Kimone L Fisher1,2, Kerishka Rajkumar-Bhugeloo1, Denelle Moodley1, Thabo Mpotje1, Duran Ramsuran1, Thumbi Ndung'u1,2,3,4, Mohlopheni J Marakalala1,2,3. 1. Africa Health Research Institute, Durban, KwaZulu-Natal, 4001, South Africa. 2. School of Laboratory Medicine and Medical Sciences, University of KwaZulu Natal, Durban, KwaZulu-Natal, 4001, South Africa. 3. Division of Infection and Immunity, University College London, London, UK. 4. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban, KwaZulu-Natal, 4001, South Africa.
Abstract
Background: Neutrophils are one of the major early role players in antimycobacterial immunity. Upon infection, neutrophils can undergo NETosis, a cell death characterized by release of neutrophil extracellular traps (NETs). The role of NETosis in TB progression remains poorly characterized. We aim to characterize mechanisms underlying NETosis during TB pathogenesis by identifying genes that drive the cell death, and to determine their potential as markers of disease progression in high-risk individuals. Finally, we intend to evaluate neutrophil associated genes as targets for host directed therapy to reduce pathological damage caused by NETosis. Methods: Quantitative PCR will be used to quantify expression of specific genes identified in the blood of individuals with active lung disease (n=30), compared to those from healthy (n=30) and latently infected individuals (LTBI) (n=30). In addition, temporal events associated with NETosis will be measured using live microscopy in a neutrophil in vitro model of Mycobacterium tuberculosis (Mtb) infection. Candidate genes found to be associated with NETosis will be targeted with pharmaceutical inhibitors. Conclusion: Genes associated with neutrophil mediated cell death may serve as potential biomarkers of pathological damage and disease progression, as well as targets for host-directed therapy. Copyright:
Background: Neutrophils are one of the major early role players in antimycobacterial immunity. Upon infection, neutrophils can undergo NETosis, a cell death characterized by release of neutrophil extracellular traps (NETs). The role of NETosis in TB progression remains poorly characterized. We aim to characterize mechanisms underlying NETosis during TB pathogenesis by identifying genes that drive the cell death, and to determine their potential as markers of disease progression in high-risk individuals. Finally, we intend to evaluate neutrophil associated genes as targets for host directed therapy to reduce pathological damage caused by NETosis. Methods: Quantitative PCR will be used to quantify expression of specific genes identified in the blood of individuals with active lung disease (n=30), compared to those from healthy (n=30) and latently infected individuals (LTBI) (n=30). In addition, temporal events associated with NETosis will be measured using live microscopy in a neutrophil in vitro model of Mycobacterium tuberculosis (Mtb) infection. Candidate genes found to be associated with NETosis will be targeted with pharmaceutical inhibitors. Conclusion: Genes associated with neutrophil mediated cell death may serve as potential biomarkers of pathological damage and disease progression, as well as targets for host-directed therapy. Copyright:
Authors: David M Lowe; Paul S Redford; Robert J Wilkinson; Anne O'Garra; Adrian R Martineau Journal: Trends Immunol Date: 2011-11-15 Impact factor: 16.687