Д.И. Ивановский ― первооткрыватель вирусов как новой формы биологической жизни

125 years ago, in 1992, a Russian scientist Dmitri Iosifovich Ivanovsky published first research data disclosing a unique form of filterable biological microlife. Further scientific progress in this discovery resulted in a new discipline of human knowledge, called «the Kingdom of viruses».A fundamental understanding of viral form of biological life was established not at once and was gradually formed under the accumulation of scientific facts. Only at the beginning of 50 years of the twentieth century, a basic understanding of viral Kingdom had been formed and 1992 year was recognized as the year of the birth of Virology. Virology, which started developing by the research of D.I. Ivanovsky, gave remarkable progress and prominent results: more than 20 scientists got Nobble Prize for the outstanding works in virology. There are all arguments and grounds to nominate the international scientific award in virology named of D.I. Ivanovsky.Открытая 125 лет назад русским ученым Д.И. Ивановским уникальная форма фильтрующейся биологической микрожизни в дальнейшем научном развитии оформилась в виде новой отрасли человеческих знаний, получившей название «царство вирусов». Фундаментальное понимание вирусной формы жизни установилось не сразу и формировалось постепенно по мере накопления научных фактов. Только к началу 50-х годов ХХ столетия сформировалось основополагающее понимание вирусного царства, а 1892 г. был признан годом рождения науки вирусологии. Вирусология, у истоков которой стоял Д.И. Ивановский, дала ощутимые плоды: более 20 ученых удостоились Нобелевской премии за выдающиеся работы в этой области. Имеются все основания для учреждения российской и международной премии в области вирусологии им. Д.И. Ивановского

Molecular Targets in the Chemotherapy of Coronavirus Infection

Abstract: In the pathogenesis of the infectious process in the respiratory tract by SARS, MERS, and COVID-19 coronaviruses, two stages can be distinguished: early (etiotropic) and late (pathogenetic) ones. In the first stage, when the virus multiplication and accumulation are prevalent under insufficient host immune response, the use of chemotherapeutic agents blocking the reproduction of the virus is reasonable to suppress the development of the disease. This article considers six major chemotherapeutic classes aimed at certain viral targets: inhibitors of viral RNA polymerase, inhibitors of viral protease Mpro, inhibitors of proteolytic activation of viral protein S allowing virus entry into the target cell, inhibitors of virus uncoating in cellular endosomes, compounds of exogenous interferons, and compounds of natural and recombinant virus-neutralizing antibodies. In the second stage, when the multiplication of the virus decreases and threatening pathological processes of excessive inflammation, acute respiratory distress syndrome, pulmonary edema, hypoxia, and secondary bacterial pneumonia and sepsis events develop, a pathogenetic therapeutic approach including extracorporeal blood oxygenation, detoxification, and anti-inflammatory and anti-bacterial therapy seems to be the most effective way for the patient’s recovery. © 2020, Pleiades Publishing, Ltd

Influenza a virus proteins NS1 and hemagglutinin along with M2 are involved in stimulation of autophagy in infected cells

The NS1 protein of influenza A virus is known to downregulate apoptosis early in infection in order to support virus replication (O. P. Zhirnov, T. E. Konakova, T. Wolff, and H. D. Klenk, J. Virol. 76:1617-1625, 2002). In the present study, we analyzed the development of autophagy, another mechanism to protect cells from degradation that depends on NS1 expression. To this end, we compared autophagy in cells infected with wild-type (WT) influenza virus and virus lacking the NS1 gene (delNS1 virus). The results show that in WT-infected cells but not in delNS1 virus-infected cells, synthesis of the autophagy marker LC3-II, the lipidated form of microtubule light chain-associated protein LC3, is stimulated and that LC3-II accumulates in a perinuclear zone enriched with double-layered membrane vesicles characteristic of autophagosomes. Transfection experiments revealed that NS1 expressed alone was unable to upregulate autophagy, whereas hemagglutinin (HA) and M2 were. Proteolytic cleavage of HA increased autophagy. Taken together, these observations indicate that NS1 stimulates autophagy indirectly by upregulating the synthesis of HA and M2. Thus, it appears that NS1, besides downregulating apoptosis, is involved in upregulation of autophagy and that it supports the survival of infected cells by both mechanisms. © 2013, American Society for Microbiology

Paramyxoviruses activation by host proteases in cultures of normaland cancer cells

Microbiology named after the honorary academician «N.F. Gamaleya», Moscow, 123098, Russian Federation Multiplication of paramyxovirus Sendai and Newcastle disease virus (NDV) was studied in cultures of normal and tumor cells. Production of noninfectious virus with uncleaved F0 was observed in canine kidney cell line MDCK (line H) and its derivatives carrying tetracycline-regulated expression of transmembrane protease HAT or TMPRSS2 with trypsin-I ike cleavage specificity. Under tetracycline induction, a cleavage F0 (65 kD)-F1 (50 kD)+F2(15 kD) and production of infectious virus were observed in these cell cultures. Under tetracycline induction, the additional subunit 38K (m.w. 38 kDa) of the F protein was detected both in infected MDCK-HAT cells and in newly synthesized Sendai virus in addition to F0, F1 and F2, indicating thereby a second HAT-sensitive proteolytic site in the F0 molecule. Highly infectious virus containing cleaved F1+F2 was produced in cultures of cancer cells Caco-2 and H1299. Virus Sendai synthesized in H1299 cells contained 38 K 'subunit indicating a cleavage of the F0 at a second site by H1299 host cell proteases. Levels of cleaved F1+F2 and infectious virions were higher at the late stage of infection in cancer cells, suggesting thus the induction of virus-activating proteases in Caco-2 and H1299 cells under infection with paramyxoviruses. NDV virus was found to induce more rapid death of cancer cells Caco-2 than Sendai virus. Cooperatively, the obtained data show that cancer cells in distinction to nonmalignant cells can synthesize protease(s) activating infectivity of paramyxoviruses. Thus, they are more vulnerable to paramyxovirus infection than normal cells

Intravirion cohesion of matrix protein M1 with ribonucleocapsid is a prerequisite of influenza virus infectivity.

Influenza virus has two major structural modules, an external lipid envelope and an internal ribonucleocapsid containing the genomic RNA in the form of the ribonucleoprotein (RNP) complex, both of which are interlinked by the matrix protein M1. Here we studied M1-RNP cohesion within virus exposed to acidic pH in vitro. The effect of acidification was dependent on the cleavage of the surface glycoprotein HA. Acidic pH caused a loss of intravirion RNP-M1 cohesion and activated RNP polymerase activity in virus with cleaved HA (HA1/2) but not in the uncleaved (HA0) virus. The in vitro acidified HA1/2 virus rapidly lost infectivity whereas the HA0 one retained infectivity, following activation by trypsin, suggesting that premature activation and release of the RNP is detrimental to viral infectivity. Rimantadine, an inhibitor of the M2 ion channel, was found to protect the HA1/2 virus interior against acidic disintegration, confirming that M2-dependent proton translocation is essential for the intravirion RNP release and suggesting that the M2 ion channel is only active in virions with cleaved HA. Acidic treatment of both HA0 and HA1/2 influenza viruses induces formation of spikeless bleb-like protrusion of ~25nm in diameter on the surface of the virion, though only the HA1/2 virus was permeable to protons and permitted RNP release. It is likely that this bleb corresponds to the M2-enriched and M1-depleted focus arising from pinching off of the virus during the completion of budding. Cooperatively, the data suggest that the influenza virus has an asymmetric structure where the M1-mediated organization of the RNP inside the virion is a prerequisite for infectious entry into target cell