Abstract
BackgroundThe inflammatory response to Mycobacterium tuberculosis results in variable degrees of lung pathology during active TB (ATB) with central involvement of neutrophils. Little is known about neutrophil-derived mediators and their role in disease severity at baseline and recovery upon TB treatment initiation.Methods107 adults with confirmed pulmonary TB were categorised based on lung pathology at baseline and following successful therapy using chest X-ray scores (Ralph scores) and GeneXpert bacterial load (Ct values). Plasma, sputum, and antigen-stimulated levels of MMP1, MMP3, MMP8, MMP9, MPO, S100A8/9, IL8, IL10, IL12/23(p40), GM-CSF, IFNγ, and TNF were analysed using multiplex cytokine arrays.ResultsAt baseline, neutrophil counts correlated with plasma levels of MMP8 (rho = 0.45, p = 2.80E−06), S100A8 (rho = 0.52, p = 3.00E−08) and GM-CSF (rho = 0.43, p = 7.90E−06). Levels of MMP8 (p = 3.00E−03), MMP1 (p = 1.40E−02), S100A8 (p = 1.80E−02) and IL12/23(p40) (p = 1.00E−02) were associated with severe lung damage, while sputum MPO levels were directly linked to lung damage (p = 1.80E−03), Mtb load (p = 2.10E−02) and lung recovery (p = 2.40E−02). Six months of TB therapy significantly decreased levels of major neutrophil-derived pro-inflammatory mediators: MMP1 (p = 4.90E−12 and p = 2.20E−07), MMP8 (p = 3.40E−14 and p = 1.30E−05) and MMP9 (p = 1.60E−04 and p = 1.50E−03) in plasma and sputum, respectively. Interestingly, following H37Rv whole cell lysate stimulation, S100A8 (p = 2.80E−02), MMP9 (p = 3.60E−02) and MPO (p = 9.10E−03) levels at month 6 were significantly higher compared to baseline. Sputum MMP1 (p = 1.50E−03), MMP3 (p = 7.58E−04), MMP9 (p = 2.60E−02) and TNF (p = 3.80E−02) levels were lower at month 6 compared to baseline in patients with good lung recovery.ConclusionIn this study, patients with severe lung pathology at baseline and persistent lung damage after treatment were associated with higher plasma and sputum levels of major pro-inflammatory neutrophil-derived mediators. Interestingly, low sputum MPO levels were associated with severe lung damage, higher Mtb burden and low recovery. Our data suggest that therapeutic agents which target these mediators should be considered for future studies on biomarkers and host-directed therapeutic approaches against TB-related lung pathology and/or lung recovery.
Highlights
Tuberculosis (TB) caused 1.2 million deaths from HIV-negative individuals in 2019 [1]
Neutrophil levels are associated with higher risk of lung damage [10] and death in TB patients [30] and we recently showed that neutrophil activation and function vary in active TB (ATB) patients based on the severity of the lung pathology [43]
We show that S100A8/9 and MMP8 contribute to increased lung damage and that MPO acts as an anti-inflammatory agent which potentially regulates TB-related lung pathology and promotes lung recovery
Summary
Tuberculosis (TB) caused 1.2 million deaths from HIV-negative individuals in 2019 [1]. It has been suggested that higher initial inflammatory responses against Mycobacterium tuberculosis (Mtb) lead to more severe lung damage prior to treatment initiation [4] and reduced of recovery following treatment. Certain neutrophil sub-types have been shown to express immunosuppressive functions including: CD16brightCD62Llow neutrophils [7] and granulocytic myeloid-derived suppressor cells (G-MDSCs) [8, 9]. These support the idea that an equilibrium between neutrophilic pro- and anti-inflammatory functions [10,11,12,13,14] determines the extend of inflammation and lung damage in TB patients. Little is known about neutrophil-derived mediators and their role in disease severity at baseline and recovery upon TB treatment initiation
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