31 research outputs found
Whole-Genome Immunoinformatic Analysis of F. tularensis: Predicted CTL Epitopes Clustered in Hotspots Are Prone to Elicit a T-Cell Response
The cellular arm of the immune response plays a central role in the defense against intracellular pathogens, such as F. tularensis. To date, whole genome immunoinformatic analyses were limited either to relatively small genomes (e.g. viral) or to preselected subsets of proteins in complex pathogens. Here we present, for the first time, an unbiased bacterial global immunoinformatic screen of the 1740 proteins of F. tularensis subs. holarctica (LVS), aiming at identification of immunogenic peptides eliciting a CTL response. The very large number of predicted MHC class I binders (about 100,000, IC50 of 1000 nM or less) required the design of a strategy for further down selection of CTL candidates. The approach developed focused on mapping clusters rich in overlapping predicted epitopes, and ranking these “hotspot” regions according to the density of putative binding epitopes. Limited by the experimental load, we selected to screen a library of 1240 putative MHC binders derived from 104 top-ranking highly dense clusters. Peptides were tested for their ability to stimulate IFNγ secretion from splenocytes isolated from LVS vaccinated C57BL/6 mice. The majority of the clusters contained one or more CTL responder peptides and altogether 127 novel epitopes were identified, of which 82 are non-redundant. Accordingly, the level of success in identification of positive CTL responders was 17–25 fold higher than that found for a randomly selected library of 500 predicted MHC binders (IC50 of 500 nM or less). Most proteins (ca. 2/3) harboring the highly dense hotspots are membrane-associated. The approach for enrichment of true positive CTL epitopes described in this study, which allowed for over 50% increase in the dataset of known T-cell epitopes of F. tularensis, could be applied in immunoinformatic analyses of many other complex pathogen genomes
Pathogen Proteins Eliciting Antibodies Do Not Share Epitopes with Host Proteins: A Bioinformatics Approach
The best way to prevent diseases caused by pathogens is by the use of vaccines. The advent of genomics enables genome-wide searches of new vaccine candidates, called reverse vaccinology. The most common strategy to apply reverse vaccinology is by designing subunit recombinant vaccines, which usually generate an humoral immune response due to B-cell epitopes in proteins. A major problem for this strategy is the identification of protective immunogenic proteins from the surfome of the pathogen. Epitope mimicry may lead to auto-immune phenomena related to several human diseases. A sequence-based computational analysis has been carried out applying the BLASTP algorithm. Therefore, two huge databases have been created, one with the most complete and current linear B-cell epitopes, and the other one with the surface-protein sequences of the main human respiratory bacterial pathogens. We found that none of the 7353 linear B-cell epitopes analysed shares any sequence identity region with human proteins capable of generating antibodies, and that only 1% of the 2175 exposed proteins analysed contain a stretch of shared sequence with the human proteome. These findings suggest the existence of a mechanism to avoid autoimmunity. We also propose a strategy for corroborating or warning about the viability of a protein linear B-cell epitope as a putative vaccine candidate in a reverse vaccinology study; so, epitopes without any sequence identity with human proteins should be very good vaccine candidates, and the other way around
A large topographic feature on the surface of the trans-Neptunian object (307261) 2002 MS measured from stellar occultations
This work aims at constraining the size, shape, and geometric albedo of the
dwarf planet candidate 2002 MS4 through the analysis of nine stellar
occultation events. Using multichord detection, we also studied the object's
topography by analyzing the obtained limb and the residuals between observed
chords and the best-fitted ellipse. We predicted and organized the
observational campaigns of nine stellar occultations by 2002 MS4 between 2019
and 2022, resulting in two single-chord events, four double-chord detections,
and three events with three to up to sixty-one positive chords. Using 13
selected chords from the 8 August 2020 event, we determined the global
elliptical limb of 2002 MS4. The best-fitted ellipse, combined with the
object's rotational information from the literature, constrains the object's
size, shape, and albedo. Additionally, we developed a new method to
characterize topography features on the object's limb. The global limb has a
semi-major axis of 412 10 km, a semi-minor axis of 385 17 km, and
the position angle of the minor axis is 121 16. From
this instantaneous limb, we obtained 2002 MS4's geometric albedo and the
projected area-equivalent diameter. Significant deviations from the fitted
ellipse in the northernmost limb are detected from multiple sites highlighting
three distinct topographic features: one 11 km depth depression followed by a
25 km height elevation next to a crater-like depression with an
extension of 322 39 km and 45.1 1.5 km deep. Our results present an
object that is 138 km smaller in diameter than derived from thermal
data, possibly indicating the presence of a so-far unknown satellite. However,
within the error bars, the geometric albedo in the V-band agrees with the
results published in the literature, even with the radiometric-derived albedo
ExoClock Project III: 450 new exoplanet ephemerides from ground and space observations
The ExoClock project has been created with the aim of increasing the
efficiency of the Ariel mission. It will achieve this by continuously
monitoring and updating the ephemerides of Ariel candidates over an extended
period, in order to produce a consistent catalogue of reliable and precise
ephemerides. This work presents a homogenous catalogue of updated ephemerides
for 450 planets, generated by the integration of 18000 data points from
multiple sources. These sources include observations from ground-based
telescopes (ExoClock network and ETD), mid-time values from the literature and
light-curves from space telescopes (Kepler/K2 and TESS). With all the above, we
manage to collect observations for half of the post-discovery years (median),
with data that have a median uncertainty less than one minute. In comparison
with literature, the ephemerides generated by the project are more precise and
less biased. More than 40\% of the initial literature ephemerides had to be
updated to reach the goals of the project, as they were either of low precision
or drifting. Moreover, the integrated approach of the project enables both the
monitoring of the majority of the Ariel candidates (95\%), and also the
identification of missing data. The dedicated ExoClock network effectively
supports this task by contributing additional observations when a gap in the
data is identified. These results highlight the need for continuous monitoring
to increase the observing coverage of the candidate planets. Finally, the
extended observing coverage of planets allows us to detect trends (TTVs -
Transit Timing Variations) for a sample of 19 planets. All products, data, and
codes used in this work are open and accessible to the wider scientific
community.Comment: Recommended for publication to ApJS (reviewer's comments
implemented). Main body: 13 pages, total: 77 pages, 7 figures, 7 tables. Data
available at http://doi.org/10.17605/OSF.IO/P298
Recommended from our members
ExoClock Project. III. 450 New Exoplanet Ephemerides from Ground and Space Observations
The ExoClock project has been created to increase the efficiency of the Ariel mission. It will achieve this by continuously monitoring and updating the ephemerides of Ariel candidates, in order to produce a consistent catalog of reliable and precise ephemerides. This work presents a homogenous catalog of updated ephemerides for 450 planets, generated by the integration of ∼18,000 data points from multiple sources. These sources include observations from ground-based telescopes (the ExoClock network and the Exoplanet Transit Database), midtime values from the literature, and light curves from space telescopes (Kepler, K2, and TESS). With all the above, we manage to collect observations for half of the postdiscovery years (median), with data that have a median uncertainty less than 1 minute. In comparison with the literature, the ephemerides generated by the project are more precise and less biased. More than 40% of the initial literature ephemerides had to be updated to reach the goals of the project, as they were either of low precision or drifting. Moreover, the integrated approach of the project enables both the monitoring of the majority of the Ariel candidates (95%), and also the identification of missing data. These results highlight the need for continuous monitoring to increase the observing coverage of the candidate planets. Finally, the extended observing coverage of planets allows us to detect trends (transit-timing variations) for a sample of 19 planets. All the products, data, and codes used in this work are open and accessible to the wider scientific community