| Autor: |
Tió-Coma M; Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., van Hooij A; Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Bobosha K; Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.; Armauer Hansen Research Institute, Addis Ababa, Ethiopia., van der Ploeg-van Schip JJ; Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Banu S; International Center for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh., Khadge S; Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal., Thapa P; Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal., Kunwar CB; Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal., Goulart IM; National Reference Center for Sanitary Dermatology and Leprosy, Faculty of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil., Bekele Y; Armauer Hansen Research Institute, Addis Ababa, Ethiopia., Hagge DA; Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal., Moraes MO; Leprosy Laboratory, Oswaldo Cruz Institute - FIOCRUZ, Rio de Janeiro, Brazil., Teles RMB; Division of Dermatology, Department of Medicine, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California (UCLA), Los Angeles, CA, USA., Pinheiro RO; Leprosy Laboratory, Oswaldo Cruz Institute - FIOCRUZ, Rio de Janeiro, Brazil., van Zwet EW; Dept. Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands., Goeman JJ; Dept. Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands., Aseffa A; Armauer Hansen Research Institute, Addis Ababa, Ethiopia., Haks MC; Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Ottenhoff THM; Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Modlin RL; Division of Dermatology, Department of Medicine, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California (UCLA), Los Angeles, CA, USA.; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California (UCLA), Los Angeles, CA, USA., Geluk A; Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands. a.geluk@lumc.nl. |
| Abstrakt: |
Early diagnosis of leprosy is challenging, particularly its inflammatory reactions, the major cause of irreversible neuropathy in leprosy. Current diagnostics cannot identify which patients are at risk of developing reactions. This study assessed blood RNA expression levels as potential biomarkers for leprosy. Prospective cohorts of newly diagnosed leprosy patients, including reactions, and healthy controls were recruited in Bangladesh, Brazil, Ethiopia and Nepal. RNA expression in 1,090 whole blood samples was determined for 103 target genes for innate and adaptive immune profiling by dual color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) followed by cluster analysis. We identified transcriptomic biomarkers associated with leprosy disease, different leprosy phenotypes as well as high exposure to Mycobacterium leprae which respectively allow improved diagnosis and classification of leprosy patients and detection of infection. Importantly, a transcriptomic signature of risk for reversal reactions consisting of five genes (CCL2, CD8A, IL2, IL15 and MARCO) was identified based on cross-sectional comparison of RNA expression. In addition, intra-individual longitudinal analyses of leprosy patients before, during and after treatment of reversal reactions, indicated that several IFN-induced genes increased significantly at onset of reaction whereas IL15 decreased. This multi-site study, situated in four leprosy endemic areas, demonstrates the potential of host transcriptomic biomarkers as correlates of risk for leprosy. Importantly, a prospective five-gene signature for reversal reactions could predict reversal reactions at least 2 weeks before onset. Thus, transcriptomic biomarkers provide promise for early detection of these acute inflammatory episodes and thereby help prevent permanent neuropathy and disability in leprosy patients. |
