Human L-ficolin, a Recognition Molecule of the Lectin Activation Pathway of Complement, Activates Complement by Binding to Pneumolysin, the Major Toxin of Streptococcus pneumoniae

Ali, Youssif M.; Kenawy, Hany I.; Muhammad, Adnan Yar; Sim, Robert B.; Andrew, Peter W.; Schwaeble, Wilhelm

doi:10.1371/journal.pone.0082583

Cited by 21 publications

(15 citation statements)

References 29 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was seen regardless whether P n was given at 6 h before infection or at 3 h or 6 h after infection. Thus, we hypothesize that complement activation also may occur on the surface of the released bacterial endotoxins, neutralizing the detrimental effects of endotoxin by C3 deposition and clearance although complement-receptor bearing host cells (42). In patients with inherited properdin deficiencies, who are known to be at high risk for frequent and severe infections with N. meningitidis and S. pneumoniae (12,23,43,44), the prophylactic administration of Pn might alleviate the predisposition to recurrent and severe infections.…”

Section: Discussionmentioning

confidence: 99%

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

Ali

Hayat

Saeed

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

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 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 n (100 μg/mouse) or buffer alone. Twelve hours later, all control mice showed clear symptoms of infectious disease while the P n treated group looked healthy. After 16 hours, all control mice developed sepsis and had to be culled, while only 10% of P 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 n at the time of infection showed no signs of bacteremia at 12 h postinfection and had prolonged survival times compared with the salinetreated control group (P < 0.0001). Our findings show a significant therapeutic benefit of P n administration and suggest that its antimicrobial activity could open new avenues for fighting infections caused by multidrug-resistant neisserial or streptococcal strains.

show abstract

Section: Discussionmentioning

confidence: 99%

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

Ali

Hayat

Saeed

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The bacterial L-ficolin ligands identified so far include PGN from S. aureus (37), LTA purified from GBS, S. aureus, Bacillus subtilis, and Streptococcus pyogenes (33), capsular polysaccharides (CPS) from GBS (34), and pneumolysin, a toxin released by S. pneumoniae (38). Binding of L-ficolin to these ligands triggers activation of the lectin complement pathway and, in the case of pneumolysin, may be used by the pathogen as an immune evasion strategy by consuming complement away from the bacterial surface (38).…”

Section: Discussionmentioning

confidence: 99%

Human L-Ficolin Recognizes Phosphocholine Moieties of Pneumococcal Teichoic Acid

Vassal-Stermann

Lacroix

Gout

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

International audienceHuman L-ficolin is a soluble protein of the innate immune system able to sense pathogens through its fibrinogen (FBG) recognition domains and to trigger activation of the lectin complement pathway through associated serine proteases. L-Ficolin has been previously shown to recognize pneumococcal clinical isolates, but its ligands and especially its molecular specificity remain to be identified. Using solid-phase binding assays, serum and recombinant L-ficolins were shown to interact with serotype 2 pneumococcal strain D39 and its unencapsulated R6 derivative. Incubation of both strains with serum triggered complement activation, as measured by C4b and C3b deposition, which was decreased by using ficolin-depleted serum. Recombinant L-ficolin and its FBG-like recognition domain bound to isolated pneumococcal cell wall extracts, whereas binding to cell walls depleted of teichoic acid (TA) was decreased. Both proteins were also shown to interact with two synthetic TA compounds, each comprising part structures of the complete lipoteichoic acid molecule with two PCho residues. Competition studies and direct interaction measurements by surface plasmon resonance identified PCho as a novel L-ficolin ligand. Structural analysis of complexes of the FBG domain of L-ficolin and PCho revealed that the phosphate moiety interacts with amino acids previously shown to define an acetyl binding site. Consequently, binding of L-ficolin to immobilized acetylated BSA was inhibited by PCho and synthetic TA. Binding of serum L-ficolin to immobilized synthetic TA and PCho-conjugated BSA triggered activation of the lectin complement pathway, thus further supporting the hypothesis of L-ficolin involvement in host antipneumococcal defense

show abstract

“…71 In addition to pore formation, domain 4 also promotes activation of both the classical and lectin pathways of complement activation. 61,72 In the case of the former, immunoglobulins (Ig) of the IgM class and IgG 3 subclass bind non-specifically to Ply via their Fc regions. 72 In the case of the latter, ficolin, a 1,3-β glucan-binding lectin with acute phase reactant properties, binds specifically to Ply, triggering binding of C3b and complement activation.…”

Section: Structure and Biological Activitiesmentioning

confidence: 99%

“…61,72 In the case of the former, immunoglobulins (Ig) of the IgM class and IgG 3 subclass bind non-specifically to Ply via their Fc regions. 72 In the case of the latter, ficolin, a 1,3-β glucan-binding lectin with acute phase reactant properties, binds specifically to Ply, triggering binding of C3b and complement activation. 72 Ply-mediated complement depletion acting in concert with the anti-phagocytic polysaccharide capsule represent effective mechanisms by which the pathogen evades phagocytosis.…”

Section: Structure and Biological Activitiesmentioning

confidence: 99%

Pneumolysin as a potential therapeutic target in severe pneumococcal disease

Feldman

2017

Journal of Infection

View full text Add to dashboard Cite

Acute pulmonary and cardiac injury remain significant causes of morbidity and mortality in those afflicted with severe pneumococcal disease, with the risk for early mortality often persisting several years beyond clinical recovery. Although remaining to be firmly established in the clinical setting, a considerable body of evidence, mostly derived from murine models of experimental infection, has implicated the pneumococcal, cholesterol-binding, pore-forming toxin, pneumolysin (Ply), in the pathogenesis of lung and myocardial dysfunction. Topics covered in this review include the burden of pneumococcal disease, risk factors, virulence determinants of the pneumococcus, complications of severe disease, antibiotic and adjuvant therapies, as well as the structure of Ply and the role of the toxin in disease pathogenesis. Given the increasing recognition of the clinical potential of Ply-neutralisation strategies, the remaining sections of the review are focused on updates of the types, benefits and limitations of currently available therapies which may attenuate, directly and/or indirectly, the injurious actions of Ply. These include recently described experimental therapies such as various phytochemicals and lipids, and a second group of more conventional agents the members of which remain the subject of ongoing clinical evaluation. This latter group, which is covered more extensively, encompasses macrolides, statins, corticosteroids, and platelet-targeted therapies, particularly aspirin.

show abstract

Human L-ficolin, a Recognition Molecule of the Lectin Activation Pathway of Complement, Activates Complement by Binding to Pneumolysin, the Major Toxin of Streptococcus pneumoniae

Cited by 21 publications

References 29 publications

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

Human L-Ficolin Recognizes Phosphocholine Moieties of Pneumococcal Teichoic Acid

Pneumolysin as a potential therapeutic target in severe pneumococcal disease

Contact Info

Product

Resources

About