Актуальность. Ведущую роль в патогенезе коронавирусной инфекции, вызванной SARS-CoV-2 (COVID-19), играют гиперкоагуляционные сдвиги в системе гемостаза, изменение функционального состояния эндотелия и системная дисфункция микроциркуляции. Принимая во внимание риск цереброваскулярных осложнений COVID-19 в острый период, а также при постковидном синдроме, особую важность приобретают исследования ультраструктурных изменений сосудов головного мозга для расширения знаний о патогенезе COVID-19-ассоциированной эндотелиопатии и разработки подходов к её фармакологической коррекции. Морфологическим эквивалентом изучения секреторной активности эндотелия сосудов может выступать кинетика структуры телец Вейбеля-Паладе, уникальных для эндотелиоцитов органелл, экзоцитоз которых определяет условия тромбообразования. Цель – электронно-микроскопическое исследование кинетики структуры телец Вейбеля-Паладе в эндотелии сосудов неокортекса сирийских хомяков в динамике инфекции SARS-CoV-2. Материалы и методы. Экспериментальную модель воспроизводили посредством интраназального введения сирийским хомякам культуры вируса, содержащей SARS-CoV-2 в количестве 4 × 104 ТЦД50/мл. На 3-и, 7-е, 14-е и 28-е сутки после заражения выполняли эвтаназию животных с последующим отбором образцов ткани неокортекса. Исследование материала проводили методом трансмиссионной электронной микроскопии. Результаты. Прослежена кинетика накопления и высвобождения секрета телец Вейбеля-Паладе в эндотелии сосудов неокортекса сирийских хомяков на экспериментальной модели SARS-CoV-2 инфекции. Выявлено увеличение секреторной активности эндотелиоцитов сосудов неокортекса у животных в период 3-7 суток после заражения в виде экзоцитоза телец Вейбеля-Паладе. Выявленные ультраструктурные изменения эндотелия у экспериментальных животных прослежены до 28 суток инфекционного процесса. Заключение. Результаты электронно-микроскопического исследования секреторной активности эндотелия сосудов неокортекса сирийских хомяков в динамике инфекции SARS-CoV-2 позволили определить риски сосудистых катастроф как в остром, так и в реконвалесцентном (28 суток) периоде заболевания. Полученные результаты значимы для расширения знаний о патогенезе эндотелиальной дисфункции, определяющей вероятность цереброваскулярных осложнений в критические периоды COVID-19, что представляет особую важность при проведении исследований, направленных на разработку и изучение новых средств терапии данной патологии. Background. Hypercoagulation, changes in the functional state of endothelium and systemic microcirculation dysfunction play a leading role in the pathogenesis of coronavirus infection caused by SARS-CoV-2 (COVID-19). Taking into account the risk of cerebrovascular complications of COVID-19 in the acute period, as well as in post-COVID-19 syndrome, studies of ultrastructural changes in cerebral vessels are of particular importance for expanding knowledge about the pathogenesis of COVID-19- associated endothelial pathology and developing approaches to its pharmacological correction. The morphological equivalent of studying the vascular endothelium secretory activity can be the structural kinetics of Weibel-Palade bodies, organelles unique to endotheliocytes, the exocytosis of which determines the conditions of thrombosis. The aim is to electron microscopic study the kinetics of Weibel–Palade body’s structure in the endothelium of the neocortex vessels of Syrian hamsters in the dynamics of SARS-CoV-2 infection. Materials and methods. The experimental model was reproduced by intranasal administration to Syrian hamsters of a virus culture containing SARS-CoV-2 in an amount of 4 × 104 TCD50/ml. On days 3, 7, 14 and 28 after infection animals were euthanized with subsequent selection of neocortex tissue. The study of the material was carried out by transmission electron microscopy. Results. The kinetics of accumulation and release of the secretion of Weibel-Palade bodies in the endothelium of the neocortex vessels of Syrian hamsters on an experimental model of SARS-CoV-2 infection was traced. It was found that secretory activity of neocortical vascular endotheliocytes in animals increases in the period 3–7 days after infection in the form of exocytosis of Weibel-Palade bodies. The revealed ultrastructural changes of the endothelium in experimental animals persist up to 28 days of the infectious process. Conclusion. The results of electron microscopic examination of the neocortex vessels endothelium secretory activity of Syrian hamsters in the dynamics of SARS-CoV-2 infection allowed us to determine the risks of vascular catastrophes both in the acute and convalescent (28 days) periods of disease. The results obtained are significant for expanding knowledge about the pathogenesis of endothelial dysfunction, which determines the likelihood of cerebrovascular complications during critical periods of COVID-19, which is of particular importance when conducting research aimed at developing and studying new therapies for this pathology.

Introduction. Taking into account the experience on the new coronavirus infection COVID-19 pandemic, the relevance of studies assessing the cellular processes of SARS-CoV-2 virus assembly and transport to justify the choice of pharmacological action points has now markedly increased. The study was aimed at analyzing morphologically assessed events of SARS-CoV-2 life cycle in neocortical neurons using electron microscopy based on its traced wide prevalence in vivo and ability to penetrate the blood-brain barrier accounts. Materials and methods. Patient-derived SARS-CoV-2 virus was obtained and accumulated in Vero(B) cell culture. An electron microscopy study (EMR) of the viral particle transport was carried out in male Syrian hamsters. Animals were inoculated intranasally with 26 mu l of virus culture in an amount of 4 x 104 TCID50/ml. Animals were euthanized on day 3, 7, and 28 post-infection. The extracted brain was prepared for EMR according to methods previously described in the literature. The results were recorded using an FEI Tecnai G2 Spitit BioTWIN electron microscope. Results. Using EMR, the morphological equivalents of virus transport variants in neocortical neurons were traced dynamically during infectious process in Syrian hamsters. After synthesis, viral membrane proteins are included in transport vesicles in the endoplasmic reticulum (ER) terminal tubules and enter the intermediate compartment (IC), a collection of smooth-walled membrane vesicles between the endoplasmic reticulum (ER) and the Golgi apparatus (AG). In the first 3 days post-infection, viral copies are included in the Ag in PC membrane-formed transport vesicles. Due to the large size, viral particles are restricted to the expanded ends of the mobile AG tanks. Morphologically, destruction of AG membranes was revealed on day 7 post-infection, which indicates an interaction between PC vesicles and preserved AG membrane elements or the implementation of their independent transport func-tion to deliver SARS-CoV-2 virus to the cell periphery and further into the intercellular space. In the neuronal processes, the transport of mature SARS-CoV-2 viral particles associated with cytoskeletal elements was observed, which was not detected in other loci of virus persistence. Conclusion. Based on data obtained, it is possible to hypothesize about a cu-mulative importance for progression and persistence of SARS-CoV-2 infection in cortical neurons. Early signs of neuron infection are represented by characteristic changes in the nuclei, ER hypertrophy and formation of "viral factories" based on the ER, PC and AG. The formation of viral biomass occurs inside neurons; virion exit from target cells is more accom-panied by cell death rather than if a virus becomes incorporated in the lysosomal-endosomal system.

The peculiarities of the influence of cytokines and metabolites of the systemic inflammatory reaction and stress-implementing and nutritional factors contributing to the transformation of the phenotype of the resident intestinal microflora with an increase in its virulence are described. From the perspective of expression of genes and conformations of proteins and phospholipids, the influence of temperature as a signaling factor in increasing the virulence of the intestinal microbiome is considered. Evolutionarily formed mechanisms of expression of the maximum pathogenic phenotype of microorganisms and, thus, achieving an increase in their biomass and maximum dissemination through the microorganism compartments increase the probability of the transmission of commensals to another biotope, i.e., increases the probability of their survival after the death of the host organism. To prevent bacterial translocation after the relief of critical conditions, early enteral administration of β-glucans in food mixtures, iron excretion, and relief of inorganic phosphate deficiency, including by induction of alkaline phosphatase synthesis, are substantiated.

The characteristics of the biology of influenza viruses and coronavirus that determine the implementation of the infectious process are presented. With provision for pathogenesis of infection possible effects of serine proteinase inhibitors, heparin, and inhibitors of heparan sulfate receptors in the prevention of cell contamination by viruses are examined. It has been determined that chelators of metals of variable valency and antioxidants should be used for the reduction of replicative activity of viruses and anti-inflammatory therapy. The possibility of a pH-dependent impairment of glycosylation of cellular and viral proteins was traced for chloroquine and its derivatives. The use of low-toxicity drugs as part of adjunct therapy increases the effectiveness of synthetic antiviral drugs and interferons and ensures the safety of baseline therapy.

The biology features of influenza viruses and coronaviruses that determine the implementation of the infectious process are described Taking into account the pathogenesis of infection, the possible effects of serine proteinase blockers, heparin and heparan sulfate receptor blockers in the prevention of cell contamination by viruses are considered The necessity of using chelators of metals of variable valency and antioxidants to reduce the replicative activity of viruses and anti-inflammatory therapy is determined The possibility of a pH-dependent violation of the glycosylation of cellular and viral proteins is traced for chloroquine and its derivatives The use of low-toxic registered drugs as part of adjuvant therapy increases the effectiveness of antiviral synthetic drugs and interferons, ensures the safety of the use of basic therapy Изложены особенности биологии вирусов гриппа и коронавирусов, определяющие реализацию инфекционного процесса С учетом патогенеза инфекции рассмотрены возможные эффекты блокаторов сериновых протеиназ, гепарина и блокаторов гепарансульфатных рецепторов в профилактике контаминации клеток вирусами Определена необходимость применения хелаторов металлов переменной валентности и антиоксидантов для снижения репликативной активности вирусов и противовоспалительной терапии Возможность pH-зависимого нарушения гликозилирования клеточных и вирусных белков прослежена для хлорохина и его производных Применение низкотоксичных лекарственных средств в составе вспомогательной терапии повышает эффективность противовирусных синтетических препаратов и интерферонов, обеспечивает безопасность применения средств базисной терапии

Описаны эффекты статинов, опосредованные преимущественно ингибированием 3-гидрокси-3-ме-тилглутарил-кофермент А-редуктазы. Блокирование синтеза мевалоната приводит к снижению продукции как холестерина, так и изопреноидов, участвующих в посттрансляционной модификации множества участников внутриклеточной трансдукции. Именно статин-зависимое модулирование (изо)пренилирования клеточных белков определяет многообразие биологических эффектов препаратов этой группы. В качестве природных продуцентов различных статинов выступают представители микофлоры. В связи с этим допустимо предположение о наличии в составе кишечного микробиома человека мутуалистического микобиома, вырабатывающего в норме ингибиторы ГМГ-КоА-редук-тазы. Дефицит этих естественных ингибиторов, прошедших длительный отбор и лишенных недостатков известных статинов, нарушает гомеостатирование липидного обмена при дисбиотических состояниях, что позволяет рассматривать дисбактериоз в качестве патогенетического фактора атеросклероза.