Immunoactivating Peptide P4 Augments Alveolar Macrophage Phagocytosis in Two Diverse Human Populations

Bangert, Mathieu; Wright, Adam; Rylance, Jamie; Kelly, Matthew; Wright, A.; Carlone, George M.; Sampson, Jacquelyn S.; Rajam, Gowrisankar; Ades, Edwin W.; Kadioglu, Aras; Gordon, Stephen B.

doi:10.1128/aac.00742-13

Cited by 9 publications

(10 citation statements)

References 9 publications

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“…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%

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%

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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“…bacterial killing using this control peptide so pragmatically used DEPC water as the vehicle control for the remainder of the study, as per previously published work (14,15). For the whole blood phagocytosis assay we noted convergence of results after 60 minutes incubation between P4 peptide and vehicle control stimulated samples.…”

Section: Discussionmentioning

confidence: 81%

“…As previously described (15), P4 mediated effects on phagocyte bacterial uptake depend on pathogen opsonisation. Our study investigated Strep.…”

Section: Discussionmentioning

confidence: 92%

“…The risk of immune hyperstimulation and organ injury is of concern for immunostimulatory therapies (27). However, P4 peptide does not stimulate inflammatory cytokine release ex vivo (15) and activated neutrophils can be retained and 'de-primed' within the lungs (28).…”

Section: Discussionmentioning

confidence: 99%

“…First, the opsonophagocytosis killing assay is an established and standardised method (29), widely used to compare phagocytic function in vaccine efficacy testing (30) and applied in previous work with P4 peptide (7,8,12,15).…”

Section: Discussionmentioning

confidence: 99%

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Augmented Passive Immunotherapy with P4 Peptide Improves Phagocyte Activity in Severe Sepsis

Morton

Mitsi

Pennington³

et al. 2016

Shock

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Utilization of Feline ELISpot to Evaluate the Immunogenicity of a T Cell-Based FIV MAP Vaccine

Sahay

Aranyos

McAvoy

et al. 2018

Methods in Molecular Biology

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The prototype and the commercial dual-subtype feline immunodeficiency virus (FIV) vaccines conferred protection against homologous FIV strains as well as heterologous FIV strains from the vaccine subtypes with closely related envelope (Env) sequences. Such protection was mediated by the FIV neutralizing antibodies (NAbs) induced by the vaccines. Remarkably, both prototype and commercial FIV vaccines also conferred protection against heterologous FIV subtypes with highly divergent Env sequences from the vaccine strains. Such protection was not mediated by the vaccine-induced NAbs but was mediated by a potent FIV-specific T-cell immunity generated by the vaccines (Aranyos et al., Vaccine 34: 1480-1488, 2016). The protective epitopes on the FIV vaccine antigen were identified using feline interleukin-2 (IL-2) and interferon-γ (IFNγ) ELISpot assays with overlapping FIV peptide stimulation of the peripheral blood mononuclear cells (PBMC) from cats immunized with prototype FIV vaccine. Two of the protective FIV peptide epitopes were identified on FIV p24 protein and another two protective peptide epitopes were found on FIV reverse transcriptase. In the current study, the multiple antigenic peptides (MAPs) of the four protective FIV peptides were combined with an adjuvant as the FIV MAP vaccine. The laboratory cats were immunized with the MAP vaccine to evaluate whether significant levels of vaccine-specific cytokine responses can be generated to the FIV MAPs and their peptides at post-second and post-third vaccinations. The PBMC from vaccinated cats and non-vaccinated control cats were tested for IL-2, IFNγ, and IL-10 ELISpot responses to the FIV MAPs and peptides. These results were compared to the results from CD4 and CD8 T-cell proliferation to the FIV MAPs and peptides. Current study demonstrates that IL-2 and IFNγ ELISpot responses can be used to detect memory responses of the T cells from vaccinated cats after the second and third vaccinations.

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Immunoactivating Peptide P4 Augments Alveolar Macrophage Phagocytosis in Two Diverse Human Populations

Cited by 9 publications

References 9 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

Augmented Passive Immunotherapy with P4 Peptide Improves Phagocyte Activity in Severe Sepsis

Utilization of Feline ELISpot to Evaluate the Immunogenicity of a T Cell-Based FIV MAP Vaccine

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