Role of Complement in Host Defense against Pneumococcal Otitis Media

Sabharwal, Vishakha; Ram, Sanjay; Figueira, Marisol; Pelton, Stephen I.

doi:10.1128/iai.01148-08

Cited by 32 publications

(41 citation statements)

References 52 publications

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“…This suggests that differences between S. pneumoniae strains in virulence in mouse models are strongly influenced by noncapsular genetic variation, so that the TIGR4 genetic background of the TIGR4(Ϫ)ϩ7F and ϩ23F strains allows these strains to be virulent in mice whereas clinical isolates that express the same serotype but have a different genetic background are not. This is supported by other data showing marked differences in virulence in mice between different S. pneumoniae strains with the same capsular serotype (9,32). Hence, although the capsular serotype can modulate virulence in mice, there is also a considerable, perhaps dominant, effect of noncapsular genetic variation.…”

Section: Discussionsupporting

confidence: 73%

Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

et al. 2010

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Streptococcus pneumoniae strains vary considerably in the ability to cause invasive disease in humans, and this is partially associated with the capsular serotype. The S. pneumoniae capsule inhibits complement-and phagocyte-mediated immunity, and differences between serotypes in these effects on host immunity may cause some of the variation in virulence between strains. However, the considerable genetic differences between S. pneumoniae strains independent of the capsular serotype prevent an unambiguous assessment of the effects of the capsular serotype on immunity using clinical isolates. We have therefore used capsular serotype-switched TIGR4 mutant strains to investigate the effects of the capsular serotype on S. pneumoniae interactions with complement. Flow cytometry assays demonstrated large differences in C3b/iC3b deposition on opaque-phase variants of TIGR4(؊)؉4, ؉6A, ؉7F, and ؉23F strains even though the thicknesses of the capsule layers were similar. There was increased C3b/iC3b deposition on TIGR4(؊)؉6A and ؉23F strains compared to ؉7F and ؉4 strains, and these differences persisted even in serum depleted of immunoglobulin G. Neutrophil phagocytosis of the TIGR4(؊)؉6A and ؉23F strains was also increased, but only in the presence of complement, showing that the effects of the capsular serotype on C3b/iC3b deposition are functionally significant. In addition, the virulence of the TIGR4(؊)؉6A and ؉23F strains was reduced in a mouse model of sepsis. These data demonstrate that resistance to complement-mediated immunity can vary with the capsular serotype independently of antibody and of other genetic differences between strains. This might be one mechanism by which the capsular serotype can affect the relative invasiveness of different S. pneumoniae strains.

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Section: Discussionsupporting

confidence: 73%

Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

et al. 2010

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“…The complement system provides the major innate immune defense mechanism against pneumococcal infections (5,12,23). It is activated in response to infection by the classical, alternative, and lectin pathways.…”

mentioning

confidence: 99%

Essential Role of Factor B of the Alternative Complement Pathway in Complement Activation and Opsonophagocytosis during Acute Pneumococcal Otitis Media in Mice

Stahl

et al. 2011

Infect Immun

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We recently reported that the complement system plays a pivotal role in innate immune defense against Streptococcus pneumoniae during acute otitis media (OM) in mice. The current study was designed to determine which of the complement pathways are activated during acute pneumococcal OM and whether components of complement are expressed in the middle ear epithelium. Gene expression was determined by quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. We found that S. pneumoniae induced increased gene expression of factor B of the alternative complement pathway and C3 in mouse middle ear epithelium. Activation of factor B and C3 in the middle ear lavage fluids was significantly greater than in simultaneously obtained serum samples as determined by Western blotting. Using mice deficient in complement C1qa, factor B, and factor B/C2, we found that complement C3 activation and opsonophagocytosis of S. pneumoniae were greatly attenuated in factor B-and factor B/C2-deficient mice. These findings support the concept that local complement activation is an important host innate immune response and that activation of the alternative complement pathway represents one of the innate immune defense mechanisms against pneumococcal infection during the early stage of acute OM.

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“…An experimental chinchilla model of experimental otitis media (EOM) was used (12). Adult chinchillas (Chinchilla lanigera) were obtained from Ryerson's Chinchilla Ranch (Plymouth, OH).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Solithromycin (CEM-101) for Experimental Otitis Media Caused by Nontypeable Haemophilus influenzae and Streptococcus pneumoniae

Figueira

Fernandes

Pelton

2016

Antimicrob Agents Chemother

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b Solithromycin (CEM-101) is a "fourth-generation" macrolide, as it has three binding site and is acid stable. The three binding sites confer activity against bacteria resistant to the older macrolides and ketolides, including multidrug-resistant Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi). The objective of this study was to evaluate solithromycin pharmacokinetics (PK), middle ear fluid (MEF) concentrations, and microbiologic efficacy in a chinchilla model of experimental otitis media (EOM) due to strains of S. pneumoniae or NTHi. Plasma PK (maximum concentration of drug in serum [C max ] and area under the concentration-time curve from 0 to 24 h [AUC 0 -24 ]) and middle ear fluid (MEF) concentrations were determined. Isolates with specified antimicrobial susceptibility patterns were inoculated directly into the middle ear (ME). Plasma and MEF were collected for PK and MEF cultures performed to determine efficacy. Solithromycin administered at 150 mg/kg of body weight/day resulted in C max and AUC 0 -24 values of 2.2 g/ml and 27.4 g · h/ml in plasma and 1.7 g/ml and 28.2 g · h/ml in extracellular MEF on day 1. By day 3, C max and AUC 0 -24 values had increased to 4.5 g/ml and 54 g · h/ml in plasma and 4.8 g/ml and 98.6 g · h/ml in extracellular MEF. For NTHi EOM, three isolates with MIC/minimal bactericidal concentration (MBC) ratios of 0.5/1 g/ml (isolate BCH1), 2/2 g/ml (isolate BMC1247C), and 4/4 g/ml (isolate BMC1213C) were selected. The MEF of >85% of animals infected with BCH1 and BMC1247C was sterilized. For NTHi BMC1213, >85% of MEF cultures remained positive. For S. pneumoniae EOM, 3 isolates with MIC/MBC ratios of 0.06/0.125 g/ml (S. pneumoniae 331), 0.125/1 g/ml (S. pneumoniae CP-645 [MLS B phenotype]), and 0.5/2 g/ml (CP-712 [mefA subclass mefA resistance]) were selected. Solithromycin sterilized MEF in 100% of animals infected with S. pneumoniae 331 and S. pneumoniae CP-645. ME infection persisted in 60% of animals infected with CP-712. In a model of EOM, solithromycin sterilized MEF in >85% of animals challenged with NTHi with an MIC of <2 g/ml and 100% of ME infected with S. pneumoniae with an MIC of <0.125 g/ml. Randomized clinical trials continue to demonstrate that antimicrobial therapy reduces the time to resolution of symptoms (i.e., persistent otoscopic signs) of acute otitis media (AOM) in children 6 to 23 months of age (1-3). However, selection of effective antimicrobial therapy is complicated by emergence of resistance to ␤-lactam and macrolides among isolates of Streptococcus pneumoniae and intrinsic resistance to macrolides among isolates of nontypeable Haemophilus influenzae (NTHi). Thus, limited choices of antimicrobials that achieve effective sterilization of the middle ear contents are available, especially for children unable to tolerate ␤-lactams.Solithromycin (CEM-101) is a "fourth-generation" macrolide and the first fluoroketolide with in vitro antibacterial activity against multidrug-resistant Streptococcus pneumoniae, including erythromycin-resistant...

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Role of Complement in Host Defense against Pneumococcal Otitis Media

Cited by 32 publications

References 52 publications

Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

Essential Role of Factor B of the Alternative Complement Pathway in Complement Activation and Opsonophagocytosis during Acute Pneumococcal Otitis Media in Mice

Efficacy of Solithromycin (CEM-101) for Experimental Otitis Media Caused by Nontypeable Haemophilus influenzae and Streptococcus pneumoniae

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