Abstract
Macrophages play a significant role in preventing infection through antimicrobial activities, particularly acidification, and proteolysis. Mycobacterium tuberculosis (Mtb) infection can lead to diverse outcomes, from latent asymptomatic infection to active disease involving multiple organs. Monocyte-derived macrophage is one of the main cell types accumulating in lungs following Mtb infection. The variation of intracellular activities of monocyte-derived macrophages in humans and the influence of these activities on the tuberculosis (TB) spectrum are not well understood. By exploiting ligand-specific bead-based assays, we investigated macrophage antimicrobial activities real-time in healthy volunteers (n = 53) with 35 cases of latent TB (LTB), and those with active TB (ATB), and either pulmonary TB (PTB, n = 70) or TB meningitis (TBM, n = 77). We found wide person-to-person variations in acidification and proteolytic activities in response to both non-immunogenic IgG and pathogenic ligands comprising trehalose 6,6'−dimycolate (TDM) from Mtb or β-glucan from Saccharamyces cerevisiase. The variation in the macrophage activities remained similar regardless of stimuli; however, IgG induced stronger acidification activity than immunogenic ligands TDM (P = 10−5, 3 × 10−5 and 0.01 at 30, 60, and 90 min) and β-glucan (P = 10−4, 3 × 10−4 and 0.04 at 30, 60, and 90 min). Variation in proteolysis activity was slightly higher in LTB than in ATB (CV = 40% in LTB vs. 29% in ATB, P = 0.03). There was no difference in measured antimicrobial activities in response to TDM and bacterial killing in macrophages from LTB and ATB, or from PTB and TBM. Our results indicate that antimicrobial activities of monocyte-derived macrophages vary among individuals and show immunological dependence, but suggest these activities cannot be solely responsible for the control of bacterial replication or dissemination in TB.
Highlights
Macrophages play an important role in innate immunity to protect the human body from microbial infection
To understand the diversity of human macrophage activities among individuals and in response to different ligands, we examined the acidification and proteolysis of hMDM from 53 healthy subjects (35 with latent Mycobacterium tuberculosis (Mtb) infection) using the reporter beads coated with the non-immunogenic IgG control antibody and with immunogenic ligands comprising TDM extracted from Mtb and β-glucan from Saccharomyces cerevisiae (Figure 1)
We investigated antimicrobial activities of macrophages from people who were healthy, had latent TB or active TB, either pulmonary TB (PTB) or Tuberculosis meningitis (TBM), to extend understanding of the impact of macrophage activities on TB disease protection and progression
Summary
Macrophages play an important role in innate immunity to protect the human body from microbial infection. The phagosomes undergo a maturation process in which they are acidified by recruiting V-ATPases (Levin et al, 2016) sequentially fuse with multiple intra-vesicles including, lastly, lysosomes to form phago-lysosomes The environment inside these vesicles is highly acidic, around pH 4.5, and enriched with an assortment of peptidases and hydrolases, which can kill the bacteria and process antigens for presentation to T cells, leading on to secondary adaptive immune responses (Flannagan et al, 2009; Levin et al, 2016). Human monocyte-derived macrophages (MDM) exhibit reduced acidification and proteolytic activities in response to the bacteria or pathogenic ligands (Yates et al, 2005; Podinovskaia et al, 2013) These observations are from studies with only one or two human participants, with no attention to the potential variation of antimicrobial activities in human macrophages from different donors in response to the stimuli
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