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

Molecular Structure
Animals
Virulence
Humans
Disease Models, Animal
Epithelial Cells/drug effects
Epithelial Cells/metabolism
Epithelial Cells/microbiology*
Structure-Activity Relationship
Virulence Factors/chemistry
Virulence Factors/metabolism*
Lipids*/chemistry
Anti-Bacterial Agents/pharmacology
Cell Membrane/drug effects
Cell Membrane/metabolism
Cell Membrane/microbiology*
Mycobacterium marinum/drug effects
Mycobacterium marinum/genetics
Mycobacterium marinum/metabolism
Mycobacterium marinum/pathogenicity*
Macrophages/drug effects
Macrophages/metabolism
Macrophages/microbiology
A549 Cells
Zebrafish
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
Host-Pathogen Interactions
THP-1 Cells
Mycobacterium Infections, Nontuberculous/metabolism
Mycobacterium Infections, Nontuberculous/microbiology*
Mycobacterium Infections, Nontuberculous/prevention & control
Animals, Genetically Modified

(all 32)

PubMed

33226343 Full text @ Elife

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

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