Toll-Like Receptors and Viruses: Induction of Innate Antiviral Immune Responses

Induction of antiviral innate immune responses depends on a family of innate immune receptors, the Toll-like receptors (TLR). TLR mediate the antiviral immune responses by recognizing virus infection, activating signaling pathways and inducing the production of antiviral cytokines and chemokines. ssRNA and dsRNA viruses can be recognized by TLR7/8 and TLR3, respectively. TLR receptors are also involved in the recognition of viruses containing genomes rich in CpG DNA motifs as well as envelope glycoproteins. Cytoplasmic recognition of dsRNA by RNA helicases such as RIG-I and MDA5 provides another means of recognizing viral nucleic acid. In order to counteract the innate host immune system viruses evolved mechanisms that block recognition and signaling through pattern recognition receptors, such as TLRs and RNA helicases. Recently, TLR agonists represent a promising approach for the treatment of infectious diseases. This review will focus on the current knowledge of TLR-mediated immune responses to several viral infections

Το δικαίωμα σύναψης γάμου και η υιοθεσία από ομόφυλα ζευγάρια : ισχύον νομικό πλαίσιο και προοπτικές

Στην παρούσα εργασία γίνεται επισκόπηση της δυνατότητας πρόσβασης των ομόφυλων ζευγαριών στον γάμο και την υιοθεσία ανηλίκων στο πλαίσιο του ελληνικού Αστικού Δικαίου, ενώ οι ισχύουσες ρυθμίσεις διηθηθούνται από τη σύμφωνη με το Σύνταγμα ερμηνεία λόγω του θεσμικού τους χαρακτήρα. Κατόπιν, εξετάζεται η νομολογία του Ευρωπαϊκού Δικαστηρίου Δικαιωμάτων του Ανθρώπου αναφορικά με τα ως άνω δικαιώματα. Από την παρούσα εργασία δεν θα μπορούσε να λείπει μία σύντομη δικαιοσυγκριτική επισκόπηση των εθνικών νομοθεσιών σε επίπεδο Συμβουλίου της Ευρώπης. Ειδικότερα, μελετώνται δύο παραδείγματα ευρωπαϊκών εννόμων τάξεων, της Αγγλίας και της Ιταλίας, οι οποίες επιλέχθηκαν με κριτήριο τη συγκρισιμότητά τους ή μη σε σχέση με την Ελλάδα αναφορικά με το επιτρεπτό του γάμου και της υιοθεσίας για τα ομόφυλα ζευγάρια. Τέλος, αναπτύσσονται οι απόψεις της γράφουσας για το επιτρεπτό de lege lata και de lege ferenda, καθώς και άλλα επιμέρους ζητήματα τα οποία προκύπτουν σαν ερωτήματα κατά τη διάρκεια της παρούσας.This paper reviews the possibility of same-sex couples having access to marriage and the adoption of minors in the context of Civil Law, while the current regulations are interpreted in a matter consistent with the Greek Constitution. At a second stage, the writer examines the case-law of the European Court of Human Rights regarding the above rights. Of course, this paper could not lack a brief comparative review of national legislations in the European area. More specifically, two examples of European legal systems, the English and the Italian one, are studied, which were chosen based on their comparability or not in relation to Greece’s legal system regarding the permissibility of marriage and adoption for same-sex couples. Finally, the writer’s views on the permissibility of marriage and adoption for same-sex couples de lege lata and de lege ferenda are developed, as well as other issues regarding the subject of this paper that arise as questions during the present study

Association of TLR7 Variants with AIDS-Like Disease and AIDS Vaccine Efficacy in Rhesus Macaques

In HIV infection, TLR7-triggered IFN-α production exerts a direct antiviral effect through the inhibition of viral replication, but may also be involved in immune pathogenesis leading to AIDS. TLR7 could also be an important mediator of vaccine efficacy. In this study, we analyzed polymorphisms in the X-linked TLR7 gene in the rhesus macaque model of AIDS. Upon resequencing of the TLR7 gene in 36 rhesus macaques of Indian origin, 12 polymorphic sites were detected. Next, we identified three tightly linked single nucleotide polymorphisms (SNP) as being associated with survival time. Genotyping of 119 untreated, simian immunodeficiency virus (SIV)-infected male rhesus macaques, including an ‘MHC adjusted’ subset, revealed that the three TLR7 SNPs are also significantly associated with set-point viral load. Surprisingly, this effect was not observed in 72 immunized SIV-infected male monkeys. We hypothesize (i) that SNP c.13G>A in the leader peptide is causative for the observed genotype-phenotype association and that (ii) the underlying mechanism is related to RNA secondary structure formation. Therefore, we investigated a fourth SNP (c.-17C>T), located 17 bp upstream of the ATG translation initiation codon, that is also potentially capable of influencing RNA structure. In c.13A carriers, neither set-point viral load nor survival time were related to the c.-17C>T genotype. In c.13G carriers, by contrast, the c.-17C allele was significantly associated with prolonged survival. Again, no such association was detected among immunized SIV-infected macaques. Our results highlight the dual role of TLR7 in immunodeficiency virus infection and vaccination and imply that it may be important to control human AIDS vaccine trials, not only for MHC genotype, but also for TLR7 genotype

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Cationic Host Defence Peptides:Potential as Antiviral Therapeutics

There is a pressing need to develop new antiviral treatments; of the 60 drugs currently available, half are aimed at HIV-1 and the remainder target only a further six viruses. This demand has led to the emergence of possible peptide therapies, with 15 currently in clinical trials. Advancements in understanding the antiviral potential of naturally occurring host defence peptides highlights the potential of a whole new class of molecules to be considered as antiviral therapeutics. Cationic host defence peptides, such as defensins and cathelicidins, are important components of innate immunity with antimicrobial and immunomodulatory capabilities. In recent years they have also been shown to be natural, broad-spectrum antivirals against both enveloped and non-enveloped viruses, including HIV-1, influenza virus, respiratory syncytial virus and herpes simplex virus. Here we review the antiviral properties of several families of these host peptides and their potential to inform the design of novel therapeutics

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

BackgroundThe PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice.MethodsFebrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed.FindingsOf 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively.InterpretationMost febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.FundingEU Horizon 2020 grant 668303