Infection with Conditionally Virulent Streptococcus pneumoniae Δ
            <i>pab</i>
            Strains Induces Antibody to Conserved Protein Antigens but Does Not Protect against Systemic Infection with Heterologous Strains

Chimalapati, Suneeta; Cohen, Jonathan; Camberlein, Emilie; Durmort, Claire; Baxendale, Helen; Vogel, Corné P. de; Belkum, Alex van; Brown, Jeremy S.

doi:10.1128/iai.05923-11

Cited by 33 publications

(49 citation statements)

References 44 publications

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“…For this purpose, pabB deletion mutants of S. mitis and S. pneumoniae were included in the blood growth assay using human blood. Since for replication pab deletion mutants depend on the presence of para-aminobenzoic acid (PABA), which is absent in whole blood, growth is abolished (36). In serum, the numbers of CFU for the ⌬pab mutants after 4 h of incubation were similar to those in the inoculum at time zero, indicating that human serum had no detectable bacterial killing activity.…”

Section: Resultsmentioning

confidence: 99%

Protective Role of the Capsule and Impact of Serotype 4 Switching on Streptococcus mitis

et al. 2014

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eThe polysaccharide capsule surrounding Streptococcus pneumoniae is essential for virulence. Recently, Streptococcus mitis, a human commensal and a close relative of S. pneumoniae, was also shown to have a capsule. In this study, the S. mitis type strain switched capsule by acquisition of the serotype 4 capsule locus of S. pneumoniae TIGR4, following induction of competence for natural transformation. Comparison of the wild type with the capsule-switching mutant and with a capsule deletion mutant showed that the capsule protected S. mitis against phagocytosis by RAW 264.7 macrophages. This effect was enhanced in the S. mitis strain expressing the S. pneumoniae capsule, which showed, in addition, increased resistance against early clearance in a mouse model of lung infection. Expression of both capsules also favored survival in human blood, and the effect was again more pronounced for the capsule-switching mutant. S. mitis survival in horse blood or in a mouse model of bacteremia was not significantly different between the wild type and the mutant strains. In all models, S. pneumoniae TIGR4 showed higher rates of survival than the S. mitis type strain or the capsule-switching mutant, except in the lung model, in which significant differences between S. pneumoniae TIGR4 and the capsule-switching mutant were not observed. Thus, we identified conditions that showed a protective function for the capsule in S. mitis. Under such conditions, S. mitis resistance to clearance could be enhanced by capsule switching to serotype 4, but it was enhanced to levels lower than those for the virulent strain S. pneumoniae TIGR4.

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Section: Resultsmentioning

confidence: 99%

Protective Role of the Capsule and Impact of Serotype 4 Switching on Streptococcus mitis

et al. 2014

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“…The S. pneumoniae TIGR4 wildtype and unencapsulated (P1672) (constructed using the Janus cassette) strains were gifts from J. Weiser (16). The TIGR4⌬pab strain was constructed as previously described and transferred to the unencapsulated P1672 strain using conventional transformation techniques (21). Bacteria were cultured at 37°C in 5% CO 2 on blood agar plates or in Todd-Hewitt broth plus 0.5% yeast extract (THY) and stored at Ϫ80°C in 10% glycerol as single-use aliquots (optical density at 580 nm [OD 580 ] of 0.4).…”

Section: Methodsmentioning

confidence: 99%

Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

Camberlein¹,

Cohen²,

José³

et al. 2015

Infect Immun

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f Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae. Microaspiration of potentially pathogenic bacteria colonizing the nasopharynx is the probable cause of most cases of bacterial pneumonia. Whether microaspiration results in pneumonia will depend on the numbers of bacteria reaching the lung, their virulence, and the host's ability to clear the invading bacteria. Defining the efficacy of different lung immune mechanisms and the bacterial characteristics for successful infection will be essential for understanding the epidemiology of pneumonia and for the design of effective preventative strategies. Initial lung immune defenses include the resident alveolar macrophages (AMs) (1-3), physical removal of microbes by mucociliary clearance, and mucosal antibacterial peptides (e.g., defensins) and proteins (e.g., lysozyme and lactoferrin) (4, 5). The importance of AMs for preventing lung infections due to Streptococcus pneumoniae, the commonest cause of bacterial pneumonia, is well established (2, 6-9). The published data indicate that AM recognition and AM phagocytosis of S. pneumoniae are essential for controlling bacterial numbers during the first few hours of lung infection. Impairment of AMmediated bacterial clearance during early infection, ...

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“…Systemic vaccination with this mutant was able to protect from homologous challenge in mouse models of sepsis and pneumonia. 112 The attenuated mutant approach has been investigated for other bacteria. For example, in S. pyogenes, the deletion of the SpeB protease creates a mutant that is impaired in tRNA modification and has the potential to be used in vaccination strategies.…”

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confidence: 99%

“…For example, the pabB deletion strain is very rapidly cleared from the mouse nasopharynx and was only weakly immunogenic after nasopharyngeal administration. 112 Repeated dosing of poorly colonizing strains may overcome this issue. 82,107,110,115 Another potential problem is the surprising lack of cross-protection induced by attenuated strains in some of these studies.…”

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confidence: 99%

“…For example, although the protein antigens targeted by protective responses are largely conserved between S. pneumoniae strains, adaptive responses to one episode of colonization or systemic vaccination with a live attenuated vaccine either were not or only weakly cross-protective against heterologous strains in mouse models. 112,115 The reasons for this poor cross-protective immunity are not clear and require further investigation to ensure that nasopharyngeal administration with a single strain can provide the broad heterologous protection required for an effective vaccine.…”

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The new first-line defense: the potential of nasopharyngeal colonization in vaccine strategies

Chan¹,

Cohen²,

Brown³

2016

VDT

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Abstract:Pathogens that can colonize the upper respiratory tract include Streptococcus pneumoniae, Hemophilus influenzae, Neisseria meningitidis, Moraxella catarrhalis, and Staphylococcus aureus. While these pathogens commonly asymptomatically colonize the nasopharynx of healthy adults, disease progression may occur in some individuals. In addition to these respiratory pathogens, there are a large number of commensal species also found in the upper respiratory tract which only very rarely cause disease, creating a complex community of bacterial species in the nasopharynx. This review addresses the novel, potential strategies that utilize the interactions between both homologous and heterologous species in the nasopharynx to vaccinate individuals against pathogenic bacteria. These strategies include the mechanisms employed by colonizing bacteria to regulate the presence of other species in the nasopharynx and the effect that colonization of the nasopharynx has on the host immune response. Interventional strategies investigated so far include the introduction of nonpathogenic bacteria to the nasopharynx to immunize against a closely related species, controlled colonization using both wild-type and attenuated species, and the use of other nonpathogenic colonizers to express antigens from potential pathogens. All these approaches harness the ability of the colonization to induce a mucosal immune response that can protect against future infection. In this review, S. pneumoniae and N. meningitidis colonization are used as case studies for this approach as the immunological effects of colonization have been widely studied in animal and human models. Colonization-based strategies have great potential, and, in particular, the attenuated strain approach has produced some encouraging data in animal models. However, the strategy for attenuating virulence must be stringent and caused by highly stable mutations that are unlikely to revert. In addition, the consequences of artificial administration of genetically modified bacteria to the nasopharynx on the usual host microbiome are unknown and would need to be monitored carefully.

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Infection with Conditionally Virulent Streptococcus pneumoniae Δ pab Strains Induces Antibody to Conserved Protein Antigens but Does Not Protect against Systemic Infection with Heterologous Strains

Cited by 33 publications

References 44 publications

Protective Role of the Capsule and Impact of Serotype 4 Switching on Streptococcus mitis

Protective Role of the Capsule and Impact of Serotype 4 Switching on Streptococcus mitis

Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

The new first-line defense: the potential of nasopharyngeal colonization in vaccine strategies

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