Abstract
Mycobacterium leprae, the causative agent of leprosy, is unique amongst human pathogens in its capacity to produce the virulence factor phenolic glycolipid (PGL)-I. In addition to mediating bacterial tropism for neurons, PGL-I interacts with Complement Receptor (CR)3 on macrophages (MPs) to promote infection. We demonstrate here that PGL-I binding to CR3 also enhances bacterial invasion of both polymorphonuclear neutrophils (PMNs) and dendritic cells (DCs). Moreover, in all cell types CR3 engagement by PGL-I activates the Syk tyrosine kinase, inducing calcineurin-dependent nuclear translocation of the transcription factor NFATc. This selectively augments the production of IL-2 by DCs, IL-10 by PMNs and IL-1β by MPs. In intranasally-infected mice PGL-I binding to CR3 heightens mycobacterial phagocytosis by lung PMNs and MPs, and stimulates NFATc-controlled production of Syk-dependent cytokines. Our study thus identifies the CR3-Syk-NFATc axis as a novel signaling pathway activated by PGL-I in innate immune cells, rewiring host cytokine responses to M. leprae.
Highlights
Leprosy, caused by Mycobacterium leprae (M. leprae) is a chronic infectious disease affecting primarily vulnerable populations in developing countries, with a global prevalence of approximately 200.000 in 2016 [1]
Ratios of bacteria recovered from dendritic cells (DCs), polymorphonuclear neutrophils (PMNs) and MPs after infection under non-opsonic conditions vs. serum-opsonizing conditions were around 50% and 20% for rBCG::phenolic glycolipid (PGL)-b and rBCG::noPGL, respectively (Figure 1C), illustrating the gain conferred by complement opsonization for these two strains
We discovered that production of the lipid virulence factor PGL-I endows M. leprae and recombinant Bacillus Calmette-Guérin (BCG) with the unique capacity to engage CR3 for potent phagocytosis in three major subsets of innate cells: DCs, PMNs, and MPs (Figure 7)
Summary
Leprosy, caused by Mycobacterium leprae (M. leprae) is a chronic infectious disease affecting primarily vulnerable populations in developing countries, with a global prevalence of approximately 200.000 in 2016 [1]. Paucibacillary (tuberculoid), or multibacillary (lepromatous) forms (LL) of the disease correlating with distinctive symptoms and immune profiles [2]. In spite of the different clinical presentations, T1R and ENL share biomarkers such as pro-inflammatory cytokines TNF, IL-1β, or MCP-1 and proteins belonging to the pentraxin family such as C-Reactive Protein in T1R, or pentraxin-3 during ENL [4] suggesting that common immune mechanisms underlie leprosy reactions. M. leprae is non-cultivable in vitro, which is a major hurdle for study of this disease-causing bacterium.
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