Antimicrobial peptides (AMPs) represent a promising and effective alternative for combating pathogens, having some advantages compared to conventional antibiotics. However, AMPs must also contend ...with complex and specialised Gram-negative bacteria envelops. The variety of lipopolysaccharide and phospholipid composition in Gram-negative bacteria strains and species are decisive characteristics regarding their susceptibility or resistance to AMPs. Such biological and structural barriers have created delays in tuning AMPs to deal with Gram-negative bacteria. This becomes even more acute because little is known about the interaction AMP-Gram-negative bacteria and/or AMPs' physicochemical characteristics, which could lead to obtaining selective molecules against Gram-negative bacteria. As a consequence, available AMPs usually have highly associated haemolytic and/or cytotoxic activity. Only one AMP has so far been FDA approved and another two are currently in clinical trials against Gram-negative bacteria. Such a pessimistic panorama suggests that efforts should be concentrated on the search for new molecules, designs and strategies for combating infection caused by this type of microorganism. This review has therefore been aimed at describing the currently available AMPs for combating Gram-negative bacteria, exploring the characteristics of these bacteria's cell envelop hampering the development of new AMPs, and offers a perspective regarding the challenges for designing new AMPs against Gram-negative bacteria.
Adjuvants represent one of the most significant biotechnological solutions regarding vaccine development, thereby broadening the amount of candidates which can now be used and tested in vaccine ...formulations targeting various pathogens, as antigens which were previously discarded due to their low or null immunogenicity can now be included. Adjuvant development research has grown side-by-side with an increasing body of knowledge regarding immune systems and their recognition of foreign microorganisms. Alum-derived adjuvants were used in human vaccines for many years, even though complete understanding of their vaccination-related mechanism of action was lacking. The amount of adjuvants approved for human use has increased recently in line with attempts to interact with and stimulate the immune system. This review is aimed at summarising what is known about adjuvants, focusing on those approved for use in humans, their mechanism of action and why they are so necessary for vaccine candidate formulations; it also discusses what the future may hold in this growing research field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Major histocompatibility class II molecule-peptide-T-cell receptor (MHCII-p-TCR) complex-mediated antigen presentation for a minimal subunit-based, multi-epitope, multistage, chemically-synthesised ...antimalarial vaccine is essential for inducing an appropriate immune response. Deep understanding of this MHCII-p-TCR complex's stereo-electronic characteristics is fundamental for vaccine development. This review encapsulates the main principles for achieving such epitopes' perfect fit into MHC-II human (HLADRβ̞1*) or
(Aona DR) molecules. The enormous relevance of several amino acids' physico-chemical characteristics is analysed in-depth, as is data regarding a 26.5 ± 2.5Å distance between the farthest atoms fitting into HLA-DRβ1* structures' Pockets 1 to 9, the role of polyproline II-like (PPII
) structures having their O and N backbone atoms orientated for establishing H-bonds with specific HLA-DRβ1*-peptide binding region (PBR) residues. The importance of residues having specific charge and orientation towards the TCR for inducing appropriate immune activation, amino acids' role and that of structures interfering with PPII
formation and other principles are demonstrated which have to be taken into account when designing immune, protection-inducing peptide structures (IMPIPS) against diseases scourging humankind, malaria being one of them.
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•The dendritic cells (DCs’) process peptides antigens and present them to T cells to promote immunity protective to Mycobacterium tuberculosis.•Twenty-one peptides evaluated were able ...to induce CD4 + lymphocyte proliferation.•They peptides promoted to inhibition of mycobacterial intracellular growth in infected macrophages.•The evaluation of peptide sequences’ antigenicity and immunogenicity, as potential candidates for designing an anti-tuberculosis synthetic vaccine using DCs’ presenting capability.
Mycobacterium tuberculosis is one of the most successful pathogens affecting humans, being the main cause of tuberculosis. It accounts for most infectious agent-related deaths worldwide; it has been estimated that a third of the world’s population are bacillus carriers. This pathogen’s evolutionary adaptation is mainly due to its ability to block a host’s immune system by preventing it using an effective immune response in cases of active tuberculosis. Peptide-based synthetic vaccines represent an alternative for counteracting tuberculosis; however, although peptide antigens can be identified, they are not recognised by a host’s immune system. An approach using dendritic cells as immunomodulating agents for increasing synthetic peptides’ antigenic capacity has thus been advanced. Dendritic cells obtained from IL to 4- and GM-CSF-treated peripheral blood mononuclear cells were pulsed with synthetic Mtb protein peptides which have been reported as participating in mycobacteria-host interactions; their amino acid sequences were modified to improve MHC-II coupling and thus increase their recognition by a host’s immune system. pMHC-II/TCR interaction triggered a lymphocyte response which controlled Mtb intracellular growth in infected macrophages. This work has been aimed at contributing to understanding dendritic cells’ role in Mycobacterium tuberculosis protein peptide antigen presentation, thereby increasing individuals’ immune response as a means of controlling the disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Self-assembly involves a set of molecules spontaneously interacting in a highly coordinated and dynamic manner to form a specific supramolecular structure having new and clearly defined properties. ...Many examples of this occur in nature and many more came from research laboratories, with their number increasing every day via ongoing research concerning complex biomolecules and the possibility of harnessing it when developing new applications. As a phenomenon, self-assembly has been described on very different types of molecules (biomolecules including), so this review focuses on what is known about peptide self-assembly, its origins, the forces behind it, how the properties of the resulting material can be tuned in relation to experimental considerations, some biotechnological applications (in which the main protagonists are peptide sequences capable of self-assembly) and what is yet to be tuned regarding their research and development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Blastocystis and Clostridioides difficile co-occurrence is considered a rare event since the colonization by Blastocystis is prevented under a decrease in beneficial bacteria in the microbiota when ...there is C. difficile infection (CDI). This scenario has been reported once, but no information on the gut microbiota profiling is available. The present study is motivated by knowing which members of the microbiota can be found in this rare scenario and how this co-occurrence may impact the abundance of other bacteria, eukaryotes or archaea present in the gut microbiota. This study aimed to describe the bacterial and eukaryotic communities using amplicon-based sequencing of the 16S- and 18S-rRNA regions of three patient groups: (1) Blastocystis and C. difficile infection (B+/C+, n = 31), (2) C. difficile infection only (B-/C+, n = 44), and (3) without Blastocystis or C. difficile (B-/C-, n = 40). Blastocystis was subtyped using amplicon-based sequencing of the 18S-rRNA gene, revealing circulation of subtypes ST1 (43.4%), ST3 (35.85%) and ST5 (20.75%) among the study population. We found that B+/C+ patients had a higher abundance of some beneficial bacteria (such as butyrate producers or bacteria with anti-inflammatory properties) compared with non-Blastocystis-colonized patients, which may suggest a shift towards an increase in beneficial bacteria when Blastocystis colonizes patients with CDI. Regarding eukaryotic communities, statistical differences in the abundance of some eukaryotic genera between the study groups were not observed. Thus, this study provides preliminary descriptive information of a potential microbiota profiling of differential presence by Blastocystis and C. difficile.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
HLA class II (HLA-II) genes' polymorphism influences the immune response to Chlamydia trachomatis (Ct), it is considered a sexually transmitted infection. However, associations between HLA-II alleles ...and Ct-infection have been little explored in humans; this study was thus aimed at determining HLA-DRB1-DQB1 alleles/haplotypes' effect on Ct-infection outcome in a cohort of Colombian women. Cervical sample DNA was used as template for detecting Ct by PCR and typing HLA-DRB1-DQB1 alleles/haplotypes by Illumina MiSeq sequencing. Survival models were adjusted for identifying the alleles/haplotypes' effect on Ct-outcome; bioinformatics tools were used for predicting secreted bacterial protein T- and B-cell epitopes. Sixteen HLA-DRB1 alleles having a significant effect on Ct-outcome were identified in the 262 women analysed. DRB1*08:02:01G and DRB1*12:01:01G were related to infection-promoting events. Only the DQB1*05:03:01G allele related to clearance/persistence events was found for HLA-DQB1. HLA-DRB1 allele homozygous women were associated with events having a lower probability of clearance and/or early occurrence of persistence. Twenty-seven peptides predicted in silico were associated with protective immunity against Ct; outer membrane and polymorphic membrane protein-derived peptides had regions having dual potential for being T- or B-cell epitopes. This article describes HLA-DRB1-DQB1 alleles/haplotypes related to Ct-infection resolution and the peptides predicted in silico which might probably be involved in host immune response. The data provides base information for developing future studies leading to the development of effective prevention measures against Ct-infection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This work describes a methodology for developing a minimal, subunit-based, multi-epitope, multi-stage, chemically-synthesised, anti-Plasmodium falciparum malaria vaccine. Some modified high activity ...binding peptides (mHABPs) derived from functionally relevant P. falciparum MSP, RH5 and AMA-1 conserved amino acid regions (cHABPs) for parasite binding to and invasion of red blood cells (RBC) were selected. They were highly immunogenic as assessed by indirect immunofluorescence (IFA) and Western blot (WB) assays and protective immune response-inducers against malarial challenge in the Aotus monkey experimental model. NetMHCIIpan 4.0 was used for predicting peptide-Aotus/human major histocompatibility class II (MHCII) binding affinity in silico due to the similarity between Aotus and human immune system molecules; ∼50% of Aotus MHCII allele molecules have a counterpart in the human immune system, being Aotus-specific, whilst others enabled recognition of their human counterparts. Some peptides’ 1H-NMR-assessed structural conformation was determined to explain residue modifications in mHABPs inducing secondary structure changes. These directly influenced immunological behaviour, thereby highlighting the relationship with MHCII antigen presentation. The data obtained in such functional, immunological, structural and predictive approach suggested that some of these peptides could be excellent components of a fully-protective antimalarial vaccine.
•Relevant proteins’ conserved regions must be modified to induce a proper immune response.•cHABP modifications induced changes in their structure and immunological behaviour.•Many mHABPs are highly immunogenic and protection-inducing in Aotus monkeys.•50% of Aotus MHCII alleles have counterparts in the human immune system.•This methodology could be used for human vaccine development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The mycobacterial cell envelope has been implicated in the pathogenicity of tuberculosis and therefore has been a prime target for the identification and characterization of surface proteins with ...potential application in drug and vaccine development. In this study, the genome of Mycobacterium tuberculosis H37Rv was screened using Machine Learning tools that included feature-based predictors, general localizers and transmembrane topology predictors to identify proteins that are potentially secreted to the surface of M. tuberculosis, or to the extracellular milieu through different secretory pathways. The subcellular localization of a set of 8 hypothetically secreted/surface candidate proteins was experimentally assessed by cellular fractionation and immunoelectron microscopy (IEM) to determine the reliability of the computational methodology proposed here, using 4 secreted/surface proteins with experimental confirmation as positive controls and 2 cytoplasmic proteins as negative controls. Subcellular fractionation and IEM studies provided evidence that the candidate proteins Rv0403c, Rv3630, Rv1022, Rv0835, Rv0361 and Rv0178 are secreted either to the mycobacterial surface or to the extracellular milieu. Surface localization was also confirmed for the positive controls, whereas negative controls were located on the cytoplasm. Based on statistical learning methods, we obtained computational subcellular localization predictions that were experimentally assessed and allowed us to construct a computational protocol with experimental support that allowed us to identify a new set of secreted/surface proteins as potential vaccine candidates.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malaria outbreaks have been reported in recent years in the Colombian Amazon region, malaria has been re-emerging in areas where it was previously controlled. Information from malaria transmission ...networks and knowledge about the population characteristics influencing the dispersal of parasite species is limited. This study aimed to determine the distribution patterns of Plasmodium vivax, P. malariae and P. falciparum single and mixed infections, as well as the significant socio-spatial groupings relating to the appearance of such infections. An active search in 57 localities resulted in 2,106 symptomatic patients being enrolled. Parasitaemia levels were assessed by optical microscopy, and parasites were detected by PCR. The association between mixed infections (in 43.2% of the population) and socio-spatial factors was modelled using logistic regression and multiple correspondence analyses. P. vivax occurred most frequently (71.0%), followed by P. malariae (43.2%), in all localities. The results suggest that a parasite density-dependent regulation model (with fever playing a central role) was appropriate for modelling the frequency of mixed species infections in this population. This study highlights the under-reporting of Plasmodium spp. mixed infections in the malaria-endemic area of the Colombian Amazon region and the association between causative and environmental factors in such areas.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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