Title

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

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology; Department of Medicine, Division of Preventive and Behavioral Medicine

Publication Date

2016-02-15

Document Type

Article

Disciplines

Bacterial Infections and Mycoses | Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease

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%) of 15 sialylated clinical N. gonorrhoeae isolates tested (including three contemporary ceftriaxone-resistant strains), mediated complement-dependent killing of 10 of 15 (67%) strains, and enhanced C3 deposition ( > /=10-fold above baseline levels) on each of the five isolates not directly killed by complement. FHD1119G/Fc facilitated opsonophagocytic killing of a serum-resistant strain by human polymorphonuclear neutrophils. FHD1119G/Fc administered intravaginally significantly reduced the duration and burden of gonococcal infection in the mouse vaginal colonization model. FHD1119G/Fc represents a novel immunotherapeutic against multidrug-resistant N. gonorrhoeae.

Keywords

complement, Neisseria gonorrhoeae, treatment, factor H, immunotherapy, Fc fusion protein

DOI of Published Version

10.4049/jimmunol.1500292

Source

J Immunol. 2016 Feb 15;196(4):1732-40. doi: 10.4049/jimmunol.1500292. Epub 2016 Jan 15. Link to article on publisher's site

Journal/Book/Conference Title

Journal of immunology (Baltimore, Md. : 1950)

Related Resources

Link to Article in PubMed

PubMed ID

26773149

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