The intricacies of the serological grouping of streptococci are discussed. The pathogenicity and accurate classification of streptococci isolated from arthritic porcine joints were in doubt. Pure cultures of these isolates were inoculated intravenously into healthy pigs to ascertain their pathogenicity and in an attempt to fulfil Koch's postulates. The pathogenesis of streptococcal arthritis in swine is discussed. On intravenous inoculation into experimental pigs the streptococcal isolates showed varying degrees of pathogenicity and arthritogenesis.
This dataset comprises expression profiles of 43 genes related to MSDC functioning and 5 reference genes in 8 blood samples and 8 brochio-alveolar lavage fluid (BALF) samples from TB patients. Also included are results from blood and BALF of 2 'other lung disease' patients each.
Myeloid-derived suppressor cells (MDSC) have been identified in the peripheral blood and granulomas of patients with active TB disease, but their phenotype-, function-, and immunosuppressive mechanism- spectrum remains unclear. Importantly, the frequency and signaling pathways of MDSC at the site of disease is unknown with no indication how this compares to MDSC identified in peripheral blood or to those of related myeloid counterparts such as alveolar macrophages and monocytes. Most phenotypic and functional markers have been described in oncological studies but have not yet been validated in TB. Using a panel of 43 genes selected from pathways previously shown to contribute to tumor-derived MDSC, we set out to evaluate if the expression of these additional functional markers and properties may also be relevant to TB-derived MDSC. Differential expression was investigated between MDSC, alveolar macrophages and monocytes enriched from bronchoalveolar lavage fluid and peripheral blood of patients with active TB, patients with other lung diseases (OLD). Results demonstrated that anatomical compartments may drive compartment-specific immunological responses and subsequent MDSC immunosuppressive functions, demonstrated by the observation that MDSC and/or monocytes from PB alone can discriminate,
Introduction Multisystem inflammatory syndrome in children (MIS-C) is a severe acute inflammatory reaction to SARS-CoV-2 infection in children. There is a lack of data describing differential expression of immune genes in MIS-C compared to healthy children or those with other inflammatory conditions and how expression changes over time. In this study, we investigated expression of immune-related genes in South African MIS-C patients and controls. Methods The cohort included 30 pre-treatment MIS-C cases and 54 healthy non-inflammatory paediatric controls. Other controls included 34 patients with juvenile systemic lupus erythematosus, Kawasaki disease or other inflammatory conditions. Longitudinal post-treatment MIS-C specimens were available at various timepoints. Expression of 80 immune-related genes was determined by real-time quantitative PCR. Results A total of 29 differentially expressed genes were identified in pre-treatment MIS-C compared to healthy controls. Up-regulated genes were found to be overrepresented in innate immune pathways including interleukin-1 processing and pyroptosis. Post-treatment follow-up data were available for up to 1,200 hours after first treatment. All down-regulated genes and 17/18 up-regulated genes resolved to normal levels in the timeframe, and all patients clinically recovered. When comparing MIS-C to other febrile conditions, only IL27 expression could differentiate these two groups with high sensitivity and specificity. Conclusions These data indicate a unique 29-gene signature of MIS-C in South African children. The up-regulation of interleukin-1 and pyroptosis pathway genes highlights the role of the innate immune system in MIS-C. IL-27 is a potent anti-inflammatory and antiviral cytokine that may distinguish MIS-C from other conditions in our setting.
Rationale: Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment. Objectives: To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. Methods: South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 mo) and persistent (QuantiFERON-TB+ for >1 yr) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ+ TNF+Mycobacterium tuberculosis-specific T cells and total CD3+ T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease and by unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (nonprogressors) or who progressed to microbiologically confirmed disease (progressors). Measurements and Main Results: In the test cohorts, frequencies of Mycobacterium tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n = 25) and QuantiFERON-TB+ (n = 47) individuals (area under the receiver operating characteristic curve, 0.94; 95% confidence interval, 0.87-1.00). ΔHLA-DR significantly discriminated between recent (n = 20) and persistent (n = 22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n = 19; 0.99; 0.96-1.00); and tuberculosis progressors (n = 22) and nonprogressors (n = 34; 0.75; 0.63-0.87). However, ΔHLA-DR median fluorescent intensity could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50-0.84). Conclusions: The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.
Background: Multiple host blood transcriptional signatures have been developed that show potential for further development as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic accuracy of 20 candidate blood transcriptomic TB signatures and identify which ones most accurately differentiate between symptomatic patients with TB and those with other respiratory diseases (ORD).Methods: Study participants presenting for care with symptoms associated with TB were recruited from primary health care clinics in Ethiopia, Malawi, Namibia, Uganda, South Africa, and The Gambia. TB was diagnosed based on clinical, microbiological, and radiological findings. Transcriptomic signatures were measured in whole blood samples using microfluidic RT-qPCR; signature scores were computed from cycle threshold values. Diagnostic performance was benchmarked against the WHO Target Product Profile (TPP) for a non-sputum TB triage test.Results: Among 541 participants, 158 had definite, microbiologically-confirmed and 32 probable TB, while 389 participants had ORD. Nine signatures achieved equivalent performance (Satproedprai7: area under the curve, AUC 0.83 [95% CI 0.79-0.87], Jacobsen3: 0.83 [0.79-0.86]; Suliman2: 0.82 [0.78-0.86]; Roe1: 0.82 [0.78-0.86]; Kaforou22: 0.82 [0.78-0.86]; Sambarey10: 0.81 [0.77-0.85]; Duffy9: 0.81 [0.76-0.86]; Gliddon3: 0.8 [0.75-0.85]; and Suliman4 0.79 [0.75-0.84] for differentiating patients with ORD from all TB cases. With sensitivity benchmarked against the WHO TPP (90%), these nine signatures achieved specificities between 44% (95% CI 38-49) and 54% (49-59), which fall short of the TPP criteria. Factors associated with signature scores included HIV and country. Country-specific analyses showed that several signatures, such as Satproedprai7 and Penn-Nicholson6, met the minimal TPP criteria for a triage test in Ethiopia, Malawi, and South Africa.Conclusion: None of the signatures met the TPP criteria in a pooled analysis of all countries, but several signatures met the minimum criteria for a non-sputum TB triage test in some countries.Funding: Both AE-TBC and ScreenTB were funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) under the 1st and 2nd European & Developing Countries Clinical Trials Partnership Programmes respectively (Grant Agreement Numbers IP_2009_32040 and DRIA2014-311). This project was supported by the Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council (SAMRC) with funds received from the South African Department of Science and Technology.Declaration of Interest: GW and TJS report grants from the Bill & Melinda Gates Foundation during the conduct of the study. TJS and NNC report grants from the South African Medical Research Council during the conduct of the study. GW reports grants from the South African National Research Foundation and EDCTP. TJS has patents of the RISK11 (Darboe11), RISK6 (Penn-Nicholson6) and RISK4 (Suliman4) signatures issued. GW and NC have patents “TB diagnostic markers” (PCT/IB2013/ 054377), “Serum host biomarkers for tuberculosis disease” [PCT/IB2017/052142], “Method for diagnosing TB” (PCT/IB2017/052142) granted but receive no royalties on these patents. All other authors had nothing to disclose.Ethical Approval: Study protocols for the ScreenTB and AE-TBC studies were approved by the Health Research Ethics Committee of Stellenbosch University, and at all participating sites. All participants provided written, informed consent in accordance with the Declaration of Helsinki. The transcriptomic signatures sub-study protocol was reviewed and approved by the University of Cape Town HREC (589/2019).
The determinants of immunological protection against Mycobacterium tuberculosis (M.tb) infection in humans are not known. Mycobacterial growth inhibition assays have potential utility as in vitro surrogates of in vivo immunological control of M.tb. We evaluated a whole blood growth inhibition assay in a setting with high burden of TB and aimed to identify immune responses that correlate with control of mycobacterial growth. We hypothesized that individuals with underlying M.tb infection will exhibit greater M.tb growth inhibition than uninfected individuals and that children aged 4 to 12 years, an age during which TB incidence is curiously low, will also exhibit greater M.tb growth inhibition than adolescents or adults. Neither M.tb infection status, age of the study participants, nor M.tb strain was associated with differential control of mycobacterial growth. Abundance and function of innate or T cell responses were also not associated with mycobacterial growth. Our data suggest that this assay does not provide a useful measure of age-associated differential host control of M.tb infection in a high TB burden setting. We propose that universally high levels of mycobacterial sensitization (through environmental non-tuberculous mycobacteria and/or universal BCG vaccination) in persons from high TB burden settings may impart broad inhibition of mycobacterial growth, irrespective of M.tb infection status. This sensitization may mask the augmentative effects of mycobacterial sensitization on M.tb growth inhibition that is typical in low burden settings.
The Validation of Correlates of Risk of TB Disease in High Risk Populations (CORTIS-HR) Study, a companion study of the CORTIS-01 Trial (ClinicalTrials.gov: NCT02735590), was conducted to test the diagnostic and prognostic performance of the RISK11 biomarker for tuberculosis (TB) disease in people living with HIV (PLHIV) in an ambulant community setting. The “CORTIS-HR pubdata.csv” is a public, subject-level dataset for the CORTIS-HR study containing key variables necessary to reconstruct the study findings. A data dictionary is provided below. The “CORTIS-HR PCR data.csv” provides subject-level TaqMan qPCR probe raw CT (cycle threshold) gene expression data from the Fluidigm microfluidic 96.96 Gene Expression Integrated Fluidic Circuits (chips) with sample quality control (“SAMPLE_QC”) results. Analyses of the qPCR probe data are ongoing; the embargo on this data ends 1 July 2021 when the data will be available on ZivaHub. “CORTIS-HR Protocol Version 1.0.pdf” and “CORTIS-HR SAP Version 1.0.pdf” are the protocol and the statistical analysis plan for the study respectively and have been included for reference.
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