A Comprehensive Review of the Immunological Response against Foot-and-Mouth Disease Virus Infection and Its Evasion Mechanisms

Foot-and-mouth disease (FMD) is a highly contagious viral disease, which has been reported for over 100 years, and against which the struggle has lasted for the same amount of time. It affects individuals from the order Artiodactyla, such as cattle, swine, sheep, wild animals from this order, and a few non-cloven hoofed species, such as mice and elephants. FMD causes large-scale economic losses for agricultural production systems; morbidity is almost 100% in an affected population, accompanied by a high mortality rate in young animals due to myocarditis or an inability to suckle if a mother is ill. The aetiological agent is an Aphthovirus from the family Picornaviridae, having seven serotypes: A, O, C, SAT1, SAT2, SAT3, and Asia 1. Serotype variability means that an immune response is serospecific and vaccines are thus designed to protect against each serotype independently. A host’s adaptive immune response is key in defence against pathogens; however, this virus uses successful strategies (along with most microorganisms) enabling it to evade a host’s immune system to rapidly and efficiently establish itself within such host, and thus remain there. This review has been aimed at an in-depth analysis of the immune response in cattle and swine regarding FMD virus, the possible evasion mechanisms used by the virus and describing some immunological differences regarding these species. Such aspects can provide pertinent knowledge for developing new FMD control and prevention strategie

Synthetic evaluation of standard and microwave-assisted solid phase peptide synthesis of a long chimeric peptide derived from four Plasmodium falciparum proteins

An 82-residue-long chimeric peptide was synthesised by solid phase peptide synthesis (SPPS), following the Fmoc protocol. Microwave (MW) radiation-assisted synthesis was compared to standard synthesis using low loading (0.20 mmol/g) of polyethylene glycol (PEG) resin. Similar synthetic difficulties were found when the chimeric peptide was obtained via these two reaction conditions, indicating that such difficulties were inherent to the sequence and could not be resolved using MW; by contrast, the number of coupling cycles and total reaction time became reduced whilst crude yield and percentage recovery after purification were higher for MW radiation-assisted synthesis. © 2018 by the authors

Mass & secondary structure propensity of amino acids explain their mutability and evolutionary replacements

Why is an amino acid replacement in a protein accepted during evolution? The answer given by bioinformatics relies on the frequency of change of each amino acid by another one and the propensity of each to remain unchanged. We propose that these replacement rules are recoverable from the secondary structural trends of amino acids. A distance measure between high-resolution Ramachandran distributions reveals that structurally similar residues coincide with those found in substitution matrices such as BLOSUM: Asn Asp, Phe Tyr, Lys Arg, Gln Glu, Ile Val, Met → Leu; with Ala, Cys, His, Gly, Ser, Pro, and Thr, as structurally idiosyncratic residues. We also found a high average correlation (\overline{R} R = 0.85) between thirty amino acid mutability scales and the mutational inertia (I X ), which measures the energetic cost weighted by the number of observations at the most probable amino acid conformation. These results indicate that amino acid substitutions follow two optimally-efficient principles: (a) amino acids interchangeability privileges their secondary structural similarity, and (b) the amino acid mutability depends directly on its biosynthetic energy cost, and inversely with its frequency. These two principles are the underlying rules governing the observed amino acid substitutions. © 2017 The Author(s)

Cationic Peptides Harboring Antibiotic Capacity are Selective for Leishmania panamensis and Leishmania major

The fairly recent appearance of Leishmania resistance to currently-used therapy has led to the search for new therapeutic strategies. This work was thus aimed at evaluating the in vitro effect of 18 cationic synthetic antimicrobial peptides for antileishmanial and cytotoxic and haemolytic activity. The viability of murine (J774) and human (U937), peripheral blood monocytes, HeLa and HepG2 cells and L. (V) panamensis and L. (L) major promastigotes was then ascertained using the aforementioned peptides. All antimicrobial peptides were synthesised and each cell and parasite line was treated with different peptide concentrations. Melittin, bombinin, mastoparan 8 (MP-8), MP-X and dermaseptin-S1 reduced human and murine host cells' viability at greater concentrations than pentamidine isethionate, human peripheral blood and U937 monocytes being the most sensitive to peptide action. Melittin had a toxic effect on all the cells evaluated in this study and L. (L) major was more sensitive than L. (V) panamensis to peptide effect. As MP-8, bombinin, dermaseptin-S1 and tracheal antimicrobial peptide (TAP) were active against both parasite species, and tachyplesin 1 and polystes MA selectively so for L. (L) major, they were selected as being promising as they had a >1 selectivity index (SI) and greater than 50 μg/mL haemolytic concentration (HC50), suggesting that they should continue to be studied in in vitro and in vivo infection assays as there have been no previous reports of MP-8, bombinin, TAP and Polystes MA activity regarding L. (V) panamensis and L. (L) major. © 2014 Lozano JM, et al

Mycobacterium tuberculosis H37Rv LpqG protein peptides can inhibit mycobacterial entry through specific interactions

Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease causing major mortality worldwide. As part of a systematic methodology for studying M. tuberculosis surface proteins which might be involved in host-pathogen interactions, our group found that LpqG surface protein (Rv3623) found in M. tuberculosis complex strains was located on the mycobacterial envelope and that peptide 16661 (21SGCDSHNSGSLGADPRQVTVY40) had high specific binding to U937 monocyte-derived macrophages and inhibited mycobacterial entry to such cells in a concentration-dependent way. A region having high specific binding to A549 alveolar epithelial cells was found which had low mycobacterial entry inhibition. As suggested in previous studies, relevant sequences in the host-pathogen interaction do not induce an immune response and peptides characterised as HABPs are poorly recognised by sera from individuals regardless of whether they have been in contact with M. tuberculosis. Our approach to designing a synthetic, multi-epitope anti-tuberculosis vaccine has been based on identifying sequences involved in different proteins' mycobacteria-target cell interaction and modifying their sequence to improve their immunogenic characteristics, meaning that peptide 16661 sequence should be considered in such design. © 2018 by the authors

Plasmodium falciparum Blood Stage Antimalarial Vaccines: An Analysis of Ongoing Clinical Trials and New Perspectives Related to Synthetic Vaccines

Plasmodium falciparum malaria is a disease causing high morbidity and mortality rates worldwide, mainly in sub-Saharan Africa. Candidates have been identified for vaccines targeting the parasite’s blood stage; this stage is important in the development of symptoms and clinical complications. However, no vaccine that can directly affect morbidity and mortality rates is currently available. This review analyzes the formulation, methodological design, and results of active clinical trials for merozoite-stage vaccines, regarding their safety profile, immunological response (phase Ia/Ib), and protective efficacy levels (phase II). Most vaccine candidates are in phase I trials and have had an acceptable safety profile. GMZ2 has made the greatest progress in clinical trials; its efficacy has been 14% in children aged less than 5 years in a phase IIb trial. Most of the available candidates that have shown strong immunogenicity and that have been tested for their protective efficacy have provided good results when challenged with a homologous parasite strain; however, their efficacy has dropped when they have been exposed to a heterologous strain. In view of these vaccines’ unpromising results, an alternative approach for selecting new candidates is needed; such line of work should be focused on how to increase an immune response induced against the highly conserved (i.e., common to all strains), functionally relevant, protein regions that the parasite uses to invade target cells. Despite binding regions tending to be conserved, they are usually poorly antigenic and/or immunogenic, being frequently discarded as vaccine candidates when the conventional immunological approach is followed. The Fundación Instituto de Inmunología de Colombia (FIDIC) has developed a logical and rational methodology based on including conserved high-activity binding peptides (cHABPs) from the main P. falciparum biologically functional proteins involved in red blood cell (RBC) invasion. Once appropriately modified (mHABPs), these minimal, subunit-based, chemically synthesized peptides can be used in a system covering the human immune system’s main genetic variables (the human leukocyte antigen HLA-DR isotype) inducing a suitable, immunogenic, and protective immune response in most of the world’s populations. © Copyright © 2019 Salamanca, Gómez, Camargo, Cuy-Chaparro, Molina-Franky, Reyes, Patarroyo and Patarroyo

Plasmodium falciparum pre-erythrocytic stage vaccine development

Worldwide strategies between 2010 and 2017 aimed at controlling malarial parasites (mainly Plasmodium falciparum) led to a reduction of just 18% regarding disease incidence rates. Many biologically-derived anti-malarial vaccine candidates have been developed to date; this has involved using many experimental animals, an immense amount of work and the investment of millions of dollars. This review provides an overview of the current state and the main results of clinical trials for sporozoite-targeting vaccines (i.e. the parasite stage infecting the liver) carried out by research groups in areas having variable malaria transmission rates. However, none has led to promising results regarding the effective control of the disease, thereby making it necessary to complement such efforts at finding/introducing new vaccine candidates by adopting a multi-epitope, multi-stage approach, based on minimal subunits of the main sporozoite proteins involved in the invasion of the liver. © 2020 The Author(s)

How frequently do clusters occur in hierarchical clustering analysis? A graph theoretical approach to studying ties in proximity

Background: Hierarchical cluster analysis (HCA) is a widely used classificatory technique in many areas of scientific knowledge. Applications usually yield a dendrogram from an HCA run over a given data set, using a grouping algorithm and a similarity measure. However, even when such parameters are fixed, ties in proximity (i.e. two equidistant clusters from a third one) may produce several different dendrograms, having different possible clustering patterns (different classifications). This situation is usually disregarded and conclusions are based on a single result, leading to questions concerning the permanence of clusters in all the resulting dendrograms; this happens, for example, when using HCA for grouping molecular descriptors to select that less similar ones in QSAR studies. Results: Representing dendrograms in graph theoretical terms allowed us to introduce four measures of cluster frequency in a canonical way, and use them to calculate cluster frequencies over the set of all possible dendrograms, taking all ties in proximity into account. A toy example of well separated clusters was used, as well as a set of 1666 molecular descriptors calculated for a group of molecules having hepatotoxic activity to show how our functions may be used for studying the effect of ties in HCA analysis. Such functions were not restricted to the tie case; the possibility of using them to derive cluster stability measurements on arbitrary sets of dendrograms having the same leaves is discussed, e.g. dendrograms from variations of HCA parameters. It was found that ties occurred frequently, some yielding tens of thousands of dendrograms, even for small data sets. Conclusions: Our approach was able to detect trends in clustering patterns by offering a simple way of measuring their frequency, which is often very low. This would imply, that inferences and models based on descriptor classifications (e.g. QSAR) are likely to be biased, thereby requiring an assessment of their reliability. Moreover, any classification of molecular descriptors is likely to be far from unique. Our results highlight the need for evaluating the effect of ties on clustering patterns before classification results can be used accurately. © 2016 Leal et al

The DNA load of six high-risk human papillomavirus types and its association with cervical lesions

Background: Analysing human papillomavirus (HPV) viral load is important in determining the risk of developing cervical cancer (CC); most knowledge to date regarding HPV viral load and cervical lesions has been related to HPV-16. This study evaluated the association between the viral load of the six most prevalent high-risk viral types in Colombia and cervical intraepithelial neoplasia (CIN) frequency. Methods: 114 women without CIN and 59 women having CIN confirmed by colposcopy, all of them positive by conventional PCR for HPV infection in the initial screening, were included in the study. Samples were tested for six high-risk HPV types to determine viral copy number by real-time PCR. Crude and adjusted odds ratios (ORa) were estimated for evaluating the association between each viral type's DNA load and the risk of cervical lesions occurring. Results: The highest viral loads were identified for HPV-33 in CIN patients and for HPV-31 in patients without lesions (9.33 HPV copies, 2.95 interquartile range (IQR); 9.41 HPV copies, 2.58 IQR). Lesions were more frequent in HPV-16 patients having a low viral load (3.53 ORa, 1.16-10.74 95%CI) compared to those having high HPV-16 load (2.62 ORa, 1.08-6.35 95%CI). High viral load in HPV-31 patients was associated with lower CIN frequency (0.34 ORa, 0.15-0.78 95%CI). Conclusions: An association between HPV DNA load and CIN frequency was seen to be type-specific and may have depended on the duration of infection. This analysis has provided information for understanding the effect of HPV DNA load on cervical lesion development.This project was supported by the Basque Development Cooperation Agency, the Spanish International Development Cooperation Agency (AECID) (Project 10-CAP1-0197) and the Colombian Science, Technology and Innovation Department (COLCIENCIAS) (contract # 0709-2013)