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Mycobacterium tuberculosis ( Mtb ) is the causative agent of tuberculosis (TB), a disease that claims ~1.6 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. Therefore, development of new anti-TB drugs remains one of the highest public health priorities. Mtb has evolved a complex cell envelope that represents a formidable barrier to antibiotics. The Mtb cell envelop consists of four distinct layers enriched for Mtb specific lipids and glycans. Although the outer membrane, comprised of mycolic acid esters, has been extensively studied, less is known about the plasma membrane, which also plays a critical role in impacting antibiotic efficacy. The Mtb plasma membrane has a unique lipid composition, with mannosylated phosphatidylinositol lipids (phosphatidyl-myoinositol mannosides, PIMs) comprising more than 50% of the lipids. However, the role of PIMs in the structure and function of the membrane remains elusive. Here, we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to shape the biophysical properties of mycobacterial plasma membranes. We assess both symmetric and asymmetric assemblies of the Mtb plasma membrane and compare this with residue distributions of Mtb integral membrane protein structures. To further validate the model, we tested known anti-TB drugs and demonstrated that our models agree with experimental results. Thus, our work sheds new light on the organization of the mycobacterial plasma membrane. This paves the way for future studies on antibiotic development and understanding Mtb membrane protein function.
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Colony-stimulating factor-1- and interleukin-34-derived macrophages differ in their susceptibility to Mycobacterium marinum
Abstract Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the leading global cause of death from an infectious agent. Mycobacteria thrive within their host Mϕs and presently, there is no animal model that permits combined in vitro and in vivo study of mycobacteria-host Mϕ interactions. Mycobacterium marinum (Mm), which causes TB in aquatic vertebrates, has become a promising model for TB research, owing to its close genetic relatedness to Mtb and the availability of alternative, natural host aquatic animal models. Here, we adopted the Xenopus laevis frog-Mm surrogate infection model to study host Mϕ susceptibility and resistance to mycobacteria. Mϕ differentiation is regulated though the CSF-1 receptor (CSF-1R), which is activated by CSF-1 and the unrelated IL-34 cytokines. Using combined in vitro and in vivo approaches, we demonstrated that CSF-1-Mϕs exacerbate Mm infections, are more susceptible to mycobacterial entry and are less effective at killing this pathogen. By contrast, IL-34-Mϕs confer anti-Mm resistance in vivo, are less susceptible to Mm entry and more effectively eliminate internalized mycobacteria. Moreover, we showed that the human CSF-1- and IL-34-Mϕs are likewise, respectively, susceptible and resistant to mycobacteria, and that both frog and human CSF-1-Mϕs are more prone to the spread of mycobacteria and to being infected by Mm-laden Mϕs than the respective IL-34-Mϕ subsets. This work marks the first report describing the roles of these Mϕ subsets in mycobacterial disease and may well lead to the development of more targeted anti-Mtb approaches.
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- Award ID(s):
- 1749427
- PAR ID:
- 10394044
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Journal of Leukocyte Biology
- Volume:
- 106
- Issue:
- 6
- ISSN:
- 0741-5400
- Page Range / eLocation ID:
- p. 1257-1269
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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