Humoral immune responses to Streptococcus pneumoniae in the setting of HIV-1 infection.

Vaccine. 2015 Jun 30. pii: S0264-410X(15)00878-6. doi: 10.1016/j.vaccine.2015.06.077. [Epub ahead of print]

Humoral immune responses to Streptococcus pneumoniae in the setting of HIV-1 infection.

Zhang L1, Li Z1, Wan Z2, Kilby A3, Kilby JM4, Jiang W5.

Author information

Abstract

Streptococcus pneumoniae (pneumococcus) remains one of the most commonly identified causes of bacterial infection in the general population, and the risk is 30-100 fold higher in HIV-infected individuals. Both innate and adaptive host immune responses to pneumococcal infection are important against pathogen invasion. Pneumococcal-specific IgA antibody (Ab) is key to control infection at the mucosal sites. Ab responses against pneumococcal infection by B cells can be generated through T cell-dependent or T cell-independent pathways. Depletion of CD4+ T cells is a hallmark of immunodeficiency in HIV infection and this defect also contributes to B cell dysfunction, which predisposes to infections such as the pneumococcus. Two pneumococcal vaccines have been demonstrated to have potential benefits for HIV-infected patients. One is a T cell dependent 13-valent pneumococcal conjugate vaccine (PCV13); the other is a T cell independent 23-valent pneumococcal polysaccharide vaccine (PPV23). However, many questions remain unknown regarding these two vaccines in the clinical setting in HIV disease. Here we review the latest research regarding B cell immune responses against pneumococcal antigens, whether derived from potentially invading pathogens or vaccinations, in the setting of HIV-1 infection.

Copyright © 2015 Elsevier Ltd. All rights reserved.

KEYWORDS:

B cells; HIV; Humoral immune responses; Streptococcus pneumoniae

PMID: 26141012 [PubMed - as supplied by publisher]

Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae.

Lab Anim Res. 2015 Jun;31(2):78-85. doi: 10.5625/lar.2015.31.2.78. Epub 2015 Jun 26.

Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae.

Jeong DG1, Seo JH2, Heo SH3, Choi YK1, Jeong ES4.

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Abstract

Streptococcus pneumoniae is a major human pathogen that is involved in community-acquired pneumonia. Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine that activates immune responses against infection, invasion, injury, or inflammation. To study the role of TNF-α during S. pneumoniae infection, a murine pneumococcal pneumonia model was used. We intranasally infected C57BL/6J wild-type (WT) and TNF-α knockout (KO) mice with S. pneumoniae D39 serotype 2. In TNF-α KO mice, continuous and distinct loss of body weight, and low survival rates were observed. Bacterial counts in the lungs and blood of TNF-α KO mice were significantly higher than those in WT mice. Histopathological lesions in the spleen of TNF-α KO mice were more severe than those in WT mice. In TNF-α KO mice, severe depletion of white pulp was observed and the number of apoptotic cells was significantly increased. Interferon-gamma (IFN-γ), IL-12p70 and IL-10 levels in serum were significantly increased in TNF-α KO mice. TNF-α is clearly involved in the regulation of S. pneumoniae infections. Early death and low survival rates of TNF-α KO mice were likely caused by a combination of impaired bacterial clearance and damage to the spleen. Our findings suggest that TNF-α plays a critical role in protecting the host from systemic S. pneumoniae infection.

KEYWORDS:

Streptococcus pneumoniae; Tumor necrosis factor-alpha knockout; pneumonia

PMID: 26155202 [PubMed] PMCID: PMC4490149 

Absence of Capsule Reveals Glycan-Mediated Binding and Recognition of Salivary Mucin MUC7 by Streptococcus pneumoniae.

Mol Oral Microbiol. 2015 Jul 14. doi: 10.1111/omi.12113. [Epub ahead of print]

Absence of Capsule Reveals Glycan-Mediated Binding and Recognition of Salivary Mucin MUC7 by Streptococcus pneumoniae.

Thamadilok S1, Roche-Håkansson H2, Håkansson AP2, Ruhl S1.

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Abstract

Salivary proteins modulate bacterial colonization in the oral cavity and interact with systemic pathogens that pass through the oropharynx. An interesting example is the opportunistic respiratory pathogen Streptococcus pneumoniae that normally resides in the nasopharynx, but belongs to the greater Mitis group of streptococci, most of which colonize the oral cavity. S. pneumoniae also expresses a serine-rich repeat (SRR) adhesin, PsrP, that is a homologue to oral Mitis group SRR adhesins, such as Hsa of S. gordonii and SrpA of S. sanguinis. Since the latter bind to salivary glycoproteins through recognition of terminal sialic acids, we wanted to determine whether S. pneumoniae also binds to salivary proteins through possibly the same mechanism. We found that only a capsule-free mutant of S. pneumoniae TIGR4 binds to salivary proteins, most prominently to mucin MUC7, but that this binding was not mediated through PsrP or recognition of sialic acid. We also found, however, that PsrP is involved in agglutination of human red blood cells (RBCs). After removal of PsrP, an additional previously masked lectin-like adhesin activity mediating agglutination of sialidase-treated RBCs becomes revealed. Using a custom-spotted glycoprotein and neoglycoprotein dot blot array, we identify candidate glycan motifs recognized by PsrP and by the putative S. pneumoniae adhesin that could perhaps be responsible for pneumococcal binding to salivary MUC7 and glycoproteins on RBCs. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

Saliva; bacterial lectins; salivary proteins; serine-rich repeat adhesins

PMID: 26172471 [PubMed - as supplied by publisher]

Chemical Synthesis Elucidates the Immunological Importance of a Pyruvate Modification in the Capsular Polysaccharide of Streptococcus pneumoniae Serotype 4.

Angew Chem Int Ed Engl. 2015 Jul 24. doi: 10.1002/anie.201504847. [Epub ahead of print]

Chemical Synthesis Elucidates the Immunological Importance of a Pyruvate Modification in the Capsular Polysaccharide of Streptococcus pneumoniae Serotype 4.

Pereira CL1,2, Geissner A3,4, Anish C3,4, Seeberger PH5,6.

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Abstract

Carbohydrate modifications are believed to strongly affect the immunogenicity of glycans. Capsular polysaccharides (CPS) from bacterial pathogens are frequently equipped with a pyruvate that can be placed across the 4,6-, 3,4-, or 2,3-positions. A trans-2,3-linked pyruvate is present on the CPS of the Gram-positive bacterium Streptococcus pneumoniae serotype 4 (ST4), a pathogen responsible for pneumococcal infections. To assess the immunological importance of this modification within the CPS repeating unit, the first total synthesis of the glycan was carried out. Glycan microarrays containing a series of synthetic antigens demonstrated how antibodies raised against natural ST4 CPS specifically recognize the pyruvate within the context of the tetrasaccharide repeating unit. The pyruvate modification is a key motif for designing minimal synthetic carbohydrate vaccines for ST4.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

KEYWORDS:

Streptococcus pneumoniae; antigens; oligosaccharides; pyruvate acetal; synthetic vaccines

PMID: 26212109 [PubMed - as supplied by publisher]

Antibiotic resistance of Streptococcus pneumoniae colonizing the nasopharynx of HIV-exposed Tanzanian infants.

Trop Med Int Health. 2015 Jul 30. doi: 10.1111/tmi.12582. [Epub ahead of print]

Antibiotic resistance of Streptococcus pneumoniae colonizing the nasopharynx of HIV-exposed Tanzanian infants.

Bles P1, de Mast Q2,3, van der Gaast-de Jongh CE1,2, Kinabo GD4, Kibiki G5, van de Ven A2,3, de Jonge MI1,2.

Author information

Abstract

OBJECTIVES:

To determine antibiotic susceptibility of colonizing pneumococcal serotypes in HIV-exposed infants before the introduction of the 13-valent Pneumococcal Conjugate Vaccine (PCV13), because HIV-exposed infants are at increased risk for invasive pneumococcal infections.

METHODS:

Antibiotic susceptibility of 104 pneumococcal isolates, cultured from the nasopharynx from Tanzanian HIV-exposed infants, was determined using the disk diffusion method and the E-test according to EUCAST version 4.0 (2014) criteria.

RESULTS:

69.2% of isolates were intermediately susceptible for benzyl penicillin (MIC 0.06 - 2 mg L-1); no high level resistance was found. All isolates but one were susceptible to ampicillin. Regarding non-beta-lactam antibiotics, 19.2% of isolates were resistant to doxycycline, 3.8% to erythromycin and 97.1% to trimethoprim/sulfamethoxazole. 15.4% of isolates were resistant to three antibiotic classes or more. There were no differences in antibiotic susceptibility between vaccine and non-vaccine serotypes. Reduced susceptibility of colonizing pneumococcal isolates for commonly used antibiotics is common in HIV-exposed Tanzanian infants.

CONCLUSIONS:

High dose penicillin and ampicillin remain appropriate first choices for non-meningeal pneumococcal infections in this group. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

Streptococcus pneumoniae ; Colonization; HIV-exposed infants; Tanzania; antibiotic resistance

PMID: 26224321 [PubMed - as supplied by publisher]

Virulence Factors of Streptococcus pneumoniae. Comparison between African and French Invasive Isolates and Implication for Future Vaccines.

PLoS One. 2015 Jul 27;10(7):e0133885. doi: 10.1371/journal.pone.0133885. eCollection 2015.

Virulence Factors of Streptococcus pneumoniae. Comparison between African and French Invasive Isolates and Implication for Future Vaccines.

Blumental S1, Granger-Farbos A2, Moïsi JC3, Soullié B2, Leroy P2, Njanpop-Lafourcade BM3, Yaro S4, Nacro B5, Hallin M6, Koeck JL2.

Author information

Abstract

BACKGROUND: 

Many surface proteins thought to promote Streptocococcus pneumoniae virulence have recently been discovered and are currently being considered as future vaccine targets. We assessed the prevalence of 16 virulence genes among 435 S. pneumoniae invasive isolates from France and the "African meningitis belt" region, with particular focus on serotype 1 (Sp1), to compare their geographical distribution, assess their association with site of infection and evaluate their potential interest as new vaccine candidates.

METHODS: 

Detection by PCR of pspA (+families), pspC (+pspC.4), pavA, lytA, phtA,B,D,E, nanA,B,C, rrgA (Pilus-1), sipA (Pilus-2), pcpA and psrp was performed on all isolates, as well as antibiotic resistance testing and MLVA typing (+MLST on 54 representative strains). Determination of ply alleles was performed by sequencing (Sp1 isolates).

RESULTS: 

MLVA and virulence genes profiles segregated Sp1 isolates into 2 groups that followed continent distribution. The ply allele 5 and most of the genes that were variable (nanC, Pilus-2, psrp, pcpA, phtD) were present in the French Sp1 isolates (PMEN clone Sweden1-28, ST306) but absent from the African ones. Whereas all African Sp1 isolates clustered into a single MLST CC (CC217), MLVA distinguished two CCs that followed temporal evolution. Pilus-2 and psrp were more prevalent in bacteraemic pneumonia yielded isolates and phtB in meningitis-related isolates. Considering vaccine candidates, phtD was less prevalent than anticipated (50%) and pcpA varied importantly between France and Africa (98% versus 34%). Pilus-1 was carried by 7-11% of isolates and associated with β-lactams resistance.

CONCLUSIONS: 

Most virulence genes were carried by the European ST306 clone but were lacking on Sp1 isolates circulating in the African meningitis belt, where a more serious pattern of infection is observed. While virulence proteins are now considered as vaccine targets, the geographical differences in their prevalence could affect the efficacy expected from future vaccines.

PMID: 26214695 [PubMed - in process] PMCID: PMC4516325 

Streptococcus pneumoniae antibody titres in patients with primary antibody deficiency receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG).

Clin Exp Immunol. 2015 Jun 9. doi: 10.1111/cei.12665. [Epub ahead of print]

Streptococcus pneumoniae antibody titres in patients with primary antibody deficiency receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG).

Knutsen AP1, Leiva LE2, Caruthers C1, Rodrigues J1, Sorensen RU2.

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Abstract

Intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) are effective in the treatment of patients with primary antibody deficiency disorders (PAD). The purpose of this study was to evaluate Streptococcus pneumoniae (Spn) antibody titres to 14 serotypes in patients receiving IVIG compared to SCIG and to correlate Spn antibody levels to clinical outcome. The doses of immunoglobulin (Ig)G/kg/month were similar in both IVIG and SCIG groups. In 11 patients treated with IVIG, Spn antibody titres were ≥ 1·3 μg/ml to 99·4 ± 2·1% of the 14 serotypes at peak IVIG but decreased to 66·9 ± 19·8% at trough IVIG. Loss of Spn titres ≥ 1·3 μg/ml was most frequent for Spn serotypes 1, 4, 9V and 23. This correlated with lower Spn antibody titres to these serotypes at peak IVIG compared to the other serotypes. In 13 patients treated with SCIG, Spn antibody titres were protective to 58·2 ± 23·3% of the serotypes 3-5 days after infusion, similar to trough IVIG. Similarly, the Spn serotypes with the least protective percentages were the same as the ones observed in trough IVIG. There were no annualized serious bacterial infections (aSBI) in either group. However, there were significantly decreased annualized other infections (aOI) in the SCIG group compared to the IVIG-treated group, 0·8 ± 0·7 versus 2·2 ± 1·2 infections/patient/year (P = 0·004). Breakthrough aOI did not correlate with protective or higher serum Spn antibody titres.

© 2015 British Society for Immunology.

KEYWORDS:

B cell; antibodies; immunodeficiency diseases

PMID: 26230522 [PubMed - as supplied by publisher]

Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo.

PLoS One. 2015 May 13;10(5):e0127098. doi: 10.1371/journal.pone.0127098. eCollection 2015.

Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo.

Nguyen DT1, Louwen R2, Elberse K3, van Amerongen G1, Yüksel S1, Luijendijk A2, Osterhaus AD1, Duprex WP4, de Swart RL1.

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Abstract

Human respiratory syncytial virus (HRSV) and Streptococcus pneumoniae are important causative agents of respiratory tract infections. Both pathogens are associated with seasonal disease outbreaks in the pediatric population, and can often be detected simultaneously in infants hospitalized with bronchiolitis or pneumonia. It has been described that respiratory virus infections may predispose for bacterial superinfections, resulting in severe disease. However, studies on the influence of bacterial colonization of the upper respiratory tract on the pathogenesis of subsequent respiratory virus infections are scarce. Here, we have investigated whether pneumococcal colonization enhances subsequent HRSV infection. We used a newly generated recombinant subgroup B HRSV strain that expresses enhanced green fluorescent protein and pneumococcal isolates obtained from healthy children in disease-relevant in vitro and in vivo model systems. Three pneumococcal strains specifically enhanced in vitro HRSV infection of primary well-differentiated normal human bronchial epithelial cells grown at air-liquid interface, whereas two other strains did not. Since previous studies reported that bacterial neuraminidase enhanced HRSV infection in vitro, we measured pneumococcal neuraminidase activity in these cultures but found no correlation with the observed infection enhancement in our model. Subsequently, a selection of pneumococcal strains was used to induce nasal colonization of cotton rats, the best available small animal model for HRSV. Intranasal HRSV infection three days later resulted in strain-specific enhancement of HRSV replication in vivo. One S. pneumoniae strain enhanced HRSV both in vitro and in vivo, and was also associated with enhanced syncytium formation in vivo. However, neither pneumococci nor HRSV were found to spread from the upper to the lower respiratory tract, and neither pathogen was transmitted to naive cage mates by direct contact. These results demonstrate that pneumococcal colonization can enhance subsequent HRSV infection, and provide tools for additional mechanistic and intervention studies.

PMID: 25970287 [PubMed - in process] PMCID: PMC4430531 

Vinpocetine Inhibits Streptococcus pneumoniae-Induced Upregulation of Mucin MUC5AC Expression via Induction of MKP-1 Phosphatase in the Pathogenesis of Otitis Media.

J Immunol. 2015 May 13. pii: 1401489. [Epub ahead of print]

Vinpocetine Inhibits Streptococcus pneumoniae-Induced Upregulation of Mucin MUC5AC Expression via Induction of MKP-1 Phosphatase in the Pathogenesis of Otitis Media.

Lee JY1, Komatsu K1, Lee BC1, Miyata M1, O'Neill Bohn A1, Xu H1, Yan C2, Li JD3.

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Abstract

Mucin overproduction is a hallmark of otitis media (OM). Streptococcus pneumoniae is one of the most common bacterial pathogens causing OM. Mucin MUC5AC plays an important role in mucociliary clearance of bacterial pathogens. However, if uncontrolled, excessive mucus contributes significantly to conductive hearing loss. Currently, there is a lack of effective therapeutic agents that suppress mucus overproduction. In this study, we show that a currently existing antistroke drug, vinpocetine, a derivative of the alkaloid vincamine, inhibited S. pneumoniae-induced mucin MUC5AC upregulation in cultured middle ear epithelial cells and in the middle ear of mice. Moreover, vinpocetine inhibited MUC5AC upregulation by inhibiting the MAPK ERK pathway in an MKP-1-dependent manner. Importantly, ototopical administration of vinpocetine postinfection inhibited MUC5AC expression and middle ear inflammation induced by S. pneumoniae and reduced hearing loss and pneumococcal loads in a well-established mouse model of OM. Thus, these studies identified vinpocetine as a potential therapeutic agent for inhibiting mucus production in the pathogenesis of OM.

Copyright © 2015 by The American Association of Immunologists, Inc.

PMID: 25972475 [PubMed - as supplied by publisher]

Feasibility and Safety of Local Treatment with Recombinant Human Tissue Factor Pathway Inhibitor in a Rat Model of Streptococcus pneumoniae Pneumonia.

PLoS One. 2015 May 18;10(5):e0127261. doi: 10.1371/journal.pone.0127261. eCollection 2015.

Feasibility and Safety of Local Treatment with Recombinant Human Tissue Factor Pathway Inhibitor in a Rat Model of Streptococcus pneumoniae Pneumonia.

van den Boogaard FE1, Hofstra JJ2, van 't Veer C3, Levi MM4, Roelofs JJ5, van der Poll T6, Schultz MJ7.

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Abstract

Pulmonary coagulopathy is intrinsic to pulmonary injury including pneumonia. Anticoagulant strategies could benefit patients with pneumonia, but systemic administration of anticoagulant agents may lead to suboptimal local levels and may cause systemic hemorrhage. We hypothesized nebulization to provide a safer and more effective route for local administration of anticoagulants. Therefore, we aimed to examine feasibility and safety of nebulization of recombinant human tissue factor pathway inhibitor (rh-TFPI) in a well-established rat model of Streptococcus (S.) pneumoniae pneumonia. Thirty minutes before and every 6 hours after intratracheal instillation of S. pneumonia causing pneumonia, rats were subjected to local treatment with rh-TFPI or placebo, and sacrificed after 42 hours. Pneumonia was associated with local as well as systemic activation of coagulation. Nebulization of rh-TFPI resulted in high levels of rh-TFPI in bronchoalveolar lavage fluid, which was accompanied by an attenuation of pulmonary coagulation. Systemic rh-TFPI levels remained undetectable, and systemic TFPI activity and systemic coagulation were not affected. Histopathology revealed no bleeding in the lungs. We conclude that nebulization of rh-TFPI seems feasible and safe; local anticoagulant treatment with rh-TFPI attenuates pulmonary coagulation, while not affecting systemic coagulation in a rat model of S. pneumoniae pneumonia.

PMID: 25992779 [PubMed - in process] 

Nonencapsulated Streptococcus pneumoniae causes otitis media during single-species infection and during polymicrobial infection with nontypeable Haemophilus influenzae.

Pathog Dis. 2015 Jul;73(5). pii: ftu011. doi: 10.1093/femspd/ftu011. Epub 2014 Dec 4.

Nonencapsulated Streptococcus pneumoniae causes otitis media during single-species infection and during polymicrobial infection with nontypeable Haemophilus influenzae.

Murrah KA1, Pang B1, Richardson S1, Perez A1, Reimche J1, King L1, Wren J1, Swords WE2.

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Abstract

Streptococcus pneumoniae strains lacking capsular polysaccharide have been increasingly reported in carriage and disease contexts. Since most cases of otitis media involve more than one bacterial species, we aimed to determine the capacity of a nonencapsulated S. pneumoniae clinical isolate to induce disease in the context of a single-species infection and as a polymicrobial infection with nontypeable Haemophilus influenzae. Using the chinchilla model of otitis media, we found that nonencapsulated S. pneumoniae colonizes the nasopharynx following intranasal inoculation, but does not readily ascend into the middle ear. However, when we inoculated nonencapsulated S. pneumoniae directly into the middle ear, the bacteria persisted for two weeks post-inoculation and induced symptoms consistent with chronic otitis media. During coinfection with nontypeable H. influenzae, both species persisted for one week and induced polymicrobial otitis media. We also observed that nontypeable H. influenzae conferred passive protection from killing by amoxicillin upon S. pneumoniae from within polymicrobial biofilms in vitro. Therefore, based on these results, we conclude that nonencapsulated pneumococci are a potential causative agent of chronic/recurrent otitis media, and can also cause mutualistic infection with other opportunists, which could complicate treatment outcomes.

© FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

KEYWORDS:

Haemophilus; coinfection; nonencapsulated; pneumococcus

PMID: 26014114 [PubMed - in process]

Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.

Thorax. 2015 May 11. pii: thoraxjnl-2014-206420. doi: 10.1136/thoraxjnl-2014-206420. [Epub ahead of print]

Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin.

Knippenberg S1, Ueberberg B1, Maus R1, Bohling J1, Ding N1, Tort Tarres M1, Hoymann HG2, Jonigk D3, Izykowski N3, Paton JC4, Ogunniyi AD4, Lindig S5, Bauer M5, Welte T6, Seeger W7, Guenther A7, Sisson TH8, Gauldie J9, Kolb M9, Maus UA10.

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Abstract

RATIONALE:

Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is characterised poorly.

OBJECTIVES:

To assess the effect of Gram-positive bacterial infection on fibrosis exacerbation in mice.

METHODS:

Fibrosis progression in response to Streptococcus pneumoniae was examined in two different mouse models of pulmonary fibrosis.

MEASUREMENTS AND MAIN RESULTS:

We demonstrate that wild-type mice exposed to adenoviral vector delivery of active transforming growth factor-β1 (TGFß1) or diphteria toxin (DT) treatment of transgenic mice expressing the DT receptor (DTR) under control of the surfactant protein C (SPC) promoter (SPC-DTR) to induce pulmonary fibrosis developed progressive fibrosis following infection with Spn, without exhibiting impaired lung protective immunity against Spn. Antibiotic treatment abolished infection-induced fibrosis progression. The cytotoxin pneumolysin (Ply) of Spn caused this phenomenon in a TLR4-independent manner, as Spn lacking Ply (SpnΔply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGFβ1-exposed Ply-challenged TLR4 KO mice. Increased apoptotic cell death of alveolar epithelial cells along with an attenuated intrapulmonary release of antifibrogenic prostaglandin E2 was found to underlie progressive fibrogenesis in Ply-challenged AdTGFβ1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFβ1-exposed mice.

CONCLUSIONS:

Our data unravel a novel mechanism by which infection with Spn through Ply release induces progression of established lung fibrosis, which can be attenuated by protein-based vaccination of mice.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

KEYWORDS:

Bacterial Infection; Idiopathic pulmonary fibrosis; Respiratory Infection

PMID: 25964315 [PubMed - as supplied by publisher]

Visualization of Streptococcus pneumoniae within Cardiac Microlesions and Subsequent Cardiac Remodeling.

J Vis Exp. 2015 Apr 7;(98). doi: 10.3791/52590.

Visualization of Streptococcus pneumoniae within Cardiac Microlesions and Subsequent Cardiac Remodeling.

Brown AO1, Orihuela CJ2.

Author information

Abstract

During bacteremia Streptococcus pneumoniae can translocate across the vascular endothelium into the myocardium and form discrete bacteria-filled microscopic lesions (microlesions) that are remarkable due to the absence of infiltrating immune cells. Due to their release of cardiotoxic products, S. pneumoniae within microlesions are thought to contribute to the heart failure that is frequently observed during fulminate invasive pneumococcal disease in adults. Herein is demonstrated a protocol for experimental mouse infection that leads to reproducible cardiac microlesion formation within 30 hr. Instruction is provided on microlesion identification in hematoxylin & eosin stained heart sections and the morphological distinctions between early and late microlesions are highlighted. Instruction is provided on a protocol for verification of S. pneumoniae within microlesions using antibodies against pneumococcal capsular polysaccharide and immunofluorescent microscopy. Last, a protocol for antibiotic intervention that rescues infected mice and for the detection and assessment of scar formation in the hearts of convalescent mice is provided. Together, these protocols will facilitate the investigation of the molecular mechanisms underlying pneumococcal cardiac invasion, cardiomyocyte death, cardiac remodeling as a result of exposure to S. pneumoniae, and the immune response to the pneumococci in the heart.

PMID: 25939051 [PubMed - in process]

Genome-wide association study of IgG1 responses to the choline-binding protein PspC of Streptococcus pneumoniae.

Genes Immun. 2015 Apr 30. doi: 10.1038/gene.2015.12. [Epub ahead of print]

Genome-wide association study of IgG1 responses to the choline-binding protein PspC of Streptococcus pneumoniae.

Anderson D1, Fakiola M2, Hales BJ1, Pennell CE3, Thomas WR1, Blackwell JM1.

Author information

Abstract

Streptococcus pneumoniae causes invasive pneumococcal disease. Delayed development of antibodies to S. pneumoniae in infancy is associated with the development of atopy and asthma. Pneumococcal surface protein C (PspC) is a vaccine candidate and variation in its choline-binding region is associated with invasive disease. This study examined 523 060 single-nucleotide polymorphisms in The Western Australian Pregnancy Cohort (Raine) Study to find loci influencing immunoglobulin G1 (IgG1) responses to PspC measured at age 14 years (n=1152). Genome-wide significance (top SNP rs9275596; P=3.1 × 10-14) was only observed at human leucocyte antigen (HLA). Imputed HLA amino-acid polymorphisms showed the strongest associations at positions DRB1 47 (P=3.2 × 10-11), 13SRG (P=9.8 × 10-10) and 11SP (P=9.8 × 10-10), and at DQA1 34 (P=6.4 × 10-10), DQB1 167R (P=9.3 × 10-6) and HLA-B 95 W (P=1.2 × 10-9). Conditional analyses showed independent contributions from DRB1 47 and DQB1 167R to the signal at rs9275596, supported by an omnibus test showing a strong signal for the haplotype DRB1_47_DQB1_167 (P=9.02 × 10-15). In silico analysis showed that DRB1 four-digit allele groups defined by DRB1 47F bind to a greater complexity of core 9-mer epitopes compared with DRB1 47Y, especially across repeats in the C-term choline-binding region. Consequent differences in CD4 T-cell help for IgG1 to PspC could have implications for vaccine design. Further analysis in other cohorts is merited.Genes and Immunity advance online publication, 30 April 2015; doi:10.1038/gene.2015.12.

PMID: 25928883 [PubMed - as supplied by publisher]

Rational Manipulation of mRNA Folding Free Energy Allows Rheostat Control of Pneumolysin Production by Streptococcus pneumoniae.

PLoS One. 2015 Mar 23;10(3):e0119823. doi: 10.1371/journal.pone.0119823. eCollection 2015.

Rational Manipulation of mRNA Folding Free Energy Allows Rheostat Control of Pneumolysin Production by Streptococcus pneumoniae.

Amaral FE1, Parker D2, Randis TM2, Kulkarni R2, Prince AS3, Shirasu-Hiza MM4, Ratner AJ2.

Author information

Abstract

The contribution of specific factors to bacterial virulence is generally investigated through creation of genetic "knockouts" that are then compared to wild-type strains or complemented mutants. This paradigm is useful to understand the effect of presence vs. absence of a specific gene product but cannot account for concentration-dependent effects, such as may occur with some bacterial toxins. In order to assess threshold and dose-response effects of virulence factors, robust systems for tunable expression are required. Recent evidence suggests that the folding free energy (ΔG) of the 5' end of mRNA transcripts can have a significant effect on translation efficiency and overall protein abundance. Here we demonstrate that rational alteration of 5' mRNA folding free energy by introduction of synonymous mutations allows for predictable changes in pneumolysin (PLY) expression by Streptococcus pneumoniae without the need for chemical inducers or heterologous promoters. We created a panel of isogenic S. pneumoniae strains, differing only in synonymous (silent) mutations at the 5' end of the PLY mRNA that are predicted to alter ΔG. Such manipulation allows rheostat-like control of PLY production and alters the cytotoxicity of whole S. pneumoniae on primary and immortalized human cells. These studies provide proof-of-principle for further investigation of mRNA ΔG manipulation as a tool in studies of bacterial pathogenesis.

PMID: 25798590

Streptococcus pneumoniae Induces Autophagy through the Inhibition of the PI3K-I/Akt/mTOR Pathway and ROS Hypergeneration in A549 Cells.

PLoS One. 2015 Mar 24;10(3):e0122753. doi: 10.1371/journal.pone.0122753. eCollection 2015.

Streptococcus pneumoniae Induces Autophagy through the Inhibition of the PI3K-I/Akt/mTOR Pathway and ROS Hypergeneration in A549 Cells.

Li P1, Shi J2, He Q1, Hu Q1, Wang YY1, Zhang LJ1, Chan WT3, Chen WX1.

Author information

Abstract

The present study focused on the action mechanism of S. pneumoniae (Sp) in inducing autophagy in human alveolar epithelial cells. Sp, a gram-positive extracellular bacterium, activates autophagy with considerably increased microtuble-associated protein light chain 3 (LC3) punctation in A549 cells. The accumulation of typical autophagosomes and conjugation of LC3 to phosphatidylethanolamine were observed in Sp-infected cells as an indication of autophagy. Using the pneumolysin (PLY) mutant, we successfully demonstrated that PLY is involved in initiating autophagy without affecting the expression levels of PI3K-III and Beclin1. PLY-mediated autophagy depends on the inhibition of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Furthermore, Sp could also lead to the reactive oxygen species (ROS) hypergeneration in A549 cells. Taken together, Sp infection-induced autophagy is PLY-mediated through ROS hypergeneration and mTOR inhibition. PI3K-I and rapamycin (autophagy inducers) enhanced bacterial clearance, whereas wortmannin (autophagy inhibitor) and acetylcysteine (ROS inhibitor) reduced intracellular bacteria clearance. Thus, Sp-induced autophagy represents a host-protective mechanism, providing new insight into the pathogenesis of respiratory tract Sp infection.

PMID: 25803050

Neonatal Streptococcus pneumoniae Infection May Aggravate Adulthood Allergic Airways Disease in Association with IL-17A.

PLoS One. 2015 Mar 27;10(3):e0123010. doi: 10.1371/journal.pone.0123010. eCollection 2015.

Neonatal Streptococcus pneumoniae Infection May Aggravate Adulthood Allergic Airways Disease in Association with IL-17A.

Yang B1, Liu R1, Yang T2, Jiang X1, Zhang L1, Wang L1, Wang Q3, Luo Z4, Liu E4, Fu Z4.

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Abstract

Epidemiologic studies have demonstrated that some bacteria colonization or infections in early-life increased the risk for subsequent asthma development. However, little is known about the mechanisms by which early-life bacterial infection increases this risk. The aim of this study was to investigate the effect of neonatal Streptococcus pneumoniae infection on the development of adulthood asthma, and to explore the possible mechanism. A non-lethal S. pneumoniae lung infection was established by intranasal inoculation of neonatal (1-week-old) female mice with D39. Mice were sensitized and challenged with ovalbumin in adulthood to induce allergic airways disease (AAD). Twenty-four hours later, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. Neonatal S. pneumoniae infection exacerbated adulthood hallmark features of AAD, with enhanced airway hyperresponsiveness and increased neutrophil recruitment into the airways, increased Th17 cells and interleukin (IL)-17A productions. Depletion of IL-17A by i.p. injection of a neutralizing monoclonal antibody reduced neutrophil recruitment into the airways, alleviated airway inflammation and decreased airway hyperresponsiveness. Furthermore, IL-17A depletion partially restored levels of inteferon-γ, but had no effect on the release of IL-5 or IL-13. Our data suggest that neonatal S. pneumoniae infection may promote the development of adulthood asthma in association with increased IL-17A production.

PMID: 25816135

Deletion analysis of Streptococcus pneumoniae late competence genes distinguishes virulence determinants that are dependent or independent of competence induction.

Mol Microbiol. 2015 Apr 2. doi: 10.1111/mmi.13016. [Epub ahead of print]

Deletion analysis of Streptococcus pneumoniae late competence genes distinguishes virulence determinants that are dependent or independent of competence induction.

Zhu L1, Lin J, Kuang Z, Vidal JE, Lau GW.

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Abstract

The competence regulon of Streptococcus pneumoniae (pneumococcus) is crucial for genetic transformation. During competence development, the alternative sigma factor ComX is activated, which in turn, initiates transcription of 80 "late" competence genes. Interestingly, only 16 late genes are essential for genetic transformation. We hypothesized that these late genes that are dispensable for competence are beneficial to pneumococcal fitness during infection. These late genes were systematically deleted, and the resulting mutants were examined for their fitness during mouse models of bacteremia and acute pneumonia. Among these, 14 late genes were important for fitness in mice. Significantly, deletion of some late genes attenuated pneumococcal fitness to the same level in both wild-type and ComX-null genetic backgrounds, suggesting that the constitutive baseline expression of these genes was important for bacterial fitness. In contrast, some mutants were attenuated only in the wild-type genetic background but not in the ComX-null background, suggesting that specific expression of these genes during competence state contributed to pneumococcal fitness. Increased virulence during competence state was partially caused by the induction of allolytic enzymes that enhanced pneumolysin release. These results distinguish the role of basal expression versus competence induction in virulence functions encoded by ComX-regulated late competence genes.

This article is protected by copyright. All rights reserved.

KEYWORDS:

Streptococcus pneumoniae; acute pneumonia; bacteremia; competence regulon; virulence factors

PMID: 25846124 

Post-operative Streptococcus pneumoniae meningoencephalitis complicating surgery for acromegaly in an identical twin.

J Clin Neurosci. 2015 Apr 7. pii: S0967-5868(15)00068-5. doi: 10.1016/j.jocn.2015.01.011. [Epub ahead of print]

Post-operative Streptococcus pneumoniae meningoencephalitis complicating surgery for acromegaly in an identical twin.

Cote DJ1, Iuliano SL1, Smith TR1, Laws ER Jr2.

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Abstract

This case report provides provocative and useful data regarding two aspects of acromegaly and its management. The patient, who is one of a pair of identical twins, has no known hereditary, genetic or otherwise potentially etiologic factors as compared to her unaffected sister. Secondly, transsphenoidal surgery, which was ultimately successful, was complicated by pneumococcal meningitis, an unusual event with only four previously reported patients, three of whom ended in death or major neurologic deficits. In this case, a 57-year-old woman gradually developed classical signs and symptoms of acromegaly while her identical twin sister remained normal with no evidence of endocrine disease. Endoscopic transsphenoidal surgery was complicated by the development of meningitis 25days after surgery. This was controlled following a difficult hospital course. Streptococcus pneumoniae meningoencephalitis is a rare but life-threatening complication of transsphenoidal surgery. A high index of suspicion for incipient meningitis should be maintained when patients present with severe headache and increased intracranial pressure, even if they initially lack the typical symptoms and signs. Immediate and aggressive treatment is necessary to avoid significant neurologic deficit.

Copyright © 2015 Elsevier Ltd. All rights reserved.

KEYWORDS:

Acromegaly; Meningitis; Pituitary adenoma; Transsphenoidal surgery

PMID: 25861890

Expression of the Streptococcus pneumoniae yoeB Chromosomal toxin gene causes Cell Death in the model plant Arabidopsis thaliana.

BMC Biotechnol. 2015 Apr 12;15(1):26. [Epub ahead of print]

Expression of the Streptococcus pneumoniae yoeB Chromosomal toxin gene causes Cell Death in the model plant Arabidopsis thaliana.

Bakar FA1, Yeo CC2, Harikrishna JA3.

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Abstract

BACKGROUND:

Bacterial toxin-antitoxin systems usually comprise of a pair of genes encoding a stable toxin and its cognate labile antitoxin and are located in the chromosome or in plasmids of several bacterial species. Chromosomally-encoded toxin-antitoxin systems are involved in bacterial stress responses and activation of the toxins usually leads to cell death or dormancy. Overexpression of the chromosomally-encoded YoeB toxin from the yefM-yoeB toxin-antitoxin locus of the Gram-positive bacterium Streptococcus pneumoniae has been shown to cause cell death in S. pneumoniae as well as E. coli.

RESULTS:

Induction of a YoeB-GFP fusion protein using a 17-β-estradiol-inducible plant expression system in Arabidopsis thaliana Col 0, was lethal in all T2 progeny. Examination of plants by fluorescent confocal microscopy showed GFP fluorescence in all parts of the leaves at 24 hours after 17-β-estradiol induction, continuing up to plant death. Quantitative RT-PCR analysis revealed that the expression of the yoeB toxin gene peaked at 3 days after induction with 17-β-estradiol, coinciding with the onset of visible effects on the plants. Moreover, we detected DNA laddering in the transgenic plants at 24 hours after yoeB induction, indicative of apoptosis.

CONCLUSIONS:

Expression of the YoeB toxin from Streptococcus pneumoniae is lethal in Arabidopsis. We believe this is the first report of a toxin from a bacterial toxin-antitoxin system functioning in plants. The results presented here mark an important milestone towards the development of a cell ablation based bio-containment strategy, which may be useful for functional studies and for the control of spread of transgenic plants.

PMID: 25887501