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C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections

Bettoni, Serena LU orcid ; Shaughnessy, Jutamas ; Maziarz, Karolina LU orcid ; Ermert, David LU ; Gulati, Sunita ; Zheng, Bo ; Mörgelin, Matthias LU ; Jacobsson, Susanne ; Riesbeck, Kristian LU orcid and Unemo, Magnus , et al. (2019) In JCI Insight 4(23).
Abstract

Gonorrhea is a sexually transmitted infection with 87 million new cases per year globally. Increasing antibiotic resistance has severely limited treatment options. A mechanism that Neisseria gonorrhoeae uses to evade complement attack is binding of the complement inhibitor C4b-binding protein (C4BP). We screened 107 porin B1a (PorB1a) and 83 PorB1b clinical isolates randomly selected from a Swedish strain collection over the last 10 years and noted that 96/107 (89.7%) PorB1a and 16/83 (19.3%) PorB1b bound C4BP; C4BP binding substantially correlated with the ability to evade complement-dependent killing (r = 0.78). We designed 2 chimeric proteins that fused C4BP domains to the backbone of IgG or IgM (C4BP-IgG; C4BP-IgM) with the aim of... (More)

Gonorrhea is a sexually transmitted infection with 87 million new cases per year globally. Increasing antibiotic resistance has severely limited treatment options. A mechanism that Neisseria gonorrhoeae uses to evade complement attack is binding of the complement inhibitor C4b-binding protein (C4BP). We screened 107 porin B1a (PorB1a) and 83 PorB1b clinical isolates randomly selected from a Swedish strain collection over the last 10 years and noted that 96/107 (89.7%) PorB1a and 16/83 (19.3%) PorB1b bound C4BP; C4BP binding substantially correlated with the ability to evade complement-dependent killing (r = 0.78). We designed 2 chimeric proteins that fused C4BP domains to the backbone of IgG or IgM (C4BP-IgG; C4BP-IgM) with the aim of enhancing complement activation and killing of gonococci. Both proteins bound gonococci (KD C4BP-IgM = 2.4 nM; KD C4BP-IgG 980.7 nM), but only hexameric C4BP-IgM efficiently outcompeted heptameric C4BP from the bacterial surface, resulting in enhanced complement deposition and bacterial killing. Furthermore, C4BP-IgM substantially attenuated the duration and burden of colonization of 2 C4BP-binding gonococcal isolates but not a non-C4BP-binding strain in a mouse vaginal colonization model using human factor H/C4BP-transgenic mice. Our preclinical data present C4BP-IgM as an adjunct to conventional antimicrobials for the treatment of gonorrhea.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
4
issue
23
article number
e131886
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85077586369
  • pmid:31661468
ISSN
2379-3708
DOI
10.1172/jci.insight.131886
language
English
LU publication?
yes
id
61674b80-3f64-4f3c-bd63-3d195c96752d
date added to LUP
2020-01-27 17:23:26
date last changed
2024-04-17 03:10:56
@article{61674b80-3f64-4f3c-bd63-3d195c96752d,
  abstract     = {{<p>Gonorrhea is a sexually transmitted infection with 87 million new cases per year globally. Increasing antibiotic resistance has severely limited treatment options. A mechanism that Neisseria gonorrhoeae uses to evade complement attack is binding of the complement inhibitor C4b-binding protein (C4BP). We screened 107 porin B1a (PorB1a) and 83 PorB1b clinical isolates randomly selected from a Swedish strain collection over the last 10 years and noted that 96/107 (89.7%) PorB1a and 16/83 (19.3%) PorB1b bound C4BP; C4BP binding substantially correlated with the ability to evade complement-dependent killing (r = 0.78). We designed 2 chimeric proteins that fused C4BP domains to the backbone of IgG or IgM (C4BP-IgG; C4BP-IgM) with the aim of enhancing complement activation and killing of gonococci. Both proteins bound gonococci (KD C4BP-IgM = 2.4 nM; KD C4BP-IgG 980.7 nM), but only hexameric C4BP-IgM efficiently outcompeted heptameric C4BP from the bacterial surface, resulting in enhanced complement deposition and bacterial killing. Furthermore, C4BP-IgM substantially attenuated the duration and burden of colonization of 2 C4BP-binding gonococcal isolates but not a non-C4BP-binding strain in a mouse vaginal colonization model using human factor H/C4BP-transgenic mice. Our preclinical data present C4BP-IgM as an adjunct to conventional antimicrobials for the treatment of gonorrhea.</p>}},
  author       = {{Bettoni, Serena and Shaughnessy, Jutamas and Maziarz, Karolina and Ermert, David and Gulati, Sunita and Zheng, Bo and Mörgelin, Matthias and Jacobsson, Susanne and Riesbeck, Kristian and Unemo, Magnus and Ram, Sanjay and Blom, Anna M.}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{23}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.131886}},
  doi          = {{10.1172/jci.insight.131886}},
  volume       = {{4}},
  year         = {{2019}},
}