PUBLICATION
Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity
- Authors
- Cambier, C.J., Banik, S.M., Buonomo, J.A., Bertozzi, C.R.
- ID
- ZDB-PUB-201124-5
- Date
- 2020
- Source
- eLIFE 9: (Journal)
- Registered Authors
- Keywords
- biochemistry, chemical biology, infectious disease, microbiology, zebrafish
- MeSH Terms
-
- A549 Cells
- Animals
- Animals, Genetically Modified
- Anti-Bacterial Agents/pharmacology
- Cell Membrane/drug effects
- Cell Membrane/metabolism
- Cell Membrane/microbiology*
- Disease Models, Animal
- Epithelial Cells/drug effects
- Epithelial Cells/metabolism
- Epithelial Cells/microbiology*
- Host-Pathogen Interactions
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
- Lipids*/chemistry
- Macrophages/drug effects
- Macrophages/metabolism
- Macrophages/microbiology
- Molecular Structure
- Mycobacterium Infections, Nontuberculous/metabolism
- Mycobacterium Infections, Nontuberculous/microbiology*
- Mycobacterium Infections, Nontuberculous/prevention & control
- Mycobacterium marinum/drug effects
- Mycobacterium marinum/genetics
- Mycobacterium marinum/metabolism
- Mycobacterium marinum/pathogenicity*
- Structure-Activity Relationship
- THP-1 Cells
- Virulence
- Virulence Factors/chemistry
- Virulence Factors/metabolism*
- Zebrafish
- PubMed
- 33226343 Full text @ Elife
Citation
Cambier, C.J., Banik, S.M., Buonomo, J.A., Bertozzi, C.R. (2020) Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity. eLIFE. 9:.
Abstract
Several virulence lipids populate the outer cell wall of pathogenic mycobacteria (Jackson, 2014). Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids (Anderson, 1929), plays important roles in both defending against host antimicrobial programs (Camacho et al., 2001; Cox et al., 1999; Murry et al., 2009) and in evading these programs altogether (Cambier et al., 2014a; Rousseau et al., 2004). Immediately following infection, mycobacteria rely on PDIM to evade Myd88-dependent recruitment of microbicidal monocytes which can clear infection (Cambier et al., 2014b). To circumvent the limitations in using genetics to understand virulence lipids, we developed a chemical approach to track PDIM during Mycobacterium marinum infection of zebrafish. We found that PDIM's methyl-branched lipid tails enabled it to spread into host epithelial membranes to prevent immune activation. Additionally, PDIM's affinity for cholesterol promoted this phenotype; treatment of zebrafish with statins, cholesterol synthesis inhibitors, decreased spreading and provided protection from infection. This work establishes that interactions between host and pathogen lipids influence mycobacterial infectivity and suggests the use of statins as tuberculosis preventive therapy by inhibiting PDIM spread.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping