eSymposia | Tuberculosis: Science Aimed at Ending the Epidemic

Dec 2, 2020 ‐ Dec 4, 2020



Sessions

Design, Synthesis and SAR of Antitubercular Benzylpiperazine Ureas.

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Design, Synthesis and SAR of Antitubercular Benzylpiperazine Ureas. Authors: Sohal Satish‡, Rohan Chitral‡, Amitkumar Kori‡, Basantkumar Sharma‡, Jayashree Puttur‡, Afreen A. Khan║, Deepali Desle║, Kavita Raikuvar║, Aaron Korkegian╪, Elvis A. F. Martis║, Krishna R. Iyer║, Evans C. Coutinho║, Tanya Parish╪ and Santosh Nandan‡* Affiliations: ‡Ambernath Organics Pvt. Ltd., 222, The Summit Business Bay, Andheri (E), Mumbai 400 093. India. ║Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098. India. ╪TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, Seattle, WA 98102, USA. Abstract: N-Furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to a molecule with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC50 ~ 80μM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with our molecule, fifty-five analogs were synthesized and screened against for MIC90, against Mtb H37Rv. The SAR suggests that the piperazine ring, benzyl urea and piperonyl moieties are essential signatures of this series. Active compounds in this series are metabolically stable; have low cellular toxicity and are valuable leads for optimization. Molecular docking suggests these molecules occupy the Q0 site of QcrB like Q203.

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Host directed therapy delivery system based on M.tb-mimicking metal organic framework for tuberculosis

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Host directed therapy delivery system based on M.tb-mimicking metal organic framework for tuberculosis Presenting Author: Ailin Guo, South Dakota State University, USA Co-Authors: Mikhail Durymanov, Moscow Institute of Physics and Technology, Russia; Angelika Mielcarek, Institut des Materiaux Poreux de Paris, France; Christian Serre, Institut des Materiaux Poreux de Paris, France; Joshua Reineke, South Dakota State University, USA Introduction Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M.tb) with an estimated 1.5 million deaths and 10 million infections each year. Due to the complications and length of treatment required for TB (3 to 6 drugs to be taken for up to 9 months), inadequate or improper administration of anti-TB drugs use is common. This has led a rise in drug-resistant M.tb strains. Multidrug-resistant TB (MDR-TB) remains a public health threat, and only one third of infected people enroll in treatment. Improved therapeutic approaches are needed to avoid drug resistance. One promising approach is to use host-directed therapy (HDT) to activate and enhance the host’s response to TB infection rather than targeting bacterium itself. However, the major concern of the HDT approach is the systematic host effects. M.tb can survive and replicate inside infected macrophages which are expected to kill bacteria. Here, we propose the implementation of biomimetic microparticles as host-directed therapy drugs carriers to overcome systemic host concerns by targeting infected cells. Metal organic frameworks (MOFs) are porous hybrid inorganic-organic materials which have been increasingly explored as a drug delivery system. We developed the MOF MIL-88A which is non-toxic, highly porous, biodegradable, and consists of surface chemistries versatile for coating. Additionally, it can be synthesized to be rod-shaped and with a size similar to M.tb. In this study, we aim to develop a drug delivery system that mimics the behaviors of M.tb and delivers a HDT drug to enhance host cells’ response to a M.tb infection. This work builds on our studies evaluating biomimetic MOFs and alveolar macrophage interactions. Methods MIL-88A(Fe) was built up from oxo-centered trimers of iron (III) in octahedral coordination that are bridged by fumaric acids. Mannose, as model ligand was first conjugated with MOFs via EDC/NHS coupling reaction. MOF particles were coated with lipids including mycolic acid; the major M.tb cell wall component, to enhance the bacterium mimicking properties. Surface functionalization of particles was developed based on direct coordination of phenolic lipid (DPGG) with iron through phase transfer reaction. Mycolic acid coated particles were obtained from DPGG-coated MOF particles via hydrophobic interaction of lipids. Particle size and lipid coating were characterized by scanning electron microscopy and transmission electron microscopy (TEM), respectively. Zeta potential of particles before and after coating was measured by ZetaSizer. Metformin-loaded particles were prepared by coprecipitation. Drug loading was confirmed by TEM elemental analysis and HPLC. The cytotoxicity, stability, internalization mechanisms, cell uptake kinetics, cellular transport, and organelle localization of the mimetic particles have been studied in the non-infected macrophage cell model. Results The synthesized MIL-88A (Fe) particles were similar to M.tb with rod-shaped and positively charged with size of (2.6±0.2) × (0.6±0.1) μm. The study of cellular viability and degradation behavior of MOFs indicated particles were nontoxic and stable. The coating with lipids on MOFs was confirmed by TEM and negative surface charge. The elemental dispersive spectroscopy and HPLC analysis indicate that metformin, as a model HDT agent for tuberculosis, was encapsuled into the biomimetic particles. The result of internalization mechanism characterization suggests that the uptake process is energy-dependent, and phagocytosis is the major endocytic pathway. The study of intracellular trafficking shows that particles accumulated in acidic compartments of alveolar macrophages. Increased cell uptake was observed in MOF particles with mannose and M.tb specific lipids. Conclusions Mannoslyated- and bacterial lipid coated- MOF particles were successfully synthesized. We successfully coated particles with bacterial outer component to form M.tb -mimetic MOFs. The M.tb -mimetic particles with HDT drug have similar alveolar macrophage uptake and trafficking as M.tb which may enable effective localized treatment.

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Evolution of Mycobacteria under temporally variable environment predominantly selects for efflux mediated resistance

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Evolution of Mycobacteria under temporally variable environment predominantly selects for efflux mediated resistance Authors: Akanksha1, Sarika Mehra1* Affiliations: 1Indian Institute of Technology, Bombay, Powai, Mumbai-400076 *Corresponding author email address: sarika@che.iitb.ac.in Abstract: Antibiotic resistance has emerged as a global health concern in present scenario leading to increased mortality rates. Moreover, rate of resistance emergence outcompetes rate of antibiotic discovery. Consequently, we are compelled to investigate different factors shaping resistance evolution in bacteria and ultimately identify strategies to restrict the same. In our study we study the effect of temporally varying environment on evolution of resistance. Mycobacterium smegmatis was chosen as the model organism which was subjected to two extreme temporal profiles. In the first case, the concentration of norfloxacin was kept constant (0.5 to 4X WT MIC) through the adaptive evolution process. In the second case, the selection pressure was increased every few generations (from 0.5 to 4X WT MIC). Strains evolved under this condition are referred to as ramp. All the evolved populations had increased resistance against Norfloxacin along with emergence of cross-resistance against some other drugs. Resistance was proportional to the selection strength during evolution with highest in case of ramp population and the constant population that evolved under Norfloxacin concentration of 4X MIC. To gain insight into factors behind increased resistance, Whole Genome Sequencing (WGS) was done for representative colonies from all evolved populations using Illumina platform. To our surprise, no mutation in gyrA (target for norfloxacin) was identified in any of the sequenced strains. Instead, all evolved populations had acquired mutation in a regulatory gene, lfrR, which negatively regulates a common efflux pump, LfrA, in M. smegmatis. This was also reflected in the expression study as lfrA gene was found to be overexpressed in all the evolved strains. Although two different types of mutations were identified in the lfrR gene, surprisingly, the expression level of lfrA was almost similar in all evolved strains suggesting that inactivation of efflux pump regulator is a common and recurrent way of increasing bacterial resistance in natural settings. Further, to understand the extent of resistance imparted by over-expression of LfrA alone, we determined MIC for Norfloxacin in the presence of CCCP, an efflux pump inhibitor. CCCP was able to reduce the resistance of all evolved strains by at least 2-fold. This restored the sensitivity for the low resistance strains similar to that of the WT suggesting that efflux is solely responsible for increased resistance in these strains. However, for attaining higher resistance levels, efflux along with other mutations are required. Consistent with this hypothesis, additional mutations were identified, through WGS, in the high resistance mutants. While the constant 16 population had a mutation in the DNA helicase (involved in DNA replication and repair), mutation in and around global regulatory genes were identified in Ramp population. Overall, this study emphasizes the importance of an alternative but rather conserved efflux mediated pathway for resistance in laboratory evolved strains as opposed to the primary target of fluoroquinolones. However, for high level resistance emergence, additional mutations affecting global regulators and core DNA replication and repair mechanisms are required along with efflux mediated resistance mechanism. Based on the central role of efflux pumps in resistance emergence, efflux pump inhibitors could prove to be excellent adjuvants along with the drugs. This would ultimately reduce the net drug dosage required which would help control and somewhat inhibit resistance emergence as soaring drug concentrations help burgeon high resistance levels in pathogens. However, this work has also highlighted the importance of additional mechanisms which are equally important in imparting resistance and therefore should be given proper attention in order to alleviate resistance emergence in deadly pathogens.

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Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses Alba Llibre1, Nikaïa Smith1, Vincent Rouilly2, Munyaradzi Musvosvi3, Elisa Nemes3, Céline Posseme1, Simba Mabwe3, Bruno Charbit4, Stanley Kimbung Mbandi3, Elizabeth Filander3, Hadn Africa3 Violaine Saint-André1,5, Vincent Bondet1, Pierre Bost6,7, Humphrey Mulenga3, Nicole Bilek3, Matthew L Albert8, Thomas J Scriba3, Darragh Duffy1,4. 1 Translational Immunology Lab, Institut Pasteur, Paris, France 2 DATACTIX, Paris, France; 3 South African Tuberculosis Vaccine Initiative (SATVI), Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; 4 Center for Translational Research, Institut Pasteur, Paris, France; 5 Bioinformatics and Biostatistics HUB, Computational Biology Department, Institut Pasteur, USR 3756 CNRS, Paris, France 6 Sorbonne Université, Complexité du vivant, F-75005 Paris, France; 7 Systems Biology Group, Center for Bioinformatics, Biostatistics, and Integrative Biology (C3BI) and USR 3756, Institut Pasteur CNRS, 8 Insitro, San Francisco, California, USA. ABSTRACT Tuberculosis (TB) remains a major public health problem and new therapies are urgently needed to end the epidemic, as specified in the WHO Global Tuberculosis Report 2020. Host-directed therapeutics offer great potential as novel treatment strategies. However, their successful development still requires a comprehensive understanding of how Mycobacterium tuberculosis (M.tb) infection impacts immune and metabolic responses. To address this challenge, we applied standardised immunomonitoring tools to compare induced immune responses between individuals with latent M.tb infection (LTBI) and active TB disease, at diagnosis and after cure. This revealed distinct responses between TB and LTBI groups at transcriptomic, proteomic and metabolomic levels. At baseline, we identified pregnane steroids and the PPARγ pathway as new immune-metabolic drivers of elevated plasma IL-1ra in TB. We also observed dysregulated induced IL-1 responses after BCG stimulation in TB patients. These were explained by differences in TNF, type I IFN signalling and granzyme mediated cleavage. Finally the downstream signalling response to IL-1β was also dramatically perturbed in TB disease but was completely restored after successful antibiotic treatment. This systems immunology approach improves our knowledge of how M.tb alters immune responses, and may support design of improved prophylactic and therapeutic tools that will aid TB eradication.

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Mycobacterial T-cell responses in BCG-vaccinated HIV-exposed infants and risk of Mycobacterium tuberculosis infection

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Mycobacterial T-cell responses in BCG-vaccinated HIV-exposed infants and risk of Mycobacterium tuberculosis infection AJ Warr1, C Anterasian2, JA Shah2,3, SM LaCourse2, SC DeRosa4, FK Nguyen2, E Maleche-Obimbo5, LM Cranmer6, D Matemo7, J Kinuthia7, GC John-Stewart2, TR Hawn2 1Baylor College of Medicine, Texas; 2U. of Washington, Washington; 3VA Puget Sound Healthcare System, Washington 4Fred Hutchinson Cancer Research Center, Washington 5U. of Nairobi, Kenya; 6Emory University and Children’s Healthcare of Atlanta, Georgia; 7Kenyatta National Hospital, Kenya The correlates of risk of BCG induced immunity to Mycobacterium tuberculosis (Mtb) infection are unknown. HIV-exposed uninfected (HEU) infants are at increased risk of Mtb infection and tuberculosis disease. We hypothesized that mycobacterial antigen-specific T-cell responses following BCG vaccination are associated with risk of Mtb infection in HEU infants. HEU infants were enrolled in Kisumu, Kenya and followed for 1 year in a randomized clinical trial of isoniazid to prevent Mtb infection and determine immunologic correlates of risk of Mtb infection (N=300). Cryopreserved PBMCs from 6-10 weeks of age were stimulated with Mtb whole cell lysate (TBWCL) or media control, and the percentage of CD4 cells expressing IFNγ, IL-2, and TNF were measured by flow cytometry. Infants underwent Quantiferon-Plus (QFT) and tuberculin skin testing (TST) at 14 months of age. TNF, IL-2, and IP-10 levels were also measured in QFT supernatants by Luminex. Infants were considered to have Mtb infection if they had a positive QFT, TST induration >=10mm, or QFT non-IFNγ cytokine expression >=90th percentile. At 14 months of age, 1.2% of infants were QFT positive, 13.3% were TST positive (induration >=10mm), and an additional 6.1% were considered positive by non-IFNγ cytokine production in QFT supernatants (cytokine level >=90th percentile). A CD4 polyfunctional antigen-specific response to TBWCL was detected in 90.3% of infants (COMPASS posterior probability) at 6-10 weeks of age following BCG vaccination at birth. TBWCL CD4 responses did not differ between infants who subsequently developed Mtb infection (detected by QFT, TST, or cytokine) at 14 months of age: median CD4 polyfunctional score of 0.15 vs 0.13 (p=0.4), IFNγ+ percentage of CD4 cells 0.01 vs 0.01 (p=0.8), IL-2+ CD4 cells 0.03 vs 0.03 (p=0.9), or TNF+ CD4 cells 0.04 vs 0.05 (p=0.5). Maternal viral load and CD4:CD8 ratio were not associated with infant CD4 cytokine production. Despite known differences in T-cell function and increased rates of Mtb infection and disease in HEU infants, Th1 T-cell responses measured at 6-10 weeks following BCG vaccination were not associated with increased risk of Mtb infection at 14 months as measured by QFT, TST, or QFT non-IFNγ cytokine production. Non-IFNγ cytokines were detected in certain infants with otherwise negative QFT results and may improve measurement of Mtb infection in children.

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Mammalian STE20 kinase (Mst1/2) and IL-27 Regulate Activity of Primary Macrophages in response to Mycobacterium tuberculosis

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Mammalian STE20 kinase (Mst1/2) and IL-27 Regulate Activity of Primary Macrophages in response to Mycobacterium tuberculosis Priyanka Namdev, Jasmine Canlas and Ankita Garg Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30606, USA, A better understanding of host responses to M. tuberculosis (Mtb) infection is essential for developing host directed therapies for controlling tuberculosis (TB). In this study, we investigated two related phagolysosomal pathways- LC3-associated phagocytosis (LAP) and autophagy in primary human macrophages, and its regulation by IL-27. Primary monocyte derived macrophages (MDM) were generated by culturing CD14+ monocytes from HIV (-) TB QFT (-) healthy individuals in the presence of M-CSF, and infected with Mtb Erdman bacilli in the presence or absence of recombinant IL-27 (rIL-27). In some experiments MDM were treated with TLR- 2, -4 blocking or isotype matched control antibodies, or MRT68921 (Unc-51 like autophagy activating kinase (ULK1/2) inhibitor) or rapamycin prior to infection. Expression of pMst1/2, IL-27, LC3B, p62, cathepsin B and GAPDH proteins in the cellular lysates were determined by immunoblotting. Data were analyzed using Student’s t test. Infection of MDM with Mtb bacilli resulted in an increased phosphorylation of Mst1/2 kinase (pMst1/2) and IL-27 expression as compared to uninfected controls (p=0.03 and p=0.04, respectively). The increase in pMst1/2 was observed as early as 3-hrs post-infection. Pre-treatment with blocking TLR-2 antibody prior to infection downregulated pMst1/2 (p=0.04) and IL-27 (p= 0.03), TLR-4 blocking had no effect on pMst1/2 and IL-27 expression. With regard to phagolysosomal function, LC3B-II expression increased in MDM at 3 -hours post-infection (p.i.) with a concomitant increase in cathepsin B; however, autophagic flux measured by p62 degradation was observed at 24-hours p.i. Treatment with MRT68921 marginally inhibited LC3B-II without affecting cathepsin B expression at 3-hrs p.i, and significantly increased LC3B-II accumulation due to inhibition in autophagic flux at 24-hours p.i., suggesting regulation of LC3B-II mediated anti-mycobacterial activity at 3-hours p.i. through a mechanism other than ULK1/2. Importantly, treatment of Mtb-infected MDM with rIL-27 decreased pMst1/2 (p=0.03), LC3B-II (p-0.02) and cathepsin B (p=0.04) expression, but did not affect p62 degradation (p=0.09). These findings demonstrate the differential regulation of LAP and autophagic activity of MDM during early and late infection with Mtb, and suggest that IL-27 inhibits the protective immunological response to Mtb. An improved understanding of macrophage responses can provide important insights into strategies to control Mtb early replication.

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Immunoproteomics & macrophage mechanisms of human resistance to TST/IGRA conversion

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Immunoproteomics & macrophage mechanisms of human resistance to TST/IGRA conversion CM. Anterasian1*, JD. Simmons1, DL. Swaney2, GJ. Peterson1, P. Benchek3, P. Van1, R. Gottardo1, CM. Stein3, H. Mayanja-Kizza4, J. Johnson5, J. Cox2, NJ. Krogan6, WH. Boom3, TR. Hawn1; 1University of Washington; 2University of California, Berkeley; 3Case Western Reserve University; 4Makerere University, Kampala, Uganda; 5Icahn School of Medicine, Mount Sinai; 6University of California, San Francisco Background: Despite long-term and intense household exposure to Mycobacterium tuberculosis (Mtb), some individuals remain resistant to traditionally defined latent TB infection (LTBI) with persistently negative tuberculin skin tests and interferon-g release assays (“RSTR” phenotype). Global proteomics can be used to detect Mtb-induced changes in RSTR versus LTBI cellular biology, including pathways that are not transcriptionally regulated. We hypothesize that macrophage immunoproteomic responses to Mtb are genetically regulated and associated with Mtb clinical outcomes. Methods: Primary human monocyte-derived macrophages (MDMs) from Ugandan individuals (RSTR n=20, LTBI n=19) were infected ex vivo with Mtb H37Rv. Protein abundance was measured at 24 hours by mass spectrometry. Differentially abundant proteins (DAPs) in RSTR versus LTBI macrophages were identified using a linear mixed effects model incorporating age, sex, and kinship. Ugandan cohort transcriptomic data from Mtb-infected monocytes and genomic data from Illumina MegaEx array were used to identify DAP polymorphisms associated with DAP mRNA expression and cytokine mRNA expression. Results: We identified 46 DAPs that define the RSTR versus LTBI Mtb-induced proteome in MDMs (false-discovery rate (FDR) < 0.20). Enrichment analysis revealed vesicle-mediated transport (FDR

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Host transcriptome of diabetic individuals with latent tuberculosis indicates increased downregulation of immune activation and host metabolic genes

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Host transcriptome of diabetic individuals with latent tuberculosis indicates increased downregulation of immune activation and host metabolic genes Kiran Iqbal Masood1, Maliha Yameen1, Nanik Ram1, Qamar Masood1, Bushra Jamil1, Amina Ajmal1, Muhammad Irfan1, Jackie Cliff2, Saba Shahid1 and Zahra Hasan1* 1The Aga Khan University, Stadium Road, P.O.Box 3500, Karachi 74800, Pakistan; 2London School of Hygiene and Tropical Medicine, UK. Submitting author email; Zahra.hasan@aku.edu Background: One third of the world’s population is thought to have latent disease (LTB) caused by infection with Mycobacterium tuberculosis (MTB). Diabetes causes a change in immune activation genes and is thought to result in unfavourable outcomes in tuberculosis (TB). We investigated the impact of LTB on DM cases in a TB endemic region using a host blood transcriptome approach. Methods: We studied host blood transcriptome analysis in healthy endemic controls (EC), those with latent TB (LTB), diabetic individuals (DM) and DM with LTB using the Clariom S Array 21,448 gene set, Affymetrix. Cellular pathway analysis of significant differentially expressed genes (DEGs) up- or down-regulated (log FC (fold change) < -2 or > 2; FDR adjusted P value

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Immunoglobulin profile and B‐cell frequencies are altered with changes in the cellular microenvironment independent of the stimulation conditions

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Immunoglobulin profile and B‐cell frequencies are altered with changes in the cellular microenvironment independent of the stimulation conditions AUTHORS Dannielle K Moore, Gina R Leisching, Candice I Snyders, Andrea Gutschmidt, Ilana C Van Rensburg and Andre G. Loxton AFFILIATION Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical ResearchCouncil Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa ABSTRACT Introduction: B‐cells are essential in the defense against Mycobacterium tuberculosis. Studies on isolated cells may not accurately reflect the responses that occur in vivo due to the presence of other cells. This study elucidated the influence of microenvironment complexity on B‐cell polarization and function in the context of tuberculosis disease. Methods: B‐cell function was tested in whole blood, peripheral blood mononuclear cells (PBMCs), and as isolated cells. The different fractions were stimulated and the B‐cell phenotype and immunoglobulin profiles analyzed. Results: The immunoglobulin profile and developmental B‐cell frequencies varied for each of the investigated sample types, while in an isolated cellular environment, secretion of immunoglobulin isotypes immunoglobulin A (IgA), IgG2, and IgG3 was hampered. The differences in the immunoglobulin profile highlight the importance of cell‐cell communication for B‐cell activation. Furthermore, a decrease in marginal zone B‐cell frequencies and an increase in T1 B‐cells was observed following cell isolation, indicating impaired B‐cell development in response to in vitro antigenic stimulation in isolation. Conclusion: Our results suggest that humoral B‐cell function and development was impaired likely due to a lack of co-stimulatory signals from other cell types. Thus, B‐cell function should ideally be studied in a PBMC or whole blood fraction. KEYWORDS B cells, IgG, PBMC, M. tuberculosis, microenvironment

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Systematic evaluation of transcriptomic disease risk and diagnostic biomarker overlap between COVID-19 and tuberculosis: a patient-level meta-analysis

Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Systematic evaluation of transcriptomic disease risk and diagnostic biomarker overlap between COVID-19 and tuberculosis: a patient-level meta-analysis Background The novel coronavirus, SARS-CoV-2, has increased the burden on healthcare systems already strained by a high incidence of tuberculosis (TB) as co-infection and dual presentation are occurring in syndemic settings. We aimed to understand the interaction between these diseases by profiling COVID-19 gene expression signatures on RNA-sequencing data from TB-infected individuals. Methods We performed a systematic review and patient-level meta-analysis by querying PubMed and pre-print servers to derive eligible COVID-19 gene expression signatures from human whole blood (WB), PBMCs or BALF studies. A WB influenza dataset served as a control respiratory disease signature. Three large TB RNA-seq datasets, comprising multiple cohorts from the UK and Africa and consisting of TB patients across the disease spectrum, were chosen to profile these signatures. Putative “COVID-19 risk scores” were generated for each sample in the TB datasets using the TBSignatureProfiler package. Risk was stratified by time to TB diagnosis in progressors and contacts of pulmonary and extra-pulmonary TB. An integrative analysis between TB and COVID-19 single-cell RNA-seq data was performed and a population-level meta-analysis was conducted to identify shared gene ontologies between the diseases and their relative enrichment in COVID-19 disease severity states. Results 35 COVID-19 gene signatures from nine eligible studies comprising 98 samples were profiled on TB RNA-seq data from 1181 samples from 853 individuals. 25 signatures had significantly higher COVID-19 risk in active TB (ATB) compared with latent TB infection (p

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  • Dylan Sheerin, PhD, The Walter & Eliza Hall Institute of Medical Research
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