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@article{Shaughnessy:2018:10.4049/jimmunol.1701666,
author = {Shaughnessy, J and Lewis, LA and Zheng, B and Carr, C and Bass, I and Gulati, S and DeOliveira, RB and Gose, S and Reed, GW and Botto, M and Rice, PA and Ram, S},
doi = {10.4049/jimmunol.1701666},
journal = {Journal of Immunology},
pages = {2700--2709},
title = {Human factor H domains 6 and 7 fused to IgG1 Fc are immunotherapeutic against neisseria gonorrhoeae},
url = {http://dx.doi.org/10.4049/jimmunol.1701666},
volume = {201},
year = {2018}
}

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TY  - JOUR
AB  - Novel therapeutics against multidrug-resistant Neisseria gonorrhoeae are urgently needed. Gonococcal lipooligosaccharide often expresses lacto-N-neotetraose (LNnT), which becomes sialylated in vivo, enhancing factor H (FH) binding and contributing to the organism’s ability to resist killing by complement. We previously showed that FH domains 18–20 (with a D-to-G mutation at position 1119 in domain 19) fused to Fc (FHD1119G/Fc) displayed complement-dependent bactericidal activity in vitro and attenuated gonococcal vaginal colonization of mice. Gonococcal lipooligosaccharide phase variation can result in loss of LNnT expression. Loss of sialylated LNnT, although associated with a considerable fitness cost, could decrease efficacy of FHD1119G/Fc. Similar to N. meningitidis, gonococci also bind FH domains 6 and 7 through Neisserial surface protein A (NspA). In this study, we show that a fusion protein comprising FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/Fc) bound to 15 wild-type antimicrobial resistant isolates of N. gonorrhoeae and to each of six lgtA gonococcal deletion mutants. FH6,7/Fc mediated complement-dependent killing of 8 of the 15 wild-type gonococcal isolates and effectively reduced the duration and burden of vaginal colonization of three gonococcal strains tested in wild-type mice, including two strains that resisted complement-dependent killing but on which FH6,7/Fc enhanced C3 deposition. FH/Fc lost efficacy when Fc was mutated to abrogate C1q binding and in C1q−/− mice, highlighting the requirement of the classical pathway for its activity. Targeting gonococci with FH6,7/Fc provides an additional immunotherapeutic approach against multidrug-resistant gonorrhea.
AU  - Shaughnessy,J
AU  - Lewis,LA
AU  - Zheng,B
AU  - Carr,C
AU  - Bass,I
AU  - Gulati,S
AU  - DeOliveira,RB
AU  - Gose,S
AU  - Reed,GW
AU  - Botto,M
AU  - Rice,PA
AU  - Ram,S
DO  - 10.4049/jimmunol.1701666
EP  - 2709
PY  - 2018///
SN  - 1550-6606
SP  - 2700
TI  - Human factor H domains 6 and 7 fused to IgG1 Fc are immunotherapeutic against neisseria gonorrhoeae
T2  - Journal of Immunology
UR  - http://dx.doi.org/10.4049/jimmunol.1701666
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000447907700016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
VL  - 201
ER  -

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