Branched chain fatty acid synthesis drives tissue-specific innate immune response and  infection dynamics of  Staphylococcus aureus

Abstract

Fatty acid-derived acyl chains of phospholipids and lipoproteins are central to bacterial membrane fluidity and lipoprotein function. Though it can incorporate exogenous unsaturated fatty acids (UFA), Staphylococcus aureus synthesizes branched chain fatty acids (BCFA), not UFA, to modulate or increase membrane fluidity. However, both endogenous BCFA and exogenous UFA can be attached to bacterial lipoproteins. Furthermore, S. aureus membrane lipid content varies based upon the amount of exogenous lipid in the environment. Thus far, the relevance of acyl chain diversity within the S. aureus cell envelope is limited to the observation that attachment of UFA to lipoproteins enhances cytokine secretion by cell lines in a TLR2-dependent manner. Here, we leveraged a BCFA auxotroph of S. aureus and determined that driving UFA incorporation disrupted infection dynamics and increased cytokine production in the liver during systemic infection of mice. In contrast, infection of TLR2-deficient mice restored inflammatory cytokines and bacterial burden to wildtype levels, linking the shift in acyl chain composition toward UFA to detrimental immune activation in vivo. In in vitro studies, bacterial lipoproteins isolated from UFA-supplemented cultures were resistant to lipase-mediated ester hydrolysis and exhibited heightened TLR2-dependent innate cell activation, whereas lipoproteins with BCFA esters were completely inactivated after lipase treatment. These results suggest that de novo synthesis of BCFA reduces lipoprotein-mediated TLR2 activation and improves lipase-mediated hydrolysis making it an important determinant of innate immunity. Overall, this study highlights the potential relevance of cell envelope acyl chain repertoire in infection dynamics of bacterial pathogens.

Volatile metabolites differentiate air–liquid interface cultures after infection with Staphylococcus aureus

“…Fatty acids are also found to control cell membrane integrity and biofilm dispersion in S. aureus. [27][28][29][30] Aromatic volatiles were decreased under normal cell growth suggesting uptake from the media and have been reported in previous studies investigating A549 cells. 26,31 Several methylated pyridine compounds were increased in infected cells compared to uninfected cells.…”

A short-chain acyl-CoA synthetase that supports branched-chain fatty acid synthesis in Staphylococcus aureus

“…CidC, a pyruvate:menaquinone oxidoreductase ( 19 ) is another candidate but this enzyme uses oxygen and also requires the activation of the resulting short-chain acid. Finally, it is known that extracellular short-chain acids, like 2-methylbutyrate (aC5), are incorporated into BCFA in Bacillus subtilis and S. aureus ( 20 , 21 , 22 , 23 ), suggesting the presence of an activation pathway to form short-chain acyl-CoAs. L. monocytogenes has a butyrate kinase/phosphotransbutyrylase (Buk/Ptb) system that is responsible for the two-step activation of extracellular aC5 to aC5-CoA ( 24 , 25 ).…”

Immunometabolites Drive Bacterial Adaptation to the Airway

“…Microbial metabolism has often been neglected in these studies, with many research groups instead turning to the use of LPS as a standard proxy for bacterial stimulation. There is increasing evidence, however, that microbial metabolic flexibility is not only critical for bacterial persistence during infection, but also in shaping the host immunometabolic response (68)(69)(70). Importantly, this metabolic interplay between host and pathogen varies by microbe and infection site.…”