The Commensal Neisseria musculi Modulates Host Innate Immunity To Promote Oral Colonization

Area of Science:

• Microbiology
• Immunology
• Genetics

Background:

• Neisseria musculi, an oral bacterium, exhibits differential colonization in mouse strains.
• C57BL/6J (B6) mice show weak colonization, while CAST/EiJ (CAST) mice are readily colonized.

Purpose of the Study:

• To investigate host response differences between CAST and B6 mice to understand N. musculi colonization mechanisms.
• To identify the role of innate immunity, specifically Toll-like receptor 4 (TLR4) and Interleukin-6 (IL-6), in N. musculi colonization.

Main Methods:

• In vivo and in vitro stimulation of splenocytes and macrophages from B6 and CAST mice.
• Analysis of gene knockouts (RAG-1, MyD88, TLR4) and IL-6 receptor deficient mice.
• Sequence analysis of TLR4 in CAST mice and genetic crosses.

Main Results:

• CAST mice exhibited a blunted inflammatory response with lower IL-6 production compared to B6 mice.
• MyD88 and TLR4 knockout mice were readily colonized, similar to CAST mice, indicating their importance in innate immunity.
• A unique TLR4 mutation was found in CAST mice, but it was not sufficient to confer susceptibility alone.
• UV-inactivated N. musculi induced high IL-6 levels, suggesting active bacterial suppression of IL-6.
• Mice deficient in the IL-6 receptor were efficiently colonized, highlighting IL-6's critical role in preventing colonization.

Conclusions:

• Host IL-6 production is a critical factor determining N. musculi colonization susceptibility.
• N. musculi actively suppresses host IL-6 production to facilitate colonization.
• Innate immune pathways involving TLR4 and MyD88 are essential for preventing N. musculi colonization in susceptible mouse strains.