A poxvirus Bcl-2-like gene family involved in regulation of host immune response: sequence similarity and evolutionary history

<p>Abstract</p> <p>Background</p> <p>Poxviruses evade the immune system of the host through the action of viral encoded inhibitors that block various signalling pathways. The exact number of viral inhibitors is not yet known. Several members of the vaccinia virus A46 and N1 families, with a Bcl-2-like structure, are involved in the regulation of the host innate immune response where they act non-redundantly at different levels of the Toll-like receptor signalling pathway. N1 also maintains an anti-apoptotic effect by acting similarly to cellular Bcl-2 proteins. Whether there are related families that could have similar functions is the main subject of this investigation.</p> <p>Results</p> <p>We describe the sequence similarity existing among poxvirus A46, N1, N2 and C1 protein families, which share a common domain of approximately 110-140 amino acids at their C-termini that spans the entire N1 sequence. Secondary structure and fold recognition predictions suggest that this domain presents an all-alpha-helical fold compatible with the Bcl-2-like structures of vaccinia virus proteins N1, A52, B15 and K7. We propose that these protein families should be merged into a single one. We describe the phylogenetic distribution of this family and reconstruct its evolutionary history, which indicates an extensive gene gain in ancestral viruses and a further stabilization of its gene content.</p> <p>Conclusions</p> <p>Based on the sequence/structure similarity, we propose that other members with unknown function, like vaccinia virus N2, C1, C6 and C16/B22, might have a similar role in the suppression of host immune response as A46, A52, B15 and K7, by antagonizing at different levels with the TLR signalling pathways.</p

Viral Control of Mitochondrial Apoptosis

Throughout the process of pathogen–host co-evolution, viruses have developed a battery of distinct strategies to overcome biochemical and immunological defenses of the host. Thus, viruses have acquired the capacity to subvert host cell apoptosis, control inflammatory responses, and evade immune reactions. Since the elimination of infected cells via programmed cell death is one of the most ancestral defense mechanisms against infection, disabling host cell apoptosis might represent an almost obligate step in the viral life cycle. Conversely, viruses may take advantage of stimulating apoptosis, either to kill uninfected cells from the immune system, or to induce the breakdown of infected cells, thereby favoring viral dissemination. Several viral polypeptides are homologs of host-derived apoptosis-regulatory proteins, such as members of the Bcl-2 family. Moreover, viral factors with no homology to host proteins specifically target key components of the apoptotic machinery. Here, we summarize the current knowledge on the viral modulation of mitochondrial apoptosis, by focusing in particular on the mechanisms by which viral proteins control the host cell death apparatus

ПЕДІАТРИЧНА ОСВІТА УКРАЇНИ У ХХІ СТОРІЧЧІ: СУЧАСНІ ВИКЛИКИ ТА ПРОБЛЕМИ МАЙБУТНЬОГО

The aim of the work – to evaluate the state of development of pediatric education in Ukraine in the beginning of the 21st century, staffing of the branch in the field of pediatrics and to develop a plan of measures to overcome the crisis phenomena in pediatric health care. The main body. The article presents data on the development of pediatric education in the early 21st century after the restoration of the educational-scientific specialty “Pediatrics” in 2017. The development of up-to-date standards for the training of pediatric doctors, based on the acquisition of future master’s degrees in pediatrics, general and professional competencies and necessary practical skills is highlighted. The current problems in the provision of pediatric health care facilities are emphasized. Conclusion. A list of measures at the sectoral and national level has been developed to restore the necessary training рediatricians for childrenʼs health care of the country and to ensure the proper methodological provision of the educational process, which may cause difficulties in providing children with quality medical care in the future.Мета роботи – оцінити стан розвитку педіатричної освіти в Україні на початку ХХІ сторіччя, кадрове забезпечення галузі за спеціальністю «Педіатрія» та розробити план заходів щодо подолання кризових явищ у педіатричній охороні здоровʼя. Основна частина. У статті наведено дані щодо розвитку педіатричної освіти на початку ХХІ сторіччя після відновлення освітньо-наукової спеціальності «Педіатрія» у 2017 р. Висвітлено розробку сучасних стандартів підготовки дитячих лікарів, що базуються на набутті майбутніми магістрами педіатрії загальних та фахових компетенцій і необхідних практичних навичок. Наголошено на теперішніх проблемах у кадровому забезпеченні педіатричних закладів охорони здоровʼя, що може викликати складнощі у забезпеченні дітей якісною медичною допомогою у майбутньому. Висновок. Розроблений перелік заходів на галузевому та загальнодержавному рівні щодо відновлення необхідних для країни обсягів підготовки дитячих лікарів та забезпечення належного методичного забезпечення навчального процесу

SARS-CoV-2 infection and transmission in the North American deer mouse

Deer mice are natural hosts for a number of human pathogens. Here, Griffin et al. report that intranasal exposure of the North American deer mouse to SARS-CoV-2 results in virus replication and shedding, despite causing only mild or asymptomatic illness. Additionally, infected deer mice can transmit SARS-CoV-2 to naïve deer mice

In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2

Interactions between Bcl-2-like proteins and BH3 domains play a key role in the regulation of apoptosis. Despite the overall structural similarity of their interaction with helical BH3 domains, Bcl-2-like proteins exhibit an intricate spectrum of binding specificities whose underlying basis is not well understood. Here, we characterize these interactions using Rosetta FlexPepBind, a protocol for the prediction of peptide binding specificity that evaluates the binding potential of different peptides based on structural models of the corresponding peptide–receptor complexes. For two prominent players, Bcl-xL and Mcl-1, we obtain good agreement with a large set of experimental SPOT array measurements and recapitulate the binding specificity of peptides derived by yeast display in a previous study. We extend our approach to a third member of this family, Bcl-2: we test our blind prediction of the binding of 180 BIM-derived peptides with a corresponding experimental SPOT array. Both prediction and experiment reveal a Bcl-2 binding specificity pattern that resembles that of Bcl-xL. Finally, we extend this application to accurately predict the specificity pattern of additional human BH3-only derived peptides. This study characterizes the distinct patterns of binding specificity of BH3-only derived peptides for the Bcl-2 like proteins Bcl-xL, Mcl-1, and Bcl-2 and provides insight into the structural basis of determinants of specificity.National Institutes of Health (U.S.) (R01GM84181

Poxviruses and the evolution of host range and virulence

Poxviruses as a group can infect a large number of animals. However, at the level of individual viruses, even closely related poxviruses display highly diverse host ranges and virulence. For example, variola virus, the causative agent of smallpox, is human-specific and highly virulent only to humans, whereas related cowpox viruses naturally infect a broad spectrum of animals and only cause relatively mild disease in humans. The successful replication of poxviruses depends on their effective manipulation of the host antiviral responses, at the cellular-, tissue- and species-specific levels, which constitutes a molecular basis for differences in poxvirus host range and virulence. A number of poxvirus genes have been identified that possess host range function in experimental settings, and many of these host range genes target specific antiviral host pathways. Herein, we review the biology of poxviruses with a focus on host range, zoonotic infections, virulence, genomics and host range genes as well as the current knowledge about the function of poxvirus host range factors and how their interaction with the host innate immune system contributes to poxvirus host range and virulence. We further discuss the evolution of host range and virulence in poxviruses as well as host switches and potential poxvirus threats for human and animal health