Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]

Publication Date:
2018-10-23
Publisher:
The American Association of Immunologists (AAI)
Print ISSN:
0022-1767
Electronic ISSN:
1550-6606
Topics:
Medicine
Published by:
http://www.aai.org/
_version_ 1836399071924846594
autor Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
beschreibung 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.
citation_standardnr 6347310
datenlieferant ipn_articles
feed_id 333
feed_publisher The American Association of Immunologists (AAI)
feed_publisher_url http://www.aai.org/
insertion_date 2018-10-23
journaleissn 1550-6606
journalissn 0022-1767
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association of Immunologists (AAI)
quelle Journal of Immunology
relation http://www.jimmunol.org/cgi/content/short/201/9/2700?rss=1
search_space articles
shingle_author_1 Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
shingle_author_2 Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
shingle_author_3 Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
shingle_author_4 Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
shingle_catch_all_1 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
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.
Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_catch_all_2 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
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.
Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_catch_all_3 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
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.
Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_catch_all_4 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
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.
Shaughnessy, J., Lewis, L. A., Zheng, B., Carr, C., Bass, I., Gulati, S., De; Oliveira, R. B., Gose, S., Reed, G. W., Botto, M., Rice, P. A., Ram, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_title_1 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
shingle_title_2 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
shingle_title_3 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
shingle_title_4 Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
timestamp 2025-06-30T23:37:09.516Z
titel Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
titel_suche Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]
topic WW-YZ
uid ipn_articles_6347310