Lipoproteins in Staphylococcus aureus mediate inflammation by TLR2 and iron-dependent growth in vivo

Area of Science:

• Immunology
• Microbiology
• Molecular Biology

Background:

• Lipoproteins (Lpp) are key components of the Staphylococcus aureus cell envelope, acting as ligands for Toll-like receptor 2 (TLR2) and signaling through the MyD88 adaptor protein.
• The precise role of Lpp in TLR2-MyD88 activation during systemic S. aureus infection and its impact on bacterial survival and host response remain largely unexplored.

Purpose of the Study:

• To investigate the benefits and costs associated with lipoprotein maturation in Staphylococcus aureus during systemic infection.
• To elucidate the contribution of Lpp to TLR2-MyD88 signaling, pathogenesis, and bacterial iron acquisition in vivo.

Main Methods:

• Utilized a Staphylococcus aureus strain deficient in prolipoprotein diacylglyceryl transferase (Deltalgt) to study Lpp maturation.
• Assessed cytokine induction in murine peritoneal macrophages stimulated with Lpp.
• Evaluated the role of Lpp in sepsis pathogenesis in C57BL/6 mice and MyD88-deficient mice, examining bacterial load, inflammation, and iron metabolism.

Main Results:

• S. aureus Lpp induced robust TLR2-MyD88-dependent cytokine production and contributed to sepsis pathogenesis, characterized by inflammation and high bacterial burdens.
• In the absence of MyD88-mediated inflammation, Lpp facilitated bacterial clearance from the liver but conferred a significant growth advantage, linked to enhanced iron uptake and storage.
• The Lpp-mediated growth advantage was observed in iron-restricted conditions in MyD88(-/-) mice, while host iron overload influenced bacterial growth differently in immunocompetent versus MyD88(-/-) mice.

Conclusions:

• Lipid anchoring of lipoproteins provides an evolutionary advantage for S. aureus by improving iron acquisition, crucial for survival during infection.
• While Lpp triggers inflammatory responses via TLR2-MyD88, its role in iron metabolism is critical for bacterial fitness, particularly under conditions of limited host immunity.