High density lipoproteins mediate in vivo protection against staphylococcal phenol-soluble modulins

Area of Science:

• Microbiology and Immunology
• Lipid Metabolism and Cardiovascular Health

Background:

• Staphylococcus aureus virulence is linked to phenol-soluble modulins (PSMs).
• PSMs activate, attract, and lyse neutrophils, contributing to infection.
• Lipoproteins, particularly high-density lipoprotein (HDL), are known to inhibit PSM functions in vitro.

Purpose of the Study:

• To investigate if lipoproteins neutralize Staphylococcus aureus PSM-associated virulence in vivo.
• To determine the role of HDL in protecting against PSM-induced pathology and infection.

Main Methods:

• Utilized LCAT and ABCA1 knockout mice, lacking high-density lipoprotein (HDL).
• Assessed PSM-induced neutrophil activation and lysis in vitro using serum from knockout mice.
• Evaluated PSM-induced peritonitis and susceptibility to Staphylococcus aureus bloodstream infections in LCAT knockout mice.
• Compared the protective effects of plasma from homozygous carriers of ABCA1 variants (low HDL) versus healthy humans against PSM functions.

Main Results:

• Serum from LCAT and ABCA1 knockout mice failed to protect against PSM-induced neutrophil activation and lysis.
• LCAT knockout mice exhibited increased peritoneal macrophage lysis and neutrophil recruitment during PSM-induced peritonitis.
• LCAT knockout mice showed increased mortality from Staphylococcus aureus bloodstream infections in a PSM-dependent manner.
• Plasma from individuals with very low HDL levels offered less protection against PSM-mediated functions compared to healthy individuals.

Conclusions:

• Lipoproteins in blood, especially HDL, play a crucial protective role against Staphylococcus aureus PSMs.
• Deficiency in HDL exacerbates PSM-induced inflammation, tissue damage, and susceptibility to S. aureus infections.
• These findings highlight HDL's importance in combating virulence factors of community-associated methicillin-resistant S. aureus (CA-MRSA).