Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity

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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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

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CJ Cambier

Department of Chemistry, Stanford University, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-0300-7377
Steven M Banik

Department of Chemistry, Stanford University, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7070-3404
Joseph A Buonomo

Department of Chemistry, Stanford University, Stanford, United States

Competing interests
No competing interests declared.
Carolyn R Bertozzi

Department of Chemistry, Stanford University, Stanford, United States

For correspondence
bertozzi@stanford.edu

Competing interests
Carolyn R Bertozzi, C.R.B. is a co-founder of OliLux Bio, Palleon Pharmaceuticals, InverVenn Bio, Enable Biosciences, and Lycia Therapeutics, and member of the Board of Directors of Eli Lilly..

"This ORCID iD identifies the author of this article:" 0000-0003-4482-2754

Funding

National Institutes of Health (AI51622)

Carolyn R Bertozzi

Damon Runyon Cancer Research Foundation (Postdoctoral Fellowship)

CJ Cambier

National Institutes of Health (F32)

Steven M Banik
Joseph A Buonomo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments performed on zebrafish were in compliance with the U.S. National Institutes of Health guidelines. All animals were handled according to approved Stanford Institutional Animal Care and Use Committee protocol APLAC-30262.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.