation. While these specific cell features were all capable of discriminating latent from active TB, irrespective of HIV status, HLA-DR expression showed the best performance for TB diagnosis [area-under-the-curve (AUC) = 0.92, 95% CI: 0.82–1.01, specificity: 82%, sensitivity: 84% for HIV− and AUC = 0.99, 95% CI: 0.98–1.01, specificity: 94%, sensitivity: 93% for HIV+]. In conclusion, these data support the idea that analysis of T cell phenotype can be diagnostically useful in TB.
Strickland N, Müller TL, Berkowitz N, et al., 2017, Characterization of Mycobacterium tuberculosis-Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease., Journal of Immunology, ISSN: 1550-6606
A major challenge for the development of an effective vaccine against tuberculosis (TB) is that the attributes of protective CD4(+) T cell responses are still elusive for human TB. Infection with HIV type 1 is a major risk factor for TB, and a better understanding of HIV-induced alterations of Mycobacterium tuberculosis-specific CD4(+) T cells that leads to failed host resistance may provide insight into protective T cell immunity to TB. A total of 86 participants from a TB-endemic setting, either HIV-infected or uninfected and with latent or active TB (aTB), were screened using M.tuberculosis-specific MHC class II tetramers. We examined the phenotype as well as function of ex vivo M. tuberculosis-specific tetramer(+)CD4(+) T cells using flow cytometry. The numbers of M. tuberculosis-specific tetramer(+)CD4(+) T cells were relatively well maintained in HIV-infected persons with aTB, despite severe immunodeficiency. However, although HIV-uninfected persons with latent TB infection exhibited ex vivo M. tuberculosis-specific CD4(+) T cells predominantly of a CXCR3(+)CCR6(+)CCR4(-) (Th1*) phenotype, aTB or HIV infection was associated with a contraction of this subset. Nevertheless, in individuals with aTB and/or HIV infection, circulating ex vivo M. tuberculosis-specific CD4(+) T cells did not display defects in exhaustion or polyfunctionality compared with healthy HIV-uninfected individuals with latent TB infection. Collectively, these data suggest that increased susceptibility to TB disease could be related to a loss of circulating Th1* CD4(+) T cells rather than major changes in the number or function of circulating CD4(+) T cells.
Oni T, Berkowitz N, Kubjane M, et al., 2017, Trilateral overlap between tuberculosis, diabetes and HIV-1 in a high burden African setting: Implications for TB control, European Respiratory Journal, Vol: 50, ISSN: 1399-3003
Background The diabetes (DM) burden is growing in countries where tuberculosis and HIVB1 remain major challenges, threatening tuberculosis control efforts. This study determined the association between tuberculosis and diabetes / impaired glucose regulation (IGR) in the context of HIVB1.Methods A crossBsectional study was conducted at a TB clinic in Cape Town. Participants were screened for DM and IGR, using fasting plasma glucose, oral glucose tolerance test and HbA1c. Results 414 TB and 438 nonBTB participants were enrolled. In multivariable analysis, diabetes was associated with tuberculosis (Odds ratio: 2.4; 95% CI 1.3 – 4.3 p=0.005); with 14% population attributable risk fraction. but this association varied by diagnostic test (driven by HbA1c). The association remained significant in HIVB1Binfected (Odds ratio: 2.4; 95% CI 1.1 – 5.2; p=0.030). A high prevalence of IGR (65.2% amongst tuberculosis cases) and a significant association with tuberculosis (Odds ratio: 2.3; 95% CI: 1.6 – 3.3; p<0.001) was also found. Conclusions Diabetes and IGR prevalence was high and associated with tuberculosis, particularly in HIVB1Binfected persons, highlighting the importance of DM screening. The variation in findings by diagnostic test highlights the need for better glycaemia markers to inform screening in the context of tuberculosis and HIVB1.
rockwood N, Sirgel F, Streicher E, et al., 2017, Low frequency of acquired isoniazid and rifampicin resistance in rifampicin-susceptible pulmonary tuberculosis in a high HIV-1 co-prevalence setting, Journal of Infectious Diseases, Vol: 216, Pages: 632-640, ISSN: 1537-6613
BackgroundWe estimated the incidence of acquired isoniazid and rifampicin resistance in rifampicin-susceptible tuberculosis in a setting of high human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis coprevalence.MethodsGeneXpert MTB/RIF–confirmed patients with rifampicin-susceptible tuberculosis were recruited at antituberculosis treatment initiation in Khayelitsha, South Africa. Liquid culture and adherence assessment were performed at 2 and 5–6 months. MTBDRplus was performed on mycobacteria-positive cultures to ascertain acquired drug resistance (ADR). Spoligotyping and whole-genome sequencing were performed to ascertain homogeneity between baseline isolates and isolates with ADR. Baseline isolates were retrospectively tested for isoniazid monoresistance. An electronic database review was performed to ascertain tuberculosis recurrences.ResultsA total of 306 participants (62% with HIV-1 coinfection, of whom 71% received antiretroviral therapy) were recruited. Ascertainment of outcomes was complete for 284 participants. Five acquired a resistant Mycobacterium tuberculosis strain during or subsequent to treatment. One strain was confirmed to have ADR, 2 were confirmed as causing exogenous reinfection, and 2 were unrecoverable for genotyping. Incident ADR was estimated to have ranged from 0.3% (95% confidence interval [CI], .1%–1.9%; 1 of 284 participants) to 1% (95% CI, .2%–3%; 3 of 284 participants). Seventeen of 279 baseline isolates (6.1%; 95% CI, 3.6%–9.6%) had isoniazid monoresistance (13 of 17 had an inhA promoter mutation), but 0 of 17 had amplified resistance.ConclusionsTreatment with standardized antituberculosis regimens dosed daily throughout, high uptake of antiretroviral therapy, and low prevalence of isoniazid monoresistance were associated with a low frequency of ADR.
Scriven JE, Graham LM, Schutz C, et al., 2017, The CSF immune response in HIV-1-associated cryptococcal meningitis: macrophage activation, correlates of disease severity, and effect of antiretroviral therapy, JAIDS-Journal of Acquired Immune Deficiency Syndromes, Vol: 75, Pages: 299-307, ISSN: 1525-4135
Background:Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART).Methodology:We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks).Findings:CSF was available from 57 persons (median CD4 34/μL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14+ and 35% CD14− monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4+, CD8+, and CD4−CD8− T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (≥30 cm H2O) was associated with fewer T cells, a higher fungal burden, and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4−CD8− T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206.Conclusions:Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease.
Rohlwink UK, Mauff K, Wilkinson KA, et al., 2017, Biomarkers of cerebral injury and inflammation in pediatric tuberculous meningitis, Clinical Infectious Diseases, Vol: 65, Pages: 1298-1307, ISSN: 1537-6591
BackgroundTuberculous meningitis (TBM) leads to death or disability in half the affected individuals. Tools to assess severity and predict outcome are lacking. Neuro-specific biomarkers could serve as markers of the severity and evolution of brain injury, but have not been widely explored in TBM. We examined biomarkers of neurological injury (neuromarkers) and inflammation in pediatric TBM and their association with outcome.MethodsBlood and cerebrospinal fluid (CSF) of children with TBM and hydrocephalus taken on admission and over 3 weeks were analysed for neuromarkers S100B, neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP), and multiple inflammatory markers. Results were compared with 2 control groups; patients with 1) a fatty filum (abnormal filum terminale of the spinal cord), and 2) pulmonary tuberculosis (pTB). Imaging was conducted on admission and at 3 weeks. Outcome was assessed at 6 months.ResultsData were collected from 44 TBM cases (median age 3.3 [0.3–13.1] years), 11 fatty filum (median age 2.8 [0.8–8] years) and 9 pTB controls (median age 3.7 [1.3–11.8] years). Seven cases (16%) died and 16 (36%) had disabilities. Neuromarkers and inflammatory markers were elevated in CSF on admission and for up to 3 weeks, but not in serum. Initial and highest concentrations in week 1 of S100B and NSE were associated with poor outcome, as were highest concentration overall and an increasing profile over time in S100B, NSE and GFAP. Combined neuromarker concentrations increased over time in patients who died, whereas inflammatory markers decreased. Cerebral infarcts were associated with highest overall neuromarker concentrations and an increasing profile over time. Tuberculomas were associated with elevated IL-12p40, IP-10 and MCP-1 concentrations, whereas infarcts were associated with elevated TNF-α, MIP-1α, IL-6 and IL-8.ConclusionCSF neuromarkers are promising biomarkers of injury severity and are predictive of
Rockwood N, Costa DL, Amaral EP, et al., 2017, Mycobacterium tuberculosis induction of heme Oxygenase-1 expression is Dependent on Oxidative stress and reflects Treatment Outcomes, FRONTIERS IN IMMUNOLOGY, Vol: 8, ISSN: 1664-3224
The antioxidant enzyme heme oxygenase-1 (HO-1) is implicated in the pathogenesis of tuberculosis (TB) and has been proposed as a biomarker of active disease. Nevertheless, the mechanisms by which Mycobacterium tuberculosis (Mtb) induces HO-1 as well as how its expression is affected by HIV-1 coinfection and successful antitubercular therapy (ATT) are poorly understood. We found that HO-1 expression is markedly increased in rabbits, mice, and non-human primates during experimental Mtb infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 coinfected and uninfected pulmonary TB patients undergoing ATT to investigate changes in expression of this biomarker in relation to HIV-1 status, radiological disease severity, and treatment outcome. We found that plasma levels of HO-1 were elevated in untreated HIV-1 coinfected TB patients and correlated positively with HIV-1 viral load and negatively with CD4+ T cell count. In both HIV-1 coinfected and Mtb monoinfected patients, HO-1 levels were substantially reduced during successful TB treatment but not in those who experienced treatment failure or subsequently relapsed. To further delineate the molecular mechanisms involved in induction of HO-1 by Mtb, we performed a series of in vitro experiments using mouse and human macrophages. We found that Mtb-induced HO-1 expression requires NADPH oxidase-dependent reactive oxygen species production induced by the early-secreted antigen ESAT-6, which in turn triggers nuclear translocation of the transcription factor NRF-2. These observations provide further insight into the utility of HO-1 as a biomarker of both disease and successful therapy in TB monoinfected and HIV-TB coinfected patients and reveal a previously undocumented pathway linking expression of the enzyme with oxidative stress.
Schnettger L, Rodgers A, Repnik U, et al., 2017, A Rab20-dependent membrane trafficking pathway controls M. tuberculosis replication by regulating phagosome spaciousness and integrity, Cell Host and Microbe, Vol: 21, Pages: 619-628.e5, ISSN: 1931-3128
The intracellular pathogen Mycobacterium tuberculosis (Mtb) lives within phagosomes and also disrupts these organelles to access the cytosol. The host pathways and mechanisms that contribute to maintaining Mtb phagosome integrity have not been investigated. Here, we examined the spatiotemporal dynamics of Mtb-containing phagosomes and identified an interferon-gamma-stimulated and Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes. This pathway functions to promote endosomal membrane influx in infected macrophages, and is required to preserve Mtb phagosome integrity and control Mtb replication. Rab20 is specifically and significantly upregulated in the sputum of human patients with active tuberculosis. Altogether, we uncover an immune-regulated cellular pathway of defense that promotes maintenance of Mtb within intact membrane-bound compartments for efficient elimination.
Walker NF, Wilkinson KA, Meintjes G, et al., 2017, Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study, Clinical Infectious Diseases, Vol: 65, Pages: 121-132, ISSN: 1058-4838
Background. Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, butthe underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a keyprocess but has not been systematically studied in HIV-associated TB.Methods. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)–infected and –uninfected TB patientsand controls, and a prospective cohort study of HIV-1–infected TB patients at risk of TB immune reconstitution inflammatorysyndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasmaprocollagen 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 Mycobacteriumtuberculosis and extracellular matrix in a 3D model of TB granuloma formation.Results. MMP activity differed between HIV-1–infected and –uninfected TB patients and corresponded with specific TB clinicalphenotypes. HIV-1–infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation,but increased plasma PIIINP, compared to HIV-1–uninfected TB patients. Elevated extrapulmonary extracellular matrix turnoverwas associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likelyneutrophil derived and M. tuberculosis–antigen driven. Mycobacterium tuberculosis–induced matrix degradation was suppressed bythe MMP inhibitor doxycycline in vitro.Conclusions. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrixturnover in HIV-1–infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibitionis a potential host-directed therapy
Esmail H, Wilkinson RJ, 2017, Minimizing Tuberculosis Risk in Patients Receiving Anti-TNF Therapy., Annals of the American Thoracic Society, Vol: 14, Pages: 621-623, ISSN: 2329-6933
Janssen S, Schutz C, Ward A, et al., 2017, Mortality in severe HIV-TB associates with innate immune activation and dysfunction of monocytes, Clinical Infectious Diseases, Vol: 65, Pages: 73-82, ISSN: 1537-6591
BACKGROUNDCase fatality rates among hospitalised patients diagnosed with HIV-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. We aimed to define the nature of innate immune responses associated with 12-week mortality in this population.METHODSThis prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalised HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with E. coli derived lipopolysaccharide, heat-killed S. pneumoniae and M. tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex) were assessed for associations with 12-week mortality using Cox-proportional hazard models. Secondly, we investigated associations of these immune markers with tuberculosis mycobacteremia.RESULTSSixty patients were included (median CD4 count 53 cells/µL (interquartile range 22-132)), sixteen (27%) died after a median of 12 (interquartile range 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony stimulating factor 3), and anti-inflammatory markers (increased interleukin-1RA and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis.CONCLUSIONSTwelve-week mortality was associated with greater pro- and anti-inflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis.
Koch AS, Brites D, Stucki D, et al., 2017, The Influence of HIV on the Evolution of Mycobacterium tuberculosis, Molecular Biology and Evolution, Vol: 34, Pages: 1654-1668, ISSN: 1537-1719
HIV significantly affects the immunological environment during tuberculosis coinfection, and therefore may influence the selective landscape upon which M. tuberculosis evolves. To test this hypothesis whole genome sequences were determined for 169 South African M. tuberculosis strains from HIV-1 coinfected and uninfected individuals and analyzed using two Bayesian codon-model based selection analysis approaches: FUBAR which was used to detect persistent positive and negative selection (selection respectively favoring and disfavoring nonsynonymous substitutions); and MEDS which was used to detect episodic directional selection specifically favoring nonsynonymous substitutions within HIV-1 infected individuals. Among the 25,251 polymorphic codon sites analyzed, FUBAR revealed that 189-fold more were detectably evolving under persistent negative selection than were evolving under persistent positive selection. Three specific codon sites within the genes celA2b, katG, and cyp138 were identified by MEDS as displaying significant evidence of evolving under directional selection influenced by HIV-1 coinfection. All three genes encode proteins that may indirectly interact with human proteins that, in turn, interact functionally with HIV proteins. Unexpectedly, epitope encoding regions were enriched for sites displaying weak evidence of directional selection influenced by HIV-1. Although the low degree of genetic diversity observed in our M. tuberculosis data set means that these results should be interpreted carefully, the effects of HIV-1 on epitope evolution in M. tuberculosis may have implications for the design of M. tuberculosis vaccines that are intended for use in populations with high HIV-1 infection rates.
Rockwood N, Wojno J, Ghebrekristos Y, et al., 2017, Utility of second generation line probe assay (Hain MTBDRplus) directly on 2-month sputa specimens to monitor tuberculosis treatment response, Journal of Clinical Microbiology, Vol: 55, Pages: 1508-1515, ISSN: 1098-660X
The utility of line probe assay (Genotype MTBDRplus) performed directly on 2-month sputa to monitor tuberculosis treatment response is unknown. We assessed if direct testing of 2-month sputa with MTBDRplus can predict 2-month culture conversion and long-term treatment outcome. Xpert® MTB/RIF-confirmed rifampicin-susceptible tuberculosis cases were recruited at tuberculosis diagnosis and followed up at 2 and 5-6 months. MTBDRplus was performed directly on 2-month sputa and on all positive culture isolates at 2 and 5-6 months. We also investigated the association of a positive direct MTBDRplus at 2 months with subsequent unsuccessful tuberculosis treatment outcome (failure/death during treatment or subsequent disease recurrence).279 cases (62% HIV-1 co-infected) were recruited. Direct MTBDRplus at 2 months had a sensitivity of 78%(95%CI 65-87) and specificity of 80%(95%CI 74-84) to predict culture positivity at 2 months with a high negative predictive value of 93%(95%CI 89-96). Inconclusive genotypic susceptibility for both rifampicin and isoniazid were seen in 26% of MTDDRplus tests performed directly on sputum. When compared to a reference of MTBDRplus performed on positive cultures, the false positive resistance rate for direct testing of MTBDRplus on sputa was 4% for rifampicin and 2% for isoniazid. Whilst a positive 2-month smear was not significantly associated with an unsuccessful treatment outcome, (aOR 2.69, 95% CI 0.88-8.21), a positive direct MTBDRplus at 2 months was associated with an unsuccessful outcome (aOR 2.87, 95%CI 1.11-7.42). There is moderate utility of direct 2-month MTBDRplus to predict culture conversion at 2 months and also to predict an unfavorable outcome.
Tientcheu LD, Koch A, Ndengane M, et al., 2017, Immunological consequences of strain variation within the Mycobacterium tuberculosis complex, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 47, Pages: 432-445, ISSN: 0014-2980
In 2015, there were an estimated 10.4 million new cases of tuberculosis (TB) globally, making it one of the leading causes of death due to an infectious disease. TB is caused by members of the Mycobacterium tuberculosis complex (MTBC), with human disease resulting from infection by M. tuberculosis sensu stricto and M. africanum. Recent progress in genotyping techniques, in particular the increasing availability of whole genome sequence data, has revealed previously under appreciated levels of genetic diversity within the MTBC. Several studies have shown that this genetic diversity may translate into differences in TB transmission, clinical manifestations of disease, and host immune responses. This suggests the existence of MTBC genotype-dependent host–pathogen interactions which may influence the outcome of infection and progression of disease. In this review, we highlight the studies demonstrating differences in innate and adaptive immunological outcomes consequent on MTBC genetic diversity, and discuss how these differences in immune response might influence the development of TB vaccines, diagnostics and new therapies.
Rockwood N, Pasipanodya J, Denti P, et al., 2017, Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis, Clinical Infectious Diseases, Vol: 64, Pages: 1350-1359, ISSN: 1537-6591
BackgroundThere is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.MethodsOne hundred patients with pulmonary tuberculosis (65% HIV-co-infected) were intensively sampled to determine rifampicin, isoniazid and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and pharmacokinetic parameters determined using non-linear-mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 and 5-6 months. Minimum inhibitory concentrations (MIC) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 24-hour-area-under-the-curve (AUC0-24), peak concentration (Cmax), AUC0-24/MIC, Cmax/MIC and % time that concentrations persisted above MIC (%TMIC).Results26% of patients had Cmax (mg/L) of rifampicin<8, pyrazinamide<35, and isoniazid<3. No relationship was found between pharmacokinetic exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was below 4.6 mg/L and rifampicin Cmax /MIC below 28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax>4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.ConclusionsPK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.
Bell L, Peyper JM, Garnett S, et al., 2017, TB-IRIS: Proteomic analysis of in vitro PBMC responses to Mycobacterium tuberculosis and response modulation by dexamethasone, Experimental and Molecular Pathology, Vol: 102, Pages: 237-246, ISSN: 0014-4800
Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) occurs in 8–54% of South African patients undergoing treatment for tuberculosis/human immunodeficiency virus co-infection. Improved TB-IRIS molecular pathogenesis understanding would enhance risk stratification, diagnosis, prognostication, and treatment. We assessed how TB-IRIS status and dexamethasone influence leukocyte proteomic responses to Mycobacterium tuberculosis (Mtb).Patient blood was obtained three weeks post-anti-retroviral therapy initiation. Isolated mononuclear cells were stimulated ex vivo with heat-killed Mtb in the presence/absence of dexamethasone. Mass spectrometry-based proteomic comparison of TB-IRIS and non-IRIS patient-derived cells facilitated generation of hypotheses regarding pathogenesis.Few represented TB-IRIS-group immune-related pathways achieved significant activation, with relative under-utilisation of “inter-cellular interaction” and “Fcγ receptor-mediated phagocytosis” (but a tendency towards apoptosis-related) pathways. Dexamethasone facilitated significant activation of innate-related pathways. Differentially-expressed non-IRIS-group proteins suggest focused and co-ordinated immunological pathways, regardless of dexamethasone status.Findings suggest a relative deficit in TB-IRIS-group responses to and clearance of Mtb antigens, ameliorated by dexamethasone.
Marais S, Lai RP-J, Wilkinson KA, et al., 2016, Inflammasome activation underlies central nervous system deterioration in HIV-associated tuberculosis, Journal of Infectious Diseases, Vol: 215, Pages: 677-686, ISSN: 1537-6613
Tuberculous meningitis (TBM) is a frequent cause of meningitis in individuals with human immunodeficiency virus (HIV) infection, resulting in death in approximately 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological tuberculosis–immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole-blood microarray analysis of HIV-infected patients with TBM and reflected the findings at the protein level. Patients in whom TBM-IRIS eventually developed had significantly more abundant neutrophil-associated transcripts, from before development of TBM-IRIS through IRIS symptom onset. After ART initiation, a significantly higher abundance of transcripts associated with canonical and noncanonical inflammasomes was detected in patients with TBM-IRIS than in non-IRIS controls. Whole-blood transcriptome findings complement protein measurement from the site of disease, which together suggest a dominant role for the innate immune system in the pathogenesis of TBM-IRIS.
Du Bruyn E, Wilkinson RJ, 2016, The Immune Interaction between HIV-1 Infection and Mycobacterium tuberculosis, MICROBIOLOGY SPECTRUM, Vol: 4
Marais BJ, Heemskerk AD, Marais SS, et al., 2016, Standardized methods for enhanced quality and comparability of tuberculous meningitis studies, Clinical Infectious Diseases, Vol: 64, Pages: 501-509, ISSN: 1058-4838
Tuberculous meningitis remains a major cause of death and disability in tuberculosis endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of tuberculous meningitis clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrolment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention tuberculous meningitis studies should improve the quality of future research outputs, facilitate multi-centre studies and meta-analyses of pooled data, and could provide the foundation for a global tuberculous meningitis data repository.
Janssen S, Schutz C, Ward A, et al., 2016, Hemostatic changes associate with mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study, Journal of Infectious Diseases, Vol: 215, Pages: 247-258, ISSN: 1537-6613
BACKGROUNDMortality of HIV-associated tuberculosis (HIV-TB) remains high and knowledge of contributing mechanisms is limited. We aimed to determine whether hemostatic changes in HIV-TB associate with mortality and the contribution of mycobacteremia herein. METHODSWe conducted a prospective study in Khayelitsha, South Africa, in hospitalized HIV-infected patients with CD4 counts <350 cells/μL and microbiologically-proven TB. HIV-infected out patients without TB served as controls. Plasma biomarkers reflecting activation of pro-and anti-coagulation, fibrinolysis, endothelial cell activation, matricellular protein release and tissue damagewere measured on admission. Cox-proportional hazard models were used to assess variables associated with 12-weekmortality.RESULTSOf 59 HIV-TB patients, 16 (27%) died after a median of 12 (interquartile range 0-24) days; 29/45 (64%) of those not on anticoagulants fulfilled criteria for disseminated intravascular coagulation. Mortality was associated with higher concentrations of markers of fibrinolysis, endothelial activation, matricellular protein release and tissue damage, and with decreased markers of anticoagulation. In patients who died coagulation factors involved in the common pathway were depleted (factor II, V, X), which corresponded with increased plasma clotting times. Mycobacteremia modestly influenced hemostatic changes without affecting mortality.
Stucki D, Brites D, Jeljeli L, et al., 2016, Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages, Nature Genetics, Vol: 48, Pages: 1535-1543, ISSN: 1061-4036
Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.
Prosser G, Brandenburg J, Reiling N, et al., 2016, The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition, Microbes and Infection, Vol: 19, Pages: 177-192, ISSN: 1286-4579
M. tuberculosis is a facultative anaerobe and its characteristic pathological hallmark, the granuloma, exhibits hypoxia in humans and in most experimental models. Thus the host and bacillary adaptation to hypoxia is of central importance in understanding pathogenesis and thereby to derive new drug treatments and vaccines.
Norval M, Coussens AK, Wilkinson RJ, et al., 2016, Vitamin D Status and Its Consequences for Health in South Africa, International Journal of Environmental Research and Public Health, Vol: 13, ISSN: 1660-4601
In this review, reports were retrieved in which vitamin D status, as assessed by serum25-hydroxyvitamin D [25(OH)D] levels, was measured in South African population groups withvaried 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 majorrole 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 recentchanges 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, withdeficiency most notably found in individuals with tuberculosis and HIV-1. Information on therelationship between vitamin D receptor variants and ethnicity, disease or treatment response in theSouth African population groups demonstrated complex interactions between genetics, epigeneticsand the environment. Whether vitamin D plays an important role in protection against the rangeof diseases that currently constitute a large burden on the health services in South Africa requiresfurther investigation. Only then can accurate advice be given about personal sun exposure or dietaryvitamin D supplementation.
Esmail H, Thienemann F, Oni T, et al., 2016, QuantiFERON conversion following tuberculin administration is common in HIV infection and relates to baseline response, BMC Infectious Diseases, Vol: 16, ISSN: 1471-2334
BACKGROUND: HIV-1 infection impairs tuberculosis (TB) specific immune responses affecting the diagnosis of latent TB. We aimed to (1) determine the proportion of HIV-1-infected adults with a negative QuantiFERON®-TB Gold in-tube (QFT-GIT) and Tuberculin skin testing (TST) that convert to QFT-GIT positive following TST, and (2) evaluate the relationship between conversion and baseline QFT-GIT results. METHODS: HIV-1 infected adults being screened for a TB vaccine study in South Africa underwent QFT-GIT followed by TST. As per protocol, QFT-GIT was repeated if randomization was delayed allowing for evaluation of TST boosting in a proportion of participants. RESULTS: Of the 22 HIV-1 infected, TST and QFT-GIT negative adults (median CD4 477/mm(3) IQR 439-621) who had QFT-GIT repeated after median 62 days (IQR 49-70), 40.9 % (95 % CI 18.6-63.2 %) converted. Converters had a significantly greater increase in the background subtracted TB antigen response (TBAg-Nil - all units IU/mL) following TST, 0.82 (IQR 0.39-1.28) vs 0.03 (IQR -0.05-0.06), p = 0.0001. Those who converted also had a significantly higher baseline TBAg-Nil 0.21(IQR 0.17-0.26) vs 0.02(IQR 0.01-0.07), p = 0.002. Converters did not differ with regard to CD4 count or ART status. ROC analysis showed a baseline cut off of 0.15 correctly classified 86.4 % of converters with 88.9 % sensitivity. CONCLUSIONS: Our findings support the possibility that there are 2 distinct groups in an HIV-1 infected population with negative QFT-GIT and TST; a true negative group and a group showing evidence of a weak Mtb specific immune response that boosts significantly following TST resulting in conversion of the test result that may represent false negatives. Further evaluation of whether a lower cut off may improve sensitivity of QFT-GIT in this population is warranted.
Esmail H, Oni T, Thienemann F, et al., 2016, Cardio-thoracic ratio is stable, reproducible and has potential as a screening tool for HIV-1 related cardiac disorders in resource poor settings, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundCardiovascular disorders are common in HIV-1 infected persons in Africa and presentation is often insidious. Development of screening algorithms for cardiovascular disorders appropriate to a resource-constrained setting could facilitate timely referral. Cardiothoracic ratio (CTR) on chest radiograph (CXR) has been suggested as a potential screening tool but little is known about its reproducibility and stability. Our primary aim was to evaluate the stability and the inter-observer variability of CTR in HIV-1 infected outpatients. We further evaluated the prevalence of cardiomegaly (CTR≥0.5) and its relationship with other risk factors in this population.MethodologyHIV-1 infected participants were identified during screening for a tuberculosis vaccine trial in Khayelitsha, South Africa between August 2011 and April 2012. Participants had a digital posterior-anterior CXR performed as well as history, examination and baseline observations. CXRs were viewed using OsiriX software and CTR calculated using digital callipers.Results450 HIV-1-infected adults were evaluated, median age 34 years (IQR 30–40) with a CD4 count 566/mm3 (IQR 443–724), 70% on antiretroviral therapy (ART). The prevalence of cardiomegaly was 12.7% (95% C.I. 9.6%-15.8%). CTR was calculated by a 2nd reader for 113 participants, measurements were highly correlated r = 0.95 (95% C.I. 0.93–0.97) and agreement of cardiomegaly substantial κ = 0.78 (95% C.I 0.61–0.95). CXR were repeated in 51 participants at 4–12 weeks, CTR measurements between the 2 time points were highly correlated r = 0.77 (95% C.I 0.68–0.88) and agreement of cardiomegaly excellent κ = 0.92 (95% C.I. 0.77–1). Participants with cardiomegaly had a higher median BMI (31.3; IQR 27.4–37.4) versus 26.9; IQR 23.2–32.4); p<0.0001) and median systolic blood pressure (130; IQR 121–141 versus 125; IQR 117–135; p = 0.01).ConclusionCTR is a robust measurement
Bana TM, Lesosky M, Pepper DJ, et al., 2016, Prolonged tuberculosis-associated immune reconstitution inflammatory syndrome: characteristics and risk factors, BMC Infectious Diseases, Vol: 16, ISSN: 1471-2334
BACKGROUND: In a proportion of patients with HIV-associated tuberculosis who develop paradoxical immune reconstitution inflammatory syndrome (IRIS), the clinical course of IRIS is prolonged necessitating substantial health care utilization for diagnostic and therapeutic interventions. Prolonged TB-IRIS has not been prospectively studied to date. We aimed to determine the proportion of patients with prolonged TB-IRIS, as well as the clinical characteristics and risk factors for prolonged TB-IRIS. METHODS: We pooled data from two prospective observational studies and a randomized controlled trial conducted in Cape Town, South Africa, that enrolled patients with paradoxical TB-IRIS. We used the same diagnostic approach and clinical case definitions for TB-IRIS in the 3 studies. Prolonged TB-IRIS was defined as TB-IRIS symptoms lasting > 90 days. Risk factors for prolonged TB-IRIS were analysed using Wilcoxon rank sum test, Fisher's exact test, multivariate logistic regression and Cox proportional hazards models. RESULTS: Two-hundred and sixteen patients with TB-IRIS were included. The median duration of TB-IRIS symptoms was 71.0 days (IQR 41.0-113.2). In 73/181 patients (40.3 %) with adequate follow-up data, IRIS duration was > 90 days. Six patients (3.3 %), mainly with lymph node involvement, had IRIS duration > 1 year. In univariate logistic regression analysis the following were significantly associated with IRIS duration > 90 days: lymph node involvement at initial TB diagnosis, drug-resistant TB, lymph node TB-IRIS, and not being hospitalised at time of TB-IRIS diagnosis. In our multivariate logistic regression model lymph node TB-IRIS (aOR 2.27, 95 % CI 1.13-4.59) and not being hospitalised at time of TB-IRIS diagnosis (aOR for being hospitalised 0.5, 95 % CI 0.25-0.99) remained significantly associated with prolonged TB-IRIS, and drug-resistant TB was of border
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