Publications
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Marais S, Van Toorn R, Chow FC, et al., 2019, Management of intracranial tuberculous mass lesions: how long should we treat for?, Wellcome Open Res, Vol: 4, ISSN: 2398-502X
Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis ( M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3 rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-ba
Schutz C, Davis AG, Sossen B, et al., 2018, Corticosteroids as an adjunct to tuberculosis therapy, Expert Review of Respiratory Medicine, Vol: 12, Pages: 881-891, ISSN: 1747-6348
Introduction: Inflammation, or the prolonged resolution of inflammation, contributes to death from tuberculosis. Interest in inflammatory mechanisms and the prospect of beneficial immune modulation as an adjunct to antibacterial therapy has revived and the concept of host directed therapies has been advanced. Such renewed attention has however, overlooked the experience of such therapy with corticosteroids.Areas covered: The authors conducted literature searches and evaluated randomized clinical trials, systematic reviews and current guidelines and summarize these findings. They found evidence of benefit in meningeal and pericardial tuberculosis in HIV-1 uninfected persons, but less so in those HIV-1 coinfected and evidence of harm in the form of opportunist malignancy in those not prescribed antiretroviral therapy. Adjunctive corticosteroids are however of benefit in the treatment and prevention of paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome.Expert commentary: Further high-quality clinical trials and experimental medicine studies are warranted and analysis of materials arising from such studies could illuminate ways to improve corticosteroid efficacy or identify novel pathways for more specific intervention.
Esmail H, Riou C, Du Bruyn E, et al., 2018, The Immune Response to Mycobacterium tuberculosis in HIV-1-Coinfected Persons, Annual Review of Immunology
Esmail H, Lai R, Lesosky M, et al., 2018, Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis, Proceedings of the National Academy of Sciences, Vol: 115, Pages: E964-E973, ISSN: 0027-8424
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 [18F]-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 (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript abundance. To validate our findings, we analyzed transcriptomic data from a publicly available dataset where samples were available in the 2 y before TB disease presentation. Transcripts representing the classical complement pathway and Fcγ receptor 1 were also differentially expressed in the 12 mo before disease presentation. Our results indicate that levels of antibody/antigen complexes increase early in disease, associated with increased gene expression of C1q and Fcγ receptors that bind them. Understanding the role this plays in disease progression may facilitate development of interventions that prevent this, leading to a more favorable outcome and may also be important to diagnostic development.
Shenje J, Lai RP, Ross IL, et al., 2017, Effect of prednisolone on inflammatory markers in pericardial tuberculosis: A pilot study, IJC Heart and Vasculature, Vol: 18, Pages: 104-108, ISSN: 2352-9067
Background: Pericardial disorders are a common cause of heart disease, and the most common cause of pericarditis in developing countries is tuberculous (TB) pericarditis. It has been shown that prednisolone added to standard anti-TB therapy leads to a lower rate of constrictive pericarditis. We conducted a pilot study to evaluate the effect of adjunctive prednisolone treatment on the concentration of inflammatory markers in pericardial tuberculosis, in order to inform immunological mechanisms at the disease site. Methods: Pericardial fluid, plasma and saliva samples were collected from fourteen patients with pericardial tuberculosis, at multiple time points. Inflammatory markers were measured using multiplex luminex analysis and ELISA. Results: In samples from 14 patients we confirmed a strongly compartmentalized immune response at the disease site and found that prednisolone significantly reduced IL-6 concentrations in plasma by 8 hours of treatment, IL-1beta concentrations in saliva, as well as IL-8 concentrations in both pericardial fluid and saliva by 24 hours. Conclusion: Monitoring the early effect of adjunctive immunotherapy in plasma or saliva is a possibility in pericarditis.
Bogers WMJM, Barnett SW, Oostermeijer H, et al., 2017, Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site, Journal of Virology, Vol: 91, ISSN: 0022-538X
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.
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.
Esmail H, Lai RP, Lesosky M, et al., 2016, Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography, Nature Medicine, Vol: 22, Pages: 1090-1093, ISSN: 1546-170X
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.
Lai RP, Meintjes G, Wilkinson RJ, 2015, HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome., Seminars in Immunopathology, Vol: 38, Pages: 185-198, ISSN: 1863-2300
Patients co-infected with HIV-1 and tuberculosis (TB) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) following commencement of antiretroviral therapy (ART). TB-IRIS is characterized by transient but severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. Here, we review the risk factors and clinical management of TB-IRIS, as well as the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis.
Lai RPJ, Meintjes G, Wilkinson KA, et al., 2015, HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling, Nature Communications, Vol: 6, ISSN: 2041-1723
Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.
Torrado E, Fountain JJ, Liao M, et al., 2015, Interleukin 27R regulates CD4<SUP>+</SUP> T cell phenotype and impacts protective immunity during <i>Mycobacterium tuberculosis</i> infection, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 212, Pages: 1449-1463, ISSN: 0022-1007
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- Citations: 53
Lai RPJ, Hock M, Radzimanowski J, et al., 2014, A Fusion Intermediate gp41 Immunogen Elicits Neutralizing Antibodies to HIV-1, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 29912-29926
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- Citations: 31
Esmail H, Lai P, Graham CM, et al., 2014, Characterisation Of A Whole Blood Transcriptional Signature Of Subclinical Tuberculosis Identified By Fdg-Pet/ct In Asymptomatic Hiv-1 Infected Adults, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
Varela M, Verschoor E, Lai RPJ, et al., 2013, Genetic Imprint of Vaccination on Simian/Human Immunodeficiency Virus Type 1 Transmitted Viral Genomes in Rhesus Macaques, PLOS ONE, Vol: 8, ISSN: 1932-6203
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Lai RPJ, Nakiwala JK, Meintjes G, et al., 2013, The immunopathogenesis of the HIV tuberculosis immune reconstitution inflammatory syndrome, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 43, Pages: 1995-2002, ISSN: 0014-2980
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- Citations: 35
Lai RPJ, Seaman MS, Tonks P, et al., 2012, Mixed Adjuvant Formulations Reveal a New Combination That Elicit Antibody Response Comparable to Freund's Adjuvants, PLOS ONE, Vol: 7, ISSN: 1932-6203
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- Citations: 39
Lai RPJ, Yan J, Heeney J, et al., 2011, Nef Decreases HIV-1 Sensitivity to Neutralizing Antibodies that Target the Membrane-proximal External Region of TMgp41, PLOS PATHOGENS, Vol: 7, ISSN: 1553-7366
Primate lentivirus nef is required for sustained virus replication in vivo and accelerated progression to AIDS. While exploring the mechanism by which Nef increases the infectivity of cell-free virions, we investigated a functional link between Nef and Env. Since we failed to detect an effect of Nef on the quantity of virion-associated Env, we searched for qualitative changes by examining whether Nef alters HIV-1 sensitivity to agents that target distinct features of Env. Nef conferred as much as 50-fold resistance to 2F5 and 4E10, two potent neutralizing monoclonal antibodies (nAbs) that target the membrane proximal external region (MPER) of TMgp41. In contrast, Nef had no effect on HIV-1 neutralization by MPER-specific nAb Z13e1, by the peptide inhibitor T20, nor by a panel of nAbs and other reagents targeting gp120. Resistance to neutralization by 2F5 and 4E10 was observed with Nef from a diverse range of HIV-1 and SIV isolates, as well as with HIV-1 virions bearing Env from CCR5- and CXCR4-tropic viruses, clade B and C viruses, or primary isolates. Functional analysis of a panel of Nef mutants revealed that this activity requires Nef myristoylation but that it is genetically separable from other Nef functions such as the ability to enhance virus infectivity and to downregulate CD4. Glycosylated-Gag from MoMLV substituted for Nef in conferring resistance to 2F5 and 4E10, indicating that this activity is conserved in a retrovirus that does not encode Nef. Given the reported membrane-dependence of MPER-recognition by 2F5 and 4E10, in contrast to the membrane-independence of Z13e1, the data here is consistent with a model in which Nef alters MPER recognition in the context of the virion membrane. Indeed, Nef and Glycosylated-Gag decreased the efficiency of virion capture by 2F5 and 4E10, but not by other nAbs. These studies demonstrate that Nef protects lentiviruses from one of the most broadly-acting classes of neutralizing antibodies. This newly discovered activit
Varela M, Landskron L, Lai RPJ, et al., 2011, Molecular Evolution Analysis of the Human Immunodeficiency Virus Type 1 Envelope in Simian/Human Immunodeficiency Virus-Infected Macaques: Implications for Challenge Dose Selection, JOURNAL OF VIROLOGY, Vol: 85, Pages: 10332-10345, ISSN: 0022-538X
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- Citations: 11
Yang X-P, Jones RA, Rivers JH, et al., 2007, Syntheses, structures and luminescent properties of new lanthanide-based coordination polymers based on 1,4-benzenedicarboxylate (bdc), DALTON TRANSACTIONS, Pages: 3936-3942, ISSN: 1477-9226
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- Citations: 70
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