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Low-dose recombinant properdin provides substantial protection against Streptococcus pneumoniae and Neisseria meningitidis infection

journal contribution
posted on 03.09.2015, 08:15 by Youssif Mohammed Ali, Azam Hayat, Bayad Mawlood Saeed, Kashif S. Haleem, Saleh Alshamrani, Hany I. Kenawy, V. P. Ferreira, G. Saggu, Anna Buchberger, P. J. Lachmann, Robert B. Sim, D. Goundis, Peter W. Andrew, Nicholas J. Lynch, Wilhelm J. Schwaeble
Modern medicine has established three central antimicrobial therapeutic concepts: vaccination, antibiotics, and, recently, the use of active immunotherapy to enhance the immune response toward specific pathogens. The efficacy of vaccination and antibiotics is limited by the emergence of new pathogen strains and the increased incidence of antibiotic resistance. To date, immunotherapy development has focused mainly on cytokines. Here we report the successful therapeutic application of a complement component, a recombinant form of properdin (P[subscript: n]), with significantly higher activity than native properdin, which promotes complement activation via the alternative pathway, affording protection against N. menigitidis and S. pneumoniae. In a mouse model of infection, we challenged C57BL/6 WT mice with N. menigitidis B-MC58 6 h after i.p. administration of P[subscript: n] (100 µg/mouse) or buffer alone. Twelve hours later, all control mice showed clear symptoms of infectious disease while the P[subscript: n] treated group looked healthy. After 16 hours, all control mice developed sepsis and had to be culled, while only 10% of P[subscript: n] treated mice presented with sepsis and recoverable levels of live Meningococci. In a parallel experiment, mice were challenged intranasally with a lethal dose of S. pneumoniae D39. Mice that received a single i.p. dose of P[subscript: n] at the time of infection showed no signs of bacteremia at 12 h postinfection and had prolonged survival times compared with the saline-treated control group (P < 0.0001). Our findings show a significant therapeutic benefit of P[subscript: n] administration and suggest that its antimicrobial activity could open new avenues for fighting infections caused by multidrug-resistant neisserial or streptococcal strains.

History

Citation

Proceedings of the National Academy of Sciences U S A, 2014, 111 (14), pp. 5301-5306

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Published in

Proceedings of the National Academy of Sciences U S A

Publisher

National Academy of Sciences

eissn

1091-6490

Acceptance date

25/02/2014

Copyright date

2015

Publisher version

http://www.pnas.org/content/111/14/5301?tab=author-info

Notes

This article contains supporting information online at http://www.pnas.org/content/suppl/2014/03/24/1401011111.DCSupplemental

Language

en