A 28‐aa Pneumococcal Surface Adhesin A–Derived Peptide, P4, Augments Passive Immunotherapy and Rescues Mice from Fatal Pneumococcal Infection

Rajam, Gowrisankar; Skinner, Julie M.; Melnick, Nikkol; Martinez, Joseph; Carlone, George M.; Sampson, Jacquelyn S.; Ades, Edwin W.

doi:10.1086/597425

Cited by 13 publications

(31 citation statements)

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“…As a consequence, impairment of Psa permease function results in an attenuation of the in vivo virulence of S. pneumoniae [5,[9][10][11][12]. In addition to its role in metal acquisition, the P4 region (residues 251-278) of PsaA is immunogenic [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to its role in metal acquisition, the P4 region (residues 251-278) of PsaA is immunogenic [13][14][15]. The P4 region has also been implicated in mediating PsaA adhesion to nasopharyngeal epithelial cells [11][12][13][14][15][16], although the in vivo relevance of this adhesin property remains contentious. The reduced efficacy of current vaccine regimes, together with the spread of multidrug resistant strains, highlights an urgent need to develop new therapeutic strategies for the management of pneumococcal infections [17].…”

Section: Introductionmentioning

confidence: 99%

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Characterizing the conformational dynamics of metal-free PsaA using molecular dynamics simulations and electron paramagnetic resonance spectroscopy

Deplazes

Begg

Wonderen

et al. 2015

Biophysical Chemistry

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After the embargo period via non-commercial hosting platforms such as their institutional repository  via commercial sites with which Elsevier has an agreement In all cases accepted manuscripts should: link to the formal publication via its DOI  bear a CC-BY-NC-ND license -this is easy to do, click here to find out how  if aggregated with other manuscripts, for example in a repository or other site, be shared in alignment with our hosting policy  not be added to or enhanced in any way to appear more like, or to substitute for, the published journal article unknown. Here, we use continuous wave electron paramagnetic resonance (EPR) spectroscopy and molecular dynamics (MD) simulations to study the relative flexibility of the structural domains in metal-free PsaA and its distribution of conformations in solution. The results show that the crystal structure of the metal-free PsaA is a good representation of the dominant conformation in solution, but the protein also samples structurally distinct conformations that are not captured by the crystal structure. Further, these results suggest that the metal binding site is larger and more solvent exposed than indicated by the metal-free crystal structure. Collectively, this study provides atomicresolution insight into the conformational dynamics of PsaA prior to metal binding and lays the groundwork for future EPR and MD based studies of PsaA in solution. 4 GRAPHICAL ABSTRACT HIGHLIGHTS• PsaA is the Mn 2+ -recruiting protein of the human pathogen Streptococcus pneumoniae• Metal-free PsA samples structurally distinct conformations not captured by the crystal structure• The metal binding site is larger and more solvent exposed than indicated by the crystal structure KEYWORDSCluster A-I solute-binding protein (SBP); Streptococcus pneumoniae; PsaA; molecular dynamics simulations, electron paramagnetic resonance (EPR) spectroscopy; protein flexibility; spin-label mobility 5

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterizing the conformational dynamics of metal-free PsaA using molecular dynamics simulations and electron paramagnetic resonance spectroscopy

Deplazes

Begg

Wonderen

et al. 2015

Biophysical Chemistry

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“…WU2 is a highly encapsulated strain (11). All these Another reason for the lack of protection against WU2 challenge is that the antibody titer against PsaA was not high enough to be effective (66). The highest reciprocal IgG antibody titer that we obtained after immunization with our first set of constructs was 2 10 (see Fig.…”

Section: Discussionmentioning

confidence: 95%

Immune Responses to Recombinant Pneumococcal PsaA Antigen Delivered by a Live Attenuated Salmonella Vaccine

Wang

Shi

et al. 2010

Infect Immun

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Streptococcus pneumoniae is a leading cause of morbidity and mortality among children worldwide and particularly in developing countries. In this study, we evaluated PsaA, a conserved antigen important for S. pneumoniae adhesion to and invasion into nasopharynx epithelia, for its ability to induce protective immunity against S. pneumoniae challenge when delivered by recombinant attenuated Salmonella vaccine (RASVs) strains. RASVs were engineered to synthesize PsaA peptides of various lengths. Vaccination with an RASV synthesizing full-length PsaA induced high titers of anti-PsaA antibodies in both systemic (IgG in serum) and mucosal (IgA in vaginal washes, nasal washes, and lung homogenates) sites. BALB/c (haplotype H2 d ) or C57BL/6 (haplotype H2 b ) mice vaccinated either orally or intranasally exhibited a significant reduction in colonization of nasopharyngeal tissues after intranasal challenge with S. pneumoniae strains compared to controls, although protection was not observed with all challenge strains. None of the vaccine constructs provided protection against intraperitoneal challenge with S. pneumoniae strain WU2 (serotype 3). Immunization with RASVs synthesizing truncated PsaA generated lower titers of IgA and IgG and did not provide significant protection. Our results showed that RASVs synthesizing full-length PsaA can provide protection against nasal colonization by some S. pneumoniae strains. PsaA may be a useful addition to a multivalent vaccine, providing protection against pneumonia, otitis media, and other diseases caused by S. pneumoniae.Streptococcus pneumoniae is responsible for a number of serious diseases in humans, including pneumonia, meningitis, bacteremia, otitis media, and sinusitis (31). It is a major cause of childhood mortality, 90% of which occurs in developing countries. The current vaccines against pneumococcal infections include a 23-valent capsular polysaccharide vaccine for adults and a 7-valent conjugate vaccine licensed for children (75,77). However, some nonvaccine serotypes have become prevalent in the face of continued use of polysaccharide vaccines (63, 79). Also, certain high-risk groups have poor immunological responses to some of the polysaccharides in the vaccine formulations (28). There are also several concerns about the conjugate vaccines related to the cost and complexity of manufacture due to the different prevalent serotypes in different geographical areas. A meta-analysis showed that vaccination appears efficacious in reducing pneumococcal pneumonia in low-risk adults but not in high-risk groups (24). A more recent meta-analysis of 22 trials involving 101,507 participants found that the current 23-valent polysaccharide vaccine does not appear to be effective in preventing pneumonia, even in populations for which the vaccine is currently recommended (33, 52). There is a need to develop an improved and effective vaccine based on conserved antigens across all capsular serotypes to induce more effective and durable immune responses that could potentially protect a...

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“…P4, a 28-amino-acid cationic peptide derived from pneumococcal surface adhesin A (PsaA), is a eukaryotic cellular activator (10). Previously, we demonstrated that the cellular activation properties of P4 can be utilized to rescue severely ill young mice from fatal pneumococcal infection in the presence of pathogen-specific antibodies and active complement (8,12). While P4 therapy was used to rescue young Swiss Webster mice (6 to 10 weeks old), we questioned its effectiveness in aged mice (11 and 15 months old).…”

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confidence: 99%

“…Intranasal inoculation of mice with Streptococcus pneumoniae WU2 (serotype 3) and P4 therapy were done using protocols previously described, with minor modifications (12). Eleven-month-old BALB/c (n ϭ 20) and 15-month-old Swiss Webster mice (n ϭ 20) were infected intranasally with S. pneumoniae WU2 (ϳ2.1 ϫ 10 7 cells/mouse).…”

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confidence: 99%

P4 Peptide Therapy Rescues Aged Mice from Fatal Pneumococcal Sepsis

Rajam¹,

Bangert

Hammons

et al. 2010

Clin Vaccine Immunol

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A 28‐aa Pneumococcal Surface Adhesin A–Derived Peptide, P4, Augments Passive Immunotherapy and Rescues Mice from Fatal Pneumococcal Infection

Abstract: P4 peptide in combination with pathogen-specific antibodies and complement enhances specific opsonophagocytosis and rescues mice from life-threatening pneumococcal infection. P4 peptide provides a fresh direction for therapeutic intervention through augmented passive immunotherapy.

Cited by 13 publications

References 27 publications

Characterizing the conformational dynamics of metal-free PsaA using molecular dynamics simulations and electron paramagnetic resonance spectroscopy

Characterizing the conformational dynamics of metal-free PsaA using molecular dynamics simulations and electron paramagnetic resonance spectroscopy

Immune Responses to Recombinant Pneumococcal PsaA Antigen Delivered by a Live Attenuated Salmonella Vaccine

P4 Peptide Therapy Rescues Aged Mice from Fatal Pneumococcal Sepsis

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