A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae

The Journal of Immunology : Official Journal of the American Association of Immunologists
Jutamas ShaughnessySanjay Ram

Abstract

Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need to develop novel therapies against gonorrhea. Many pathogens, including N. gonorrhoeae, bind the complement inhibitor factor H (FH) to evade complement-dependent killing. Sialylation of gonococcal lipooligosaccharide, as occurs in vivo, augments binding of human FH through its domains 18-20 (FH18-20). We explored the use of fusing FH18-20 with IgG Fc (FH18-20/Fc) to create a novel anti-infective immunotherapeutic. FH18-20 also binds to select host glycosaminoglycans to limit unwanted complement activation on host cells. To identify mutation(s) in FH18-20 that eliminated complement activation on host cells, yet maintained binding to N. gonorrhoeae, we created four mutations in domains 19 or 20 described in atypical hemolytic uremic syndrome that prevented binding of mutated fH to human erythrocytes. One of the mutant proteins (D to G at position 1119 in domain 19; FHD1119G/Fc) facilitated complement-dependent killing of gonococci similar to unmodified FH18-20/Fc but, unlike FH18-20/Fc, did not lyse human erythrocytes. FHD1119G/Fc bound to all (100%) ...Continue Reading

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Citations

Nov 1, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anna M BlomDavid Ermert
Sep 30, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jutamas ShaughnessySanjay Ram
Apr 1, 2018·Biological Chemistry·Michelle Galeas-PenaDerek Pociask
May 18, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Srinjoy ChakrabortiSanjay Ram
Sep 29, 2020·Frontiers in Immunology·Maisem LaabeiAnna M Blom
Dec 13, 2016·Cellular and Molecular Life Sciences : CMLS·Raffaella ParenteAnthony J Day
Jan 27, 2021·Antibiotics·Katherine Y L LimCharlene M Kahler
Mar 16, 2021·Frontiers in Immunology·Sara R MooreViviana P Ferreira
Oct 1, 2018·Journal of Innate Immunity·Maisem Laabei, David Ermert

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