Deciphering how PAMP manipulation prevents neutrophils from casting NETs in infection 2821

Abstract Description Production of phagosomal reactive oxygen species (ROS) drives neutrophil extracellular trap release (NETosis); however, ROS is a universal antimicrobial response, yet only a fraction of neutrophils undergoes NETosis. This indicates additional processes inherent to neutrophil or microbial functions dictating whether a neutrophil undergoes NETosis. Herein, we leverage Staphylococcus aureus as a biologically relevant inducer of NET release and identify staphylococcal secreted lipase, glycerol ester hydrolase (GEH), as a suppressor of NETosis. GEH has been shown to support S. aureus survival in the host by inactivation of S. aureus lipoproteins, a major pathogen-associated molecular pattern, and suppressing TLR2-associated immune responses in macrophages. We identify a similar role for GEH in neutrophils where GEH dampens TLR2 activation and NETosis. While S. aureus can synthesize saturated fatty acids (FAs), it cannot make unsaturated FAs but can incorporate them from exogenous sources. Similarly, GEH dampens NETosis in response to staphylococcal lipoproteins containing saturated FAs but supplementation of unsaturated FAs results in S. aureus generating lipoproteins that are poor substrates for GEH and heightens NETosis. These findings provide insight into the impacts of obesity and diet on innate immunity and imply that diets rich in healthier unsaturated FAs create an immunological environment that is less permissive for staphylococcal infection. Funding Sources UTK startup funds NIH 1R35GM154838 UT Human Health and Wellness Research Development Program Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)