Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the...

Area of Science:

• Immunology
• Microbiology
• Drug Discovery

Background:

• Multidrug-resistant pathogens pose a significant global health threat, necessitating novel therapeutic strategies.
• The complement system is crucial for innate immunity, but pathogens like Neisseria gonorrhoeae and Neisseria meningitidis evade it using host-mimicking glycans, such as N-acetylneuraminic acid (Neu5Ac).
• Neu5Ac inhibits complement activation by enhancing the binding of complement inhibitor Factor H (FH) to microbial surfaces.

Purpose of the Study:

• To develop novel therapeutic strategies to enhance complement activation against Neisseria species.
• To investigate the efficacy of engineered Factor H-Fc fusion proteins and sialic acid analogs in combating Neisseria infections.

Main Methods:

• Engineered microbial binding domains of FH (FH18-20 and FH6,7) fused to IgG Fc to create FH18-20/Fc and FH6,7/Fc.
• Utilized CMP-nonulosonate (CMP-NulO) analogs of sialic acid to prevent complement inhibition by physiologic CMP-Neu5Ac.
• Tested efficacy in vitro complement-dependent killing assays and in vivo animal models of gonorrhea and meningococcal bacteremia.

Main Results:

• FH18-20/Fc and FH6,7/Fc mediated complement-dependent killing of Neisseria species in vitro.
• Engineered FH-Fc fusion proteins demonstrated efficacy in animal models of gonorrhea and meningococcal bacteremia.
• CMP-NulO analogs incorporated into lipooligosaccharides (LOS) attenuated gonococcal infection in mice by preventing complement inhibition.

Conclusions:

• Targeting complement activation on microbial surfaces represents a promising strategy against antimicrobial-resistant organisms.
• Engineered Factor H fragments and sialic acid analogs are potential therapeutic candidates for treating Neisseria infections.
• Further safety studies are required before clinical application.