PUBLICATION
Nitrogen deprivation induces triacylglycerol accumulation, drug tolerance and hypervirulence in mycobacteria
- Authors
- Santucci, P., Johansen, M.D., Point, V., Poncin, I., Viljoen, A., Cavalier, J.F., Kremer, L., Canaan, S.
- ID
- ZDB-PUB-190619-3
- Date
- 2019
- Source
- Scientific Reports 9: 8667 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Antitubercular Agents/pharmacology*
- Carbon/metabolism
- Drug Tolerance
- Embryo, Nonmammalian
- Fatty Acids/metabolism
- Humans
- Isoniazid/pharmacology
- Ligases/genetics
- Ligases/metabolism
- Lipid Droplets/metabolism
- Lipolysis
- Longevity/drug effects
- Macrophages/drug effects
- Macrophages/microbiology
- Mycobacterium Infections, Nontuberculous/drug therapy
- Mycobacterium Infections, Nontuberculous/metabolism*
- Mycobacterium Infections, Nontuberculous/microbiology
- Mycobacterium Infections, Nontuberculous/mortality
- Mycobacterium abscessus/drug effects*
- Mycobacterium abscessus/metabolism
- Mycobacterium abscessus/pathogenicity
- Mycobacterium smegmatis/drug effects*
- Mycobacterium smegmatis/metabolism
- Mycobacterium smegmatis/pathogenicity
- Mycobacterium tuberculosis/drug effects
- Mycobacterium tuberculosis/metabolism
- Mycobacterium tuberculosis/pathogenicity
- Nitrogen/deficiency*
- Rifampin/pharmacology
- Triglycerides/biosynthesis*
- Virulence
- Zebrafish
- PubMed
- 31209261 Full text @ Sci. Rep.
Citation
Santucci, P., Johansen, M.D., Point, V., Poncin, I., Viljoen, A., Cavalier, J.F., Kremer, L., Canaan, S. (2019) Nitrogen deprivation induces triacylglycerol accumulation, drug tolerance and hypervirulence in mycobacteria. Scientific Reports. 9:8667.
Abstract
Mycobacteria share with other actinomycetes the ability to produce large quantities of triacylglycerol (TAG), which accumulate as intracytoplasmic lipid inclusions (ILI) also known as lipid droplets (LD). Mycobacterium tuberculosis (M. tb), the etiologic agent of tuberculosis, acquires fatty acids from the human host which are utilized to synthesize TAG, subsequently stored in the form of ILI to meet the carbon and nutrient requirements of the bacterium during long periods of persistence. However, environmental factors governing mycobacterial ILI formation and degradation remain poorly understood. Herein, we demonstrated that in the absence of host cells, carbon excess and nitrogen starvation promote TAG accumulation in the form of ILI in M. smegmatis and M. abscessus, used as surrogate species of M. tb. Based on these findings, we developed a simple and reversible in vitro model to regulate ILI biosynthesis and hydrolysis in mycobacteria. We also showed that TAG formation is tgs1 dependent and that lipolytic enzymes mediate TAG breakdown. Moreover, we confirmed that the nitrogen-deprived and ILI-rich phenotype was associated with an increased tolerance towards several drugs used for treating mycobacterial infections. Importantly, we showed that the presence of ILI substantially enhanced the bacterial burden and granuloma abundance in zebrafish embryos infected with lipid-rich M. abscessus as compared to embryos infected with lipid-poor M. abscessus, suggesting that ILI are actively contributing to mycobacterial virulence and pathogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping