TLR-7 activation enhances IL-22-mediated colonization resistance against vancomycin-resistant enterococcus

Area of Science:

• Microbiology
• Immunology
• Infectious Diseases

Background:

• Antibiotics disrupt gut microbiota, impairing colonization resistance against pathogens.
• Vancomycin-resistant Enterococcus faecium (VRE) exploits this vulnerability, causing severe hospital infections.
• Viral infections can enhance resistance to bacterial pathogens through poorly understood mechanisms.

Purpose of the Study:

• To investigate if innate antiviral immune stimulation can restore colonization resistance against VRE.
• To identify mechanisms by which TLR-7 agonists impact VRE colonization.

Main Methods:

• Mice treated with antibiotics to induce loss of colonization resistance.
• Infection with VRE and monitoring of bacterial density.
• Administration of Resiquimod (R848), a TLR-7 ligand.
• Analysis of immune cell populations, cytokine expression (IL-23, IL-22), and antimicrobial peptide Reg3γ.

Main Results:

• Murine norovirus infection reduced VRE density in antibiotic-treated mice.
• Resiquimod (R848) administration restored Reg3γ expression and colonization resistance against VRE.
• Oral R848 activated TLR-7 on dendritic cells, leading to IL-23 and IL-22 production by innate lymphoid cells.

Conclusions:

• Stimulating innate antiviral immunity via TLR-7 activation can restore gut colonization resistance.
• An orally bioavailable TLR-7 ligand effectively combats antibiotic-resistant bacterial pathogens like VRE.