Recombinants between Deformed wing virus and Varroa destructor virus-1 may prevail in Varroa destructor-infested honeybee colonies

We have used high-throughput Illumina sequencing to identify novel recombinants between deformed wing virus (DWV) and Varroa destructor virus-1 (VDV-1), which accumulate to higher levels than DWV in both honeybees and Varroa destructor mites. The recombinants, VDV-1VVD and VDV-1DVD, exhibit crossovers between the 5’-untranslated region (5’-UTR), and/or the regions encoding the structural (capsid) and non-structural viral proteins. This implies the genomes are modular and that each region may evolve independently, as demonstrated in human enteroviruses. Individual honeybee pupae were infected with a mixture of observed recombinants and DWV. The strong correlation between VDV-1DVD levels in honeybee pupae and the associated mites was observed, suggesting that this recombinant, with a DWV-derived 5’-UTR and non-structural protein region flanking VDV- 1-derived capsid encoding region, is better adapted to transmission between V. destructor and honeybees than the parental DWV or a recombinant bearing the VDV-1-derived 5’-UTR (VDV-1VVD)

Microevolution of tick-borne encephalitis virus in course of host alternation

AbstractTwo tick-borne encephalitis (TBE) virus variants were studied: mouse brain-adapted strain EK-328 and its derivate adapted to Hyalomma marginatum ticks. The tick-adapted virus exhibited small-plaque phenotype and slower replication in PEK cells, higher yield in ticks, decreased neuroinvasiveness in mice, increased binding to heparin-sepharose. A total of 15 nucleotide substitutions distinguished genomes of these variants, six substitutions resulted in protein sequence alterations, and two were in 5′NTR. Two amino acid substitutions in E protein were responsible for the observed phenotypic differences. Data obtained during reverse passaging of the tick-adapted virus in vivo and in vitro suggest that TBE virus exists as a heterogeneous population that contains virus variants most adapted to reproduction in either ticks or mammals. Host switch results in a change in the ratio of these variants in the population. Plaque purification of the tick-adapted virus resulted in the prompt emergence of new mutants with different virulence for mammals

Targeted Deletion of HIF-1α Gene in T Cells Prevents their Inhibition in Hypoxic Inflamed Tissues and Improves Septic Mice Survival

Sepsis patients may die either from an overwhelming systemic immune response and/or from an immunoparalysis-associated lack of anti-bacterial immune defence. We hypothesized that bacterial superantigen-activated T cells may be prevented from contribution into anti-bacterial response due to the inhibition of their effector functions by the hypoxia inducible transcription factor (HIF-1alpha) in inflamed and hypoxic areas.Using the Cre-lox-P-system we generated mice with a T-cell targeted deletion of the HIF-1alpha gene and analysed them in an in vivo model of bacterial sepsis. We show that deletion of the HIF-1alpha gene leads to higher levels of pro-inflammatory cytokines, stronger anti-bacterial effects and much better survival of mice. These effects can be at least partially explained by significantly increased NF-kappaB activation in TCR activated HIF-1 alpha deficient T cells.T cells can be recruited to powerfully contribute to anti-bacterial response if they are relieved from inhibition by HIF-1alpha in inflamed and hypoxic areas. Our experiments uncovered the before unappreciated reserve of anti-bacterial capacity of T cells and suggest novel therapeutic anti-pathogen strategies based on targeted deletion or inhibition of HIF-1 alpha in T cells

Противоопухолевый ингибитор протеинтирозинкиназ иматиниб как потенциальный корректор пневмофиброза COVID-19

Imatinib mesilate is a well-known antitumor target inhibitor of protein tyrosine kinase, which is effective in different cancer types expressing Bcr / Abl and, in particular, in hemoblastosis. A higher interest to imatinib during the COVID-19 epidemic is explained by the fact that cancer patients are one of the COVID-19 risk groups. Moreover, imatinib target mechanism of action, which is effective in cancer, can have a high potential against the most severe COVID-19 complication such as the disease associated pulmonary fibrosis. COVID-19 associated interstitial pulmonary fibrosis develops as an autoimmune process caused by systemic inflammation with atypical (idiopathic) pneumonia resulting from acute respiratory distress syndrome with the tyrosine kinase mechanism of signaling pathway activation and cellular response. Experi-mental and clinical results showing antifibrotic and dose-related antithrombotic imatinib effect demonstrate perspective use of this antitumor agent to correct COVID-19 associated pneumonia causing a high death rate of patients with COVID-19.The review presents literature data of 2001–2020 discussing pathologic genetic and clinical characteristics of the fibrosis which exacerbates COVID-19 pneumonia in adults. The sequence of the disease processes demonstrates that disease progression with the decreasing oxygen saturation in the peripheral blood intensifies local thrombosis in the lungs. As a result, hypoxia is developing, which is difficult to control and can cause lethal outcome in severe cases. Yet, the conventional antifibrotic and thrombolytic agents can only partially control the process of pneumofibrosis including that of cancer patients. The approximate antifibrotic dose of imatinib 400 mg / day is therapeutic for oncopatho-logy. The antitumor drug registered in many countries and well described side effects and contraindications needs no long-term registration studies for a new indication, therefore, it may be easily prepared for clinical testing.Иматиниб мезилат – известный противоопухолевый таргетный ингибитор протеиновых тирозинкиназ, эффективный при раз-личной онкологической патологии с экспрессией Bcr / Abl, особенно при гемобластозах. На фоне пандемии коронавируса COVID-19 интерес к иматинибу возрос в связи с тем, что онкологические пациенты относятся к одной из групп риска заболевания COVID-19. Более того, определяющий применение иматиниба при онкологических заболеваниях таргетный механизм дейст-вия может быть перспективен для коррекции наиболее опасного осложнения – COVID-19-ассоциированного пневмофиброза. COVID-19-ассоциированный интерстициальный пневмофиброз возникает аутоиммунно вследствие системного воспаления с развитием атипичной (идиопатической) пневмонии под действием острого респираторного дистресс-синдрома с тирозин-киназным механизмом активации сигнальных путей и клеточного ответа. Экспериментальные и клинические данные, выявив-шие антифибротическое и дозозависимое антитромботическое действие иматиниба, свидетельствуют о целесообразности применения этого противоопухолевого препарата для коррекции COVID-19-ассоциированной пневмонии – причины высокой смертности пациентов с COVID-19.В обзоре приведены данные литературы 2001–2020 гг., посвященные патогенетическим и клиническим особенностям развития пневмофиброза, проанализированы данные об особенностях течения пневмонии COVID-19 у взрослых. Приведенная последователь-ность событий показывает, что прогрессирование процесса со снижением сатурации кислорода в периферической крови усили-вает локальное тромбообразование в легких. В результате возникает плохо управляемая гипоксия, которая в тяжелых случаях является причиной летального исхода. Воздействие на процесс развития пневмофиброза с помощью известных антифибротиче-ских и тромболитических препаратов позволяет лишь частично контролировать процесс, в том числе у онкологических пациен-тов. Ориентировочная антифибротическая доза иматиниба 400 мг / сут считается терапевтической для онкологической пато-логии. Зарегистрированный во многих странах противоопухолевый препарат не требует длительных регистрационных исследований по новому показанию, а известные побочные эффекты и противопоказания к применению позволяют быстро под-готовить его клиническую апробацию

Multiannual Analysis of Epidemiological Process Manifestations as Regards Enteroviral Infection in the Khabarovsk Territory, and the Key Factors that Predetermine Aggravation of Epidemiological Situation under the Terms of Flood

Carried out has been retrospective analysis of epidemiological process manifestations as regards enteroviral infection in the Khabarovsk Region over the period of 7 years, prior to rainfall floods in 2013. Revealed is the possibility of aggravation of epidemiological situation during hydrological emergency situation. The premises are as follows: persistent due to specific climate conditions prevalent in the Khabarovsk Territory (high air and surface water temperatures, and high humidity rates) unfavorable epidemiological situation on enteroviral infections, virus-carriage in “healthy” people and extensive dissemination of enteroviruses in the water bodies of ambient environment. Moreover, widespread circulation of different enterovirus genotypes, including the isolates with high genetic similarity to the strains identified earlier in the adjoining People’s Republic of China, takes place

Genetic Relationship between Cocirculating Human Enteroviruses Species C

Recombination events between human enteroviruses (HEV) are known to occur frequently and to participate in the evolution of these viruses. In a previous study, we reported the isolation of a panel of viruses belonging to the Human enterovirus species C (HEV-C) that had been cocirculating in a small geographic area of Madagascar in 2002. This panel included type 2 vaccine-derived polioviruses (PV) that had caused several cases of acute flaccid paralysis in humans. Previous partial sequencing of the genome of these HEV-C isolates revealed considerable genetic diversity, mostly due to recombination. In the work presented herein, we carried out a more detailed characterization of the genomes of viruses from this collection. First, we determined the full VP1 sequence of 41 of these isolates of different types. These sequences were compared with those of HEV-C isolates obtained from other countries or in other contexts. The sequences of the Madagascan isolates of a given type formed specific clusters clearly differentiated from those formed by other strains of the same type isolated elsewhere. Second, we sequenced the entire genome of 10 viruses representing most of the lineages present in this panel. All but one of the genomes appeared to be mosaic assemblies of different genomic fragments generated by intra- and intertypic recombination. The location of the breakpoints suggested potential preferred genomic regions for recombination. Our results also suggest that recombination between type HEV-99 and other HEV-C may be quite rare. This first exhaustive genomic analysis of a panel of non-PV HEV-C cocirculating in a small human population highlights the high frequency of inter and intra-typic genetic recombination, constituting a widespread mechanism of genetic plasticity and continually shifting the HEV-C biodiversity

From ‘Hellstrom Paradox–to anti-adenosinergic cancer immunotherapy

Cancer therapy by endogenous or adoptively transferred anti-tumor T cells is considered complementary to conventional cancer treatment by surgery, radiotherapy or chemotherapy. However, the scope of promising immunotherapeutic protocols is currently limited because tumors can create a ‘hostile–immunosuppressive microenvironment that prevents their destruction by anti-tumor T cells. There is a possibility to develop better and more effective immunotherapies by inactivating mechanisms that inhibit anti-tumor T cells in the tumor microenvironment and thereby protect cancerous tissues from immune damage. This may be now possible because of the recent demonstration that genetic deletion of immunosuppressive A2A and A2B adenosine receptors (A2AR and A2BR) or their pharmacological inactivation can prevent the inhibition of anti-tumor T cells by the hypoxic tumor microenvironment and as a result facilitate full tumor rejection [Ohta A, Gorelik E, Prasad SJ et al (2006) Proc Natl Acad Sci USA 103(35):13132–3137]. This approach is based on in vivo genetic evidence that A2AR play a critical role in the protection of normal tissues from overactive immune cells in acutely inflamed and hypoxic areas. The observations of much improved T-cell-mediated rejection of tumors in mice with inactivated A2AR strongly suggest that A2AR also protects hypoxic cancerous tissues and that A2AR should be inactivated in order to improve tumor rejection by anti-tumor T cells

A hepatitis B virus causes chronic infections in equids worldwide

Preclinical testing of novel therapeutics for chronic hepatitis B (CHB) requires suitable animal models. Equids host homologs of hepatitis C virus (HCV). Because coinfections of hepatitis B virus (HBV) and HCV occur in humans, we screened 2,917 specimens from equids from five continents for HBV. We discovered a distinct HBV species (Equid HBV, EqHBV) in 3.2% of donkeys and zebras by PCR and antibodies against EqHBV in 5.4% of donkeys and zebras. Molecular, histopathological, and biochemical analyses revealed that infection patterns of EqHBV resembled those of HBV in humans, including hepatotropism, moderate liver damage, evolutionary stasis, and potential horizontal virus transmission. Naturally infected donkeys showed chronic infections resembling CHB with high viral loads of up to 2.6 × 109 mean copies per milliliter serum for >6 mo and weak antibody responses. Antibodies against Equid HCV were codetected in 26.5% of donkeys seropositive for EqHBV, corroborating susceptibility to both hepatitis viruses. Deltavirus pseudotypes carrying EqHBV surface proteins were unable to infect human cells via the HBV receptor NTCP (Na+/taurocholate cotransporting polypeptide), suggesting alternative viral entry mechanisms. Both HBV and EqHBV deltavirus pseudotypes infected primary horse hepatocytes in vitro, supporting a broad host range for EqHBV among equids and suggesting that horses might be suitable for EqHBV and HBV infections in vivo. Evolutionary analyses suggested that EqHBV originated in Africa several thousand years ago, commensurate with the domestication of donkeys. In sum, EqHBV naturally infects diverse equids and mimics HBV infection patterns. Equids provide a unique opportunity for preclinical testing of novel therapeutics for CHB and to investigate HBV/ HCV interplay upon coinfection