C4 Deficiency Is a Predisposing Factor for Streptococcus pneumoniae-Induced Autoantibody Production.

J Immunol. 2014 Oct 22. pii: 1401462. [Epub ahead of print]

C4 Deficiency Is a Predisposing Factor for Streptococcus pneumoniae-Induced Autoantibody Production.

Yammani RD1, Leyva MA1, Jennings RN1, Haas KM2.

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Abstract

Reductions in C4 levels may predispose individuals to infection with encapsulated bacteria as well as autoimmunity. In this study, we examined the role C4 has in protection against Streptococcus pneumoniae-induced autoimmunity. Mild respiratory infection with serotype 19F pneumococci selectively induced systemic anti-dsDNA IgA production in naive C4-/- mice, but not in C3-/- or wild-type mice. Systemic challenge with virulent serotype 3 pneumococci also induced anti-dsDNA IgA production in immune C4-/- mice. Remarkably, pneumococcal polysaccharide (PPS) vaccination alone induced C4-/- mice to produce increased anti-dsDNA IgA levels that were maintained in some mice for months. These effects were most pronounced in female C4-/- mice. Importantly, immunization-induced increases in anti-dsDNA IgA levels were strongly associated with increased IgA deposition in kidneys. Cross-reactivity between pneumococcal Ags and dsDNA played a partial role in the induction of anti-dsDNA IgA, but a major role for PPS-associated TLR2 agonists was also revealed. Administration of the TLR2/4 antagonist, OxPAPC, at the time of PPS immunization completely blocked the production of anti-dsDNA IgA in C4-/- mice without suppressing PPS-specific Ab production. The TLR2 agonist, Pam3CSK4, similarly induced anti-dsDNA IgA production in C4-/- mice, which OxPAPC also prevented. LPS, a TLR4 agonist, had no effect. Pam3CSK4, but not LPS, also induced dsDNA-specific IgA production by C4-/- splenic IgA+ B cells in vitro, indicating that TLR2 agonists can stimulate autoantibody production via B cell-intrinsic mechanisms. Collectively, our results show an important role for C4 in suppressing autoantibody production elicited by cross-reactive Ags and TLR2 agonists associated with S. pneumoniae.

Copyright © 2014 by The American Association of Immunologists, Inc.

PMID: 25339671 [PubMed - as supplied by publisher]

Recent advances in our understanding of Streptococcus pneumoniae infection.

F1000Prime Rep. 2014 Sep 4;6:82. doi: 10.12703/P6-82. eCollection 2014.

Recent advances in our understanding of Streptococcus pneumoniae infection.

Feldman C1, Anderson R2.

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Abstract

A number of significant challenges remain with regard to the diagnosis, treatment, and prevention of infections with Streptococcus pneumoniae (pneumococcus), which remains the most common bacterial cause of community-acquired pneumonia. Although this infection is documented to be extremely common in younger children and in older adults, the burden of pneumonia it causes is considerably underestimated, since the incidence statistics are derived largely from bacteremic infections, because they are easy to document, and yet the greater burden of pneumococcal pneumonias is non-invasive. It has been estimated that for every bacteremic pneumonia that is documented, three non-bacteremic infections occur. Management of these infections is potentially complicated by the increasing resistance of the isolates to the commonly used antibiotics. Furthermore, it is well recognized that despite advances in medical care, the mortality of bacteremic pneumococcal pneumonia has remained largely unchanged over the past 50 years and averages approximately 12%. Much recent research interest in the field of pneumococcal infections has focused on important virulence factors of the organism, on improved diagnostic and prognostication tools, on defining risk factors for death, on optimal treatment strategies involving both antibiotics and adjunctive therapies, and on disease prevention. It is hoped that through these endeavors the outlook of pneumococcal infections will be improved.

PMID: 25343039 [PubMed] PMCID: PMC4166932 

Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses.

Mucosal Immunol. 2014 Oct 29. doi: 10.1038/mi.2014.95. [Epub ahead of print]

Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses.

Wilson R1, Cohen JM2, Jose RJ1, de Vogel C3, Baxendale H4, Brown JS1.

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Abstract

Streptococcus pneumoniae is a common cause of pneumonia and infective exacerbations of chronic lung disease, yet there are few data on how adaptive immunity can specifically prevent S. pneumoniae lung infection. We have used a murine model of nasopharyngeal colonization by the serotype 19F S. pneumoniae strain EF3030 followed by lung infection to investigate whether colonization protects against subsequent lung infection and the mechanisms involved. EF3030 colonization induced systemic and local immunoglobulin G against a limited number of S. pneumoniae protein antigens rather than capsular polysaccharide. During lung infection, previously colonized mice had increased early cytokine responses and neutrophil recruitment and reduced bacterial colony-forming units in the lungs and bronchoalveolar lavage fluid compared with control mice. Colonization-induced protection was lost when experiments were repeated in B-cell- or neutrophil-deficient mice. Furthermore, the improved interleukin (IL)-17 response to infection in previously colonized mice was abolished by depletion of CD4+ cells, and prior colonization did not protect against lung infection in mice depleted of CD4+ cells or IL17. Together these data show that naturally acquired protective immunity to S. pneumoniae lung infection requires both humoral and cell-mediated immune responses, providing a template for the design of improved vaccines that can specifically prevent pneumonia or acute bronchitis.Mucosal Immunology advance online publication, 29 October 2014; doi:10.1038/mi.2014.95.

PMID: 25354319 [PubMed - as supplied by publisher]

UlaR activates the expression of the ula operon in Streptococcus pneumoniae in the presence of ascorbic acid.

Microbiology. 2014 Oct 29. pii: mic.0.083899-0. doi: 10.1099/mic.0.083899-0. [Epub ahead of print]

UlaR activates the expression of the ula operon in Streptococcus pneumoniae in the presence of ascorbic acid.

Afzal M1, Shafeeq S2, Henriques-Normark B2, Kuipers OP3.

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Abstract

In this study, the regulatory mechanism of the ula (utilization of L-ascorbic acid) operon putatively responsible for transport and utilization of ascorbic acid in Streptococcus pneumoniae D39 strain is studied. β-galactosidase assay data demonstrate that the expression of the ula operon is increased in the presence of ascorbic acid, as compared to the effects of other sugar sources, including glucose. The ula operon consists of nine genes, including a BglG-family transcriptional regulator UlaR, and is transcribed as a single transcriptional unit. We demonstrate the role of the BglG-family transcriptional regulator UlaR as a transcriptional activator of the ula operon in the presence of ascorbic acid and show that activation of the ula operon genes by UlaR is CcpA-independent. Furthermore, we predict a 16-bp regulatory site (5'-AACAGTCCGCTGTGTA-3') for UlaR in the promoter region of ulaA. Deletion of the half- or full UlaR regulatory site in the PulaA confirmed that the UlaR regulatory site present in PulaA is functional.

Copyright © 2014, the Society for General Microbiology.

KEYWORDS:

Ascorbic acid; Pneumococcus; UlaR; carbon source; ula operon

PMID: 25355938 [PubMed - as supplied by publisher]

Regional and global antimicrobial susceptibility among isolates of Streptococcus pneumoniae and Haemophilus influenzae collected as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) from 2009 to 2012 and comparison with previous years of T.E.S.T. (2004-2008).

Ann Clin Microbiol Antimicrob. 2014 Nov 7;13(1):52. [Epub ahead of print]

Regional and global antimicrobial susceptibility among isolates of Streptococcus pneumoniae and Haemophilus influenzae collected as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) from 2009 to 2012 and comparison with previous years of T.E.S.T. (2004-2008).

Tomic V, Dowzicky MJ.

Abstract

BackgroundWe report here on 14438 Streptococcus pneumoniae and 14770 Haemophilus influenzae isolates collected from 560 centres globally between 2004 and 2012 as a part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.).MethodsMIC testing was performed using broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) using CLSI-approved breakpoints; US Food and Drug Administration breakpoints were used for tigecycline as CLSI breakpoints are not available.ResultsAt least 99% of S. pneumoniae isolates globally were susceptible to levofloxacin, linezolid, tigecycline or vancomycin. Penicillin resistance was observed among 14.8% of S. pneumoniae and was highest in Asia/Pacific Rim (30.1%) and Africa (27.6%); 23.4% of S. pneumoniae isolates were penicillin-intermediate, which were most common in Africa (37.6%). Minocycline susceptibility among S. pneumoniae decreased by 20% between 2004-2008 and 2009-2012. High (>98.5%) susceptibility was reported among H. influenzae to all antimicrobial agents on the T.E.S.T. panel excluding ampicillin, to which only 78.3% were susceptible. ß-lactamase production was observed among 20.2% of H. influenzae isolates; 1.5% of isolates were ß-lactamase negative, ampicillin-resistant.Conclusions S. pneumoniae remained highly susceptible to levofloxacin, linezolid, tigecycline and vancomycin while H. influenzae was susceptible to most antimicrobial agents in the testing panel (excluding ampicillin).

PMID: 25376749 [PubMed - as supplied by publisher] 

Mechanism of β-Lactam Action in Streptococcus pneumoniae: the Piperacillin Paradox.

Antimicrob Agents Chemother. 2014 Nov 10. pii: AAC.04283-14. [Epub ahead of print]

Mechanism of β-Lactam Action in Streptococcus pneumoniae: the Piperacillin Paradox.

Philippe J1, Gallet B1, Morlot C1, Denapaite D2, Hakenbeck R3, Chen Y4, Vernet T1, Zapun A5.

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Abstract

The human pathogen Streptococcus pneumoniae has been fought for decades with β-lactam antibiotics. Resistance is now widespread, mediated by the expression of mosaic variants of the target enzymes, the penicillin-binding proteins or PBPs. Understanding the mode of action of β-lactams, not only in molecular details, but also in their physiological consequences, will be crucial to improve these drugs and counter resistance. In this work, we investigate the piperacillin paradox, by which this β-lactam selects primarily variants of PBP2b, whereas its most reactive target is PBP2x. These PBPs are both essential mono-functional transpeptidases involved in peptidoglycan assembly. PBP2x participates to septal synthesis, while PBP2b functions in peripheral elongation. The formation of "lemon"-shaped cells induced by piperacillin treatment is consistent with the inhibition of PBP2x. Following the examination of treated and untreated cells by electron microscopy, localization of the PBPs by epifluorescence microscopy, and determination of the inhibition time-course of the different PBPs, we propose a model of peptidoglycan assembly that can account for the piperacillin paradox.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

PMID: 25385114 [PubMed - as supplied by publisher]

Unencapsulated Streptococcus pneumoniae from conjunctivitis encode variant traits and belong to a distinct phylogenetic cluster.

Nat Commun. 2014 Nov 12;5:5411. doi: 10.1038/ncomms6411.

Unencapsulated Streptococcus pneumoniae from conjunctivitis encode variant traits and belong to a distinct phylogenetic cluster.

Valentino MD1, McGuire AM2, Rosch JW3, Bispo PJ4, Burnham C3, Sanfilippo CM5, Carter RA3, Zegans ME6, Beall B7, Earl AM2, Tuomanen EI3, Morris TW5, Haas W4, Gilmore MS1.

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Abstract

Streptococcus pneumoniae, an inhabitant of the upper respiratory mucosa, causes respiratory and invasive infections as well as conjunctivitis. Strains that lack the capsule, a main virulence factor and the target of current vaccines, are often isolated from conjunctivitis cases. Here we perform a comparative genomic analysis of 271 strains of conjunctivitis-causing S. pneumoniae from 72 postal codes in the United States. We find that the vast majority of conjunctivitis strains are members of a distinct cluster of closely related unencapsulated strains. These strains possess divergent forms of pneumococcal virulence factors (such as CbpA and neuraminidases) that are not shared with other unencapsulated nasopharyngeal S. pneumoniae. They also possess putative adhesins that have not been described in encapsulated pneumococci. These findings suggest that the unencapsulated strains capable of causing conjunctivitis utilize a pathogenesis strategy substantially different from that described for S. pneumoniae at other infection sites.

PMID: 25388376 [PubMed - in process]