Host-derived fatty acids activate type VII secretion in<i>Staphylococcus aureus</i>

Lopez, Michael S.; Tan, Irene S.; Yan, Donghong; Kang, Jing; McCreary, Mark; Modrušan, Zora; Austin, Cary D.; Xu, Min; Brown, Eric J.

doi:10.1073/pnas.1700627114

Cited by 71 publications

(67 citation statements)

References 41 publications

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“…Together with the results obtained using geh and geh lip mutants, this finding implies that an active modification of human LDL-derived fatty acids is required for S. aureus triclosan resistance, reducing the possibility that protection occurs via a nonspecific triclosan-LDL interaction. A recent study using a murine systemic infection model with a fakA mutant found that this mutant is attenuated for colonization of the liver but not the kidneys (73). This finding is intriguing, considering our results demonstrating that FakA is necessary for the ability of S. aureus to utilize LDLs, as the biogenesis of host lipoprotein particles occurs predominantly in the liver.…”

Section: Discussionsupporting

confidence: 44%

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

et al. 2018

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Methicillin-resistant (MRSA) is a threat to global health. Consequently, much effort has focused on the development of new antimicrobials that target novel aspects of physiology. Fatty acids are required to maintain cell viability, and bacteria synthesize fatty acids using the type II fatty acid synthesis pathway (FASII). FASII is significantly different from human fatty acid synthesis, underscoring the therapeutic potential of inhibiting this pathway. However, many Gram-positive pathogens incorporate exogenous fatty acids, bypassing FASII inhibition and leaving the clinical potential of FASII inhibitors uncertain. Importantly, the source(s) of fatty acids available to pathogens within the host environment remains unclear. Fatty acids are transported throughout the body by lipoprotein particles in the form of triglycerides and esterified cholesterol. Thus, lipoproteins, such as low-density lipoprotein (LDL) represent a potentially rich source of exogenous fatty acids for during infection. We sought to test the ability of LDLs to serve as a fatty acid source for and show that cells cultured in the presence of human LDLs demonstrate increased tolerance to the FASII inhibitor, triclosan. Using mass spectrometry, we observed that host-derived fatty acids present in the LDLs are incorporated into the staphylococcal membrane and that tolerance to triclosan is facilitated by the fatty acid kinase A, FakA, and Geh, a triacylglycerol lipase. Finally, we demonstrate that human LDLs support the growth of fatty acid auxotrophs. Together, these results suggest that human lipoprotein particles are a viable source of exogenous fatty acids for during infection. Inhibition of bacterial fatty acid synthesis is a promising approach to combating infections caused by and other human pathogens. However, incorporates exogenous fatty acids into its phospholipid bilayer. Therefore, the clinical utility of targeting bacterial fatty acid synthesis is debated. Moreover, the fatty acid reservoir(s) exploited by are not well understood. Human low-density lipoprotein particles represent a particularly abundant source of fatty acids and are present in tissues colonizes. Herein, we establish that is capable of utilizing the fatty acids present in low-density lipoproteins to bypass both chemical and genetic inhibition of fatty acid synthesis. These findings imply that targets LDLs as a source of fatty acids during pathogenesis.

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Section: Discussionsupporting

confidence: 44%

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

et al. 2018

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“…Incorporation of SCUFAs into S. aureus membrane has been shown to impact host-pathogen interactions. Lopez et al showed that incorporation of cis SCUFAs from the host into membrane phospholipids activated the type VII secretion system for multiple virulence factors (26). On the other hand, Nguyen et al demonstrated that SCUFAs C16:1, C18:1, and C18:2 were taken up, elongated, and incorporated into membrane phospholipids and the lipid moiety of lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…Supplementation of medium with blood or blood products for antimicrobial susceptibility testing of fastidious pathogens is a common practice (24, 25). The lipid composition of S. aureus has an impact on the interaction of the organism with the host’s defense systems (26, 27).…”

Section: Introductionmentioning

confidence: 99%

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

Hines

Alvarado

Chen

et al. 2020

Preprint

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26Staphylococcus aureus can incorporate exogenous straight-chain unsaturated and 27 saturated fatty acids (SCUFAs and SCFAs, respectively) to replace some of the normally 28 biosynthesized branched-chain fatty acids and SCFAs. In this study, the impact of human serum 29 on the S. aureus lipidome and cell envelope structure was comprehensively characterized. When 30 grown in the presence of 20% human serum, typical human serum lipids, such as cholesterol, 31 sphingomyelin, phosphatidylethanolamines, and phosphatidylcholines, were present in the total 32 lipid extracts. Mass spectrometry showed that SCUFAs were incorporated into all major S. 33 aureus lipid classes, i.e., phosphatidylglycerols, lysyl-phosphatidylglycerols, cardiolipins, and 34 diglucosyldiacylglycerols. Heat-killed S. aureus retained much fewer serum lipids and failed to 35 incorporate SCUFAs, suggesting that association and incorporation of serum lipids with S. 36 aureus requires a living or non-denatured cell. Cytoplasmic membranes isolated from 37 lysostaphin-produced protoplasts of serum-grown cells retained serum lipids, but washing cells 38 with Triton X-100 removed most of them. Furthermore, electron microscopy studies showed that 39 serum-grown cells had thicker cell envelopes and associated material on the surface, which was 40 partially removed by Triton X-100 washing. To investigate which serum lipids were 41 preferentially hydrolyzed by S. aureus lipases for incorporation, we incubated individual serum 42 lipid classes with S. aureus and found that cholesteryl esters (CEs) and triglycerides (TGs) are 43 the major donors of the incorporated fatty acids. Further experiments using purified Geh lipase 44 confirmed CEs and TGs being the substrates of this enzyme. Thus, growth in the presence of 45 serum altered the nature of the cell surface with implications for interactions with the host. 46 Page 3 of 38 IMPORTANCE 47Comprehensive lipidomics of S. aureus grown in the presence of human serum suggests 48 human serum lipids can associate with the cell envelope without being truly integrated into the 49 lipid membrane. However, fatty acids-derived from human serum lipids, including unsaturated 50 fatty acids, can be incorporated into lipid classes that can be biosynthesized by S. aureus itself. 51Cholesteryl esters and triglycerides are found to be the major source of incorporated fatty acids 52 upon hydrolysis by lipases. These findings have significant implications for the nature of the S. 53 aureus cell surface when grown in vivo. Changes in phospholipid and glycolipid abundances and 54 fatty acid composition could affect membrane biophysics and function and the activity of 55 membrane-targeting antimicrobials. Finally, the association of serum lipids with the cell envelope 56 has implications for the physicochemical nature of the cell surface and its interaction with host 57 defense systems. 58 KEYWORDS 59 Lipidomics, human serum lipids, fatty acid incorporation, lipid association, cell envelope 60 structure 61 62 63 64 65 6...

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“…Host-and in vitro-derived exogenous fatty acids were demonstrated to influence bacterial membrane physiology. This resulted in altered phenotypes such as virulence, motility, antimicrobial peptide susceptibility, or biofilm formation [47][48][49][50][51][52]. It was proposed that exogenous polyunsaturated fatty acids were directly incorporated into the bacterial membrane and thus to affect membrane permeability.…”

Section: Discussionmentioning

confidence: 99%

Establishment of an induced memory response in Pseudomonas aeruginosa during infection of a eukaryotic host

et al. 2019

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In a given habitat, bacterial cells often experience recurrent exposures to the same environmental stimulus. The ability to memorize the past event and to adjust current behaviors can lead to efficient adaptation to the recurring stimulus. Here we demonstrate that the versatile bacterium Pseudomonas aeruginosa adopts a virulence phenotype after serial passage in the invertebrate model host Galleria mellonella. The virulence phenotype was not linked to the acquisition of genetic variations and was sustained for several generations, despite cultivation of the ex vivo virulence-adapted P. aeruginosa cells under rich medium conditions in vitro. Transcriptional reprogramming seemed to be induced by a host-specific food source, as reprogramming was also observed upon cultivation of P. aeruginosa in rich medium supplemented with polyunsaturated long-chain fatty acids. The establishment of induced memory responses adds a time dimension and seems to fill the gap between long-term evolutionary genotypic adaptation and short-term induced individual responses. Efforts to unravel the fundamental mechanisms that underlie the carry-over effect to induce such memory responses will continue to be of importance as hysteretic behavior can serve survival of bacterial populations in changing and challenging habitats.

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Host-derived fatty acids activate type VII secretion inStaphylococcus aureus

Cited by 71 publications

References 41 publications

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

Establishment of an induced memory response in Pseudomonas aeruginosa during infection of a eukaryotic host

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