BACKGROUND: Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) is a common complication of combined antiretroviral therapy (cART) in HIV-TB co-infected patients. However, the disease mechanism is poorly understood, prognosis of TB-IRIS is currently impossible, and diagnosis is highly challenging. We analyzed whether the gene expression of monocytes could be correlated with TB-IRIS pathogenesis and could be used to classify patients predisposed to TB-IRIS. METHODS: Monocyte gene expression was compared between patients who developed TB-IRIS and matched controls. We carried out whole-genome expression profiling using Affymetrix GeneChip(®) ST 1.1 arrays at two time-points: before cART initiation (baseline) and at week two post-cART initiation. For each time-point, we used different statistical approaches to identify molecular signatures which could be used as classifiers. We also functionally mapped the modulated cellular pathways using the software package Ingenuity Pathway Analysis. RESULTS: At baseline, before introduction of cART and before onset of symptoms, monocyte gene expression was already perturbed in patients who subsequently developed TB-IRIS, indicating a possible involvement of monocytes in TB-IRIS predisposition. The differences in monocyte gene expression in TB-IRIS patients became even more clear after two weeks of cART (when TB-IRIS commonly occurs), with more than 100 genes for which expression showed a fold change greater than 1.5. Both at baseline and at week two post-cART initiation, a classifier of 8 and 9 genes, respectively could be built, which allowed discrimination of TB-IRIS cases and controls. Pathway analyses revealed that the majority of the dysregulated genes in TB-IRIS - at the time of the IRIS episode, but also already at baseline - are associated with infection and inflammation. Relevant biological functions which were perturbed before/during TB-IRIS included "Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses" and "Complement System". CONCLUSION: Our results indicate an involvement of monocytes in predisposition to/development of TB-IRIS, and suggest a number of functional pathways which may play a role in TB-IRIS development. This comprehensive study of gene regulation in monocytes provides baseline data for further studies into biomarkers for prognosis and diagnosis of TB-IRIS.
BACKGROUND:Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) is a common complication of combined antiretroviral therapy (cART) in HIV-TB co-infectedpatients. However, the disease mechanism is poorly understood, prognosis of TB-IRIS is currently impossible, and diagnosis is highly challenging. We analyzed whether the gene expression of monocytes could be correlated with TB-IRIS pathogenesis and could be used to classify patients predisposed to TB-IRIS. METHODS: Monocyte gene expression was compared between patients who developed TB-IRIS and matched controls. We carried out whole-genome expression profiling using Affymetrix GeneChip(®) ST 1.1 arrays at two time-points: before cART initiation (baseline) and at week two post-cART initiation. For each time-point, we used different statistical approaches to identify molecular signatures which could be used as classifiers. We also functionally mapped the modulated cellular pathways using the software package Ingenuity Pathway Analysis. RESULTS: At baseline, before introduction of cART and before onset of symptoms, monocyte gene expression was already perturbed in patients who subsequently developed TB-IRIS, indicating a possible involvement of monocytes in TB-IRIS predisposition. The differences in monocyte gene expression in TB-IRIS patients became even more clear after two weeks of cART (when TB-IRIS commonly occurs), with more than 100 genes for which expression showed a fold change greater than 1.5. Both at baseline and at week two post-cART initiation, a classifier of 8 and 9 genes, respectively could be built, which allowed discrimination of TB-IRIS cases and controls. Pathway analyses revealed that the majority of the dysregulated genes in TB-IRIS - at the time of the IRIS episode, but also already at baseline - are associated with infection and inflammation. Relevant biological functions which were perturbed before/during TB-IRIS included "Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses" and "Complement System". CONCLUSION: Our results indicate an involvement of monocytes in predisposition to/development of TB-IRIS, and suggest a number of functional pathways which may play a role in TB-IRIS development. This comprehensive study of gene regulation in monocytes provides baseline data for further studies into biomarkers for prognosis and diagnosis of TB-IRIS.
Authors: Kathryn M Dupnik; Thomas B Bair; Andressa O Maia; Francianne M Amorim; Marcos R Costa; Tatjana S L Keesen; Joanna G Valverde; Maria do Carmo A P Queiroz; Lúcio L Medeiros; Nelly L de Lucena; Mary E Wilson; Mauricio L Nobre; Warren D Johnson; Selma M B Jeronimo Journal: J Infect Dis Date: 2014-11-14 Impact factor: 5.226
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Authors: Stanley Kimbung Mbandi; Hannah Painter; Adam Penn-Nicholson; Asma Toefy; Mzwandile Erasmus; Willem A Hanekom; Thomas J Scriba; Rachel P J Lai; Suzaan Marais; Helen A Fletcher; Graeme Meintjes; Robert J Wilkinson; Mark F Cotton; Savita Pahwa; Mark J Cameron; Elisa Nemes Journal: Eur J Immunol Date: 2022-04-27 Impact factor: 6.688
Authors: Luxin Pei; Kiyoshi F Fukutani; Rafael Tibúrcio; Adam Rupert; Eric W Dahlstrom; Frances Galindo; Elizabeth Laidlaw; Andrea Lisco; Maura Manion; Bruno B Andrade; Irini Sereti Journal: Front Immunol Date: 2021-06-15 Impact factor: 7.561