Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus

Area of Science:

• Immunology
• Microbiology
• Molecular Biology

Background:

• Group B Streptococcus (GBS) is a leading cause of neonatal sepsis and meningitis.
• GBS potently activates inflammatory macrophage genes via myeloid differentiation antigen 88 (MyD88).
• The precise downstream signaling events following MyD88 activation in response to GBS remain incompletely understood.

Purpose of the Study:

• To elucidate the specific adapter proteins and signaling pathways involved in the macrophage response to GBS.
• To determine the roles of various Toll-like receptor (TLR) adapter proteins and downstream signaling molecules in GBS-induced inflammation.

Main Methods:

• Investigated the role of MyD88, MAL/TIRAP, TRIF, and TRAM in mediating GBS-induced cytokine and chemokine responses.
• Analyzed GBS-induced phosphorylation of mitogen-activated protein kinase p38 and its downstream targets, including AP-1, Egr-1, NF-kappaB, and Elk-1.
• Utilized macrophages from Elk-1-deficient mice to assess the necessity of Elk-1 in GBS and TLR agonist responses.

Main Results:

• MyD88, but not MAL/TIRAP, TRIF, or TRAM, was essential for GBS-induced TNF, IL-6, and RANTES responses.
• GBS-induced p38 phosphorylation activated AP-1 and Egr-1, but not NF-kappaB.
• Elk-1 phosphorylation by p38 was observed, but Elk-1 was dispensable for GBS-induced TNF production and responses to TLR2/TLR4 agonists in macrophages.

Conclusions:

• MyD88 is the essential adapter protein mediating GBS-induced inflammatory cytokine responses.
• The p38/Egr-1 pathway is critical for GBS-induced macrophage activation.
• Elk-1 is not essential for the inflammatory cytokine response to GBS organisms in macrophages, contrary to in vitro findings.