title: The contribution of neutrophils to lung pathology in tuberculosis
Creators: name: Sambou, Basil
Publisher: name: The Open University
Year: 2024

description: The significant number of deaths by a single infectious agent (<i>Mycobacterium tuberculosis</i> (<i>M.tb</i>)), ranking above HIV/AIDS is of great global health significance. TB is treatable, yet lung related morbidities are often observed in 50% of patients despite successful treatment. This is due to chronic inflammation, and the interaction between <i>M.tb</i> and the host immune armoury usually leads to collateral tissue damage. In recent research, neutrophils which form part of the first innate immune cells recruited to the lung, as well as their associated protein markers, have been implicated to mediate these collateral lung tissue destructions.<br><br>
The aim of this study was to determine the contribution of neutrophils to lung pathology at diagnosis (baseline) and lung recovery following 6-months of standard therapy for pulmonary TB. Neutrophils (including neutrophil ratio to other cell types) and their associated soluble mediators (MMP-8,-9, MPO, IL-8, S100A8/A9, Emmprin, Lipocalin 2, TIMP-1 and -2) were analysed in sputum and blood samples of TB patients (at baseline, day 14 and month 2) and correlated with lung pathology by chest x-ray and lung function impairment by spirometry.<br><br>
Lung pathology defined by chest x-ray Ralph scores was found to be significantly correlated with blood neutrophil percentages (r = 0.3, p = 0.04) and sputum neutrophil absolute numbers (r = 0.4, p = 0.01) at baseline (diagnosis). ELISA analysis of neutrophil markers in sputum showed the strongest correlation with sputum neutrophil ratios at baseline including levels of MMP-8 (r = 0.6, p = 0.0001), TIMP-2 (r = 0.6, p = 0.0002), MMP-9 (r = 0.4, p = 0.005), IL-8 (r = 0.4, p = 0.005), TIMP-1 (r = 0.4, p = 0.009) and MPO (r = 0.4, p = 0.02). The weakest correlation was observed in S100A8/A9 (r = 0.4, p = 0.03) and Lipocalin-2 (r = 0.3, p = 0.07). Interestingly, EMMPRIN (r = - 0.4, p = 0.02) was inversely correlated with neutrophil ratios in sputum at baseline. The levels of neutrophil-associated plasma MMP-9 (baseline), plasma MPO (D14) and sputum MMP-8 (D14) were all significantly higher in patients with severe lung pathology. There was no significant difference in the levels of mediators between patients with Good or Poor recovery at all time points. However, sputum MMP-9 levels in patients with poor lung recovery significantly increased at D14 [Median 1400.8 (IQR) = (561.9 – 2112.6)] (p = 0.0251) but declined again by month 2 [Median (IQR) = 629.1 (80.9 – 1330.2)] (p = 0.028). In addition, patients with improved lung function by the end of treatment had significantly higher sputum MPO levels at D14 than in patients with stable or impaired lung function [Median (IQR) = 119,490 (79,820 – 124,165), 2,850 (2,125 – 8,740) and 17,720 (9,495 – 33,215) respectively]; p = 0.0018 and p = 0.0085 respectively.<br><br>
In conclusion, this study showed an elevated level of MMP-8, MMP-9 and MPO among patients with severe lung pathology compared to mild lung pathology patients at baseline. This supports the need to further investigate the role that neutrophils and associated mediators play in inflammation and subsequent lung pathology, as potential targets for host directed therapies to minimise lung damage in tuberculosis patients.