A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice

Benton, Kimberly A.; Everson, Michael P.; Briles, David E.

doi:10.1128/iai.63.2.448-455.1995

Cited by 118 publications

(44 citation statements)

References 29 publications

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“…For instance, in a rabbit model of pneumococcal keratitis, there was a significant improvement of corneal lesions after local application of cholesterol to the eye (42). One major contribution of PLY during the first few hours of local pneumococcal infection is to enable the pneumococcus to cause acute sepsis rather than chronic bacteremia (43). Based on hemolytic assays, the functional stoichiometry of cholesterol:PLY is considered to be 1:1, meaning that very low levels of free cholesterol are sufficient to neutralize the hemolytic activity of PLY.…”

Section: Discussionmentioning

confidence: 99%

Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia

et al. 2012

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Community-acquired pneumonia presents a spectrum of clinical phenotypes, from lobar pneumonia to septic shock, while mechanisms underlying progression are incompletely understood. In a transcriptomic and metabolomic study across tissues, we examined serotype-specific regulation of signaling and metabolic pathways in C57BL/6 mice intratracheally instilled with either serotype 19F Streptococcus pneumoniae (S19; causing lobar pneumonia), or serotype 2 S. pneumoniae (S2; causing septic pneumococcal disease,) or vehicle (Todd-Hewitt broth). Samples of lung, liver, and blood were collected at 6 and 24 h postinfection and subjected to microarray analysis and mass spectrometry. Results comprise a preferential induction of cholesterol biosynthesis in lobar pneumonia at low-infection doses (10(5) colony forming units/mouse) leading to increased plasma cholesterol (vehicle: 1.8±0.12 mM, S2: 2.3±0.10 mM, S19: 2.9±0.15 mM; P<0.05, comparing S19 to vehicle and S2). This induction was pneumolysin dependent, as a pneumolysin-deficient strain of serotype 19F failed to induce cholesterol biosynthesis (S19ΔPLY: 1.9±0.03 mM). Preincubation of pneumolysin with purified cholesterol or plasma from hypercholesterolemic mice prior to intratracheal instillation protected against lung barrier dysfunction and alveolar macrophage necrosis. Cholesterol may attenuate disease severity by neutralizing pneumolysin in the alveolar compartment and thus prevent septic disease progression.

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Section: Discussionmentioning

confidence: 99%

Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia

et al. 2012

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“…Purified capsular extracts do not have an inflammatory or toxic effect (31,32). Among the proteins considered to be virulence factors (17,45) are pneumolysin (3,7,12), autolysin (4,12,56), hyaluronidase (5), pneumococcal surface protein A (PspA) (8), PsaA (6), neuraminidase (10), immunoglobulin A1 (IgA1) protease (46,59), and pyruvate oxidase (55), although for some of them a role in virulence has not been demonstrated.…”

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confidence: 99%

Large-Scale Identification of Virulence Genes from Streptococcus pneumoniae

Polissi¹,

Pontiggia²,

Feger³

et al. 1998

Infect Immun

385

147

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Streptococcus pneumoniae is the major cause of bacterial pneumonia, and it is also responsible for otitis media and meningitis in children. Apart from the capsule, the virulence factors of this pathogen are not completely understood. Recent technical advances in the field of bacterial pathogenesis (in vivo expression technology and signature-tagged mutagenesis [STM]) have allowed a large-scale identification of virulence genes. We have adapted to S. pneumoniae the STM technique, originally used for the discovery of Salmonella genes involved in pathogenicity. A library of pneumococcal chromosomal fragments (400 to 600 bp) was constructed in a suicide plasmid vector carrying unique DNA sequence tags and a chloramphenicol resistance marker. The recent clinical isolate G54 was transformed with this library. Chloramphenicol-resistant mutants were obtained by homologous recombination, resulting in genes inactivated by insertion of the suicide vector carrying a unique tag. In a mouse pneumonia model, 1.250 candidate clones were screened; 200 of these were not recovered from the lungs were therefore considered virulence-attenuated mutants. The regions flanking the chloramphenicol gene of the attenuated mutants were amplified by inverse PCR and sequenced. The sequence analysis showed that the 200 mutants had insertions in 126 different genes that could be grouped in six classes: (i) known pneumococcal virulence genes; (ii) genes involved in metabolic pathways; (iii) genes encoding proteases; (iv) genes coding for ATP binding cassette transporters; (v) genes encoding proteins involved in DNA recombination/repair; and (vi) DNA sequences that showed similarity to hypothetical genes with unknown function. To evaluate the virulence attenuation for each mutant, all 126 clones were individually analyzed in a mouse septicemia model. Not all mutants selected in the pneumonia model were confirmed in septicemia, thus indicating the existence of virulence factors specific for pneumonia.

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“…Streptococcus pneumoniae is the causative agent for a number of diseases, including pneumonia, otitis media, meningitis, and sepsis (Mitchell & Dalziel, 2014). PLY has a significant role in the pathogenesis of pneumococcal pneumonia and sepsis (Benton, Everson, & Briles, 1995;Berry, Yother, Briles, Hansman, & Paton, 1989). In a mouse S. pneumoniae upper respiratory tract infection model, S. pneumoniae strains with PLY were shed in nasal secretions at higher levels than PLY-deficient strains, and PLY was required for transmission (Zafar, Wang, Hamaguchi, & Weiser, 2017).…”

Section: Plymentioning

confidence: 99%

Listeriolysin O: A phagosome-specific cytolysin revisited

Nguyen

Peterson

Portnoy

2019

Cellular Microbiology

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Listeriolysin O (LLO) is an essential determinant of Listeria monocytogenes pathogenesis that mediates the escape of L. monocytogenes from host cell vacuoles, thereby allowing replication in the cytosol without causing appreciable cell death. As a member of the cholesterol‐dependent cytolysin (CDC) family of pore‐forming toxins, LLO is unique in that it is secreted by a facultative intracellular pathogen, whereas all other CDCs are produced by pathogens that are largely extracellular. Replacement of LLO with other CDCs results in strains that are extremely cytotoxic and 10,000‐fold less virulent in mice. LLO has structural and regulatory features that allow it to function intracellularly without causing cell death, most of which map to a unique N‐terminal region of LLO referred to as the proline, glutamic acid, serine, threonine (PEST)‐like sequence. Yet, while LLO has unique properties required for its intracellular site of action, extracellular LLO, like other CDCs, affects cells in a myriad of ways. Because all CDCs form pores in cholesterol‐containing membranes that lead to rapid Ca2+ influx and K+ efflux, they consequently trigger a wide range of host cell responses, including mitogen‐activated protein kinase activation, histone modification, and caspase‐1 activation. There is no debate that extracellular LLO, like all other CDCs, can stimulate multiple cellular activities, but the primary question we wish to address in this perspective is whether these activities contribute to L. monocytogenes pathogenesis.

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A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice

Cited by 118 publications

References 29 publications

Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia

Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia

Large-Scale Identification of Virulence Genes from Streptococcus pneumoniae

Listeriolysin O: A phagosome-specific cytolysin revisited

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