Investigating neutrophil cell death in TB pathogenesis

Kimone L Fisher; Kerishka Rajkumar-Bhugeloo; Denelle Moodley; Thabo Mpotje; Duran Ramsuran; Thumbi Ndung'u; Mohlopheni J Marakalala

doi:10.12688/gatesopenres.13472.2

Investigating neutrophil cell death in TB pathogenesis

Gates Open Res. 2022 Apr 29:5:175. doi: 10.12688/gatesopenres.13472.2. eCollection 2021.

Authors

Kimone L Fisher^{1

2}, Kerishka Rajkumar-Bhugeloo¹, Denelle Moodley¹, Thabo Mpotje¹, Duran Ramsuran¹, Thumbi Ndung'u^{1

2

3

4}, Mohlopheni J Marakalala^{1

2

3}

Affiliations

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.

Keywords: NETosis; Neutrophils; Tuberculosis.

Grants and funding

MJM was funded by Grand Challenges, an initiative of the Bill & Melinda Gates Foundation (grant #OPP1210776, grant# INV-016239) and the Wellcome Trust (grant#206751/A/17/Z). The work reported herein was made possible through funding by the South African Medical Research Council through its Division of Research Capacity Development under the Internship Scholarship Programme (KLF) and Mid-Career Scientist Programme (MJM) from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of the funders.