Vol 10, No 2 (2020)

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Full Issue


Born in Wuhan: lessons from COVID-19 epidemic in China

Semenov A.V., Pshenichnaya N.Y.


The COVID-19 epidemic curve in China can be divided into several stages. Despite transparency in informing the world public about clusters of undiagnosed viral pneumonia, the country’s health care at the first stage of the epidemic was not ready to provide adequate and rapid response for a fast increase in the number of patients with COVID-19, infection control measures were not fully implemented, which also led to a large number of nosocomial cases of infection among medical workers and patients. Socially vulnerable groups of the population did not refer for medical assistance in a timely manner due to the lack of the disease danger understanding and also in connection with the high cost for them of medical aid. At the second stage, simultaneously with the restrictive measures introduced by the government, the entire health care system was rebooted: free medical care for patients with COVID-19 was provided and the strictest infection control measures were implemented, multi-level contact tracking system using IT technologies was organized, and the capacity of hospitals was increased many times. Through the joint efforts of ministries, mass media, social networks and volunteer movements, an unprecedented social mobilization of the population was achieved. Strict implementation of the entire set of measures aimed at fighting the epidemic allowed to take it under strict control at the third stage and practically eliminate the epidemic after 2,5 months. China’s response to the COVID-19 epidemic can be useful to other countries, in fighting the current pandemic and in preparing for a response to biological threats in the future.

Russian Journal of Infection and Immunity. 2020;10(2):210-220
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History of investigation and current classification of coronaviruses (Nidovirales: Coronaviridae)

Shchelkanov M.Y., Popova A.Y., Dedkov V.G., Akimkin V.G., Maleyev V.V.


An epidemic of COVID-19 (Coronavirus disease 2019) etiologically associated with the SARS-CoV-2 (Severe acute respiratory syndrome-related coronavirus 2) that occurred at the turn of 2019–2020 firstly in Wuhan (Hubei province of China) and then spread to many countries around the world rose a new wave of interest to coronaviruses. The first coronaviruses – members of the Coronaviridae family belonging to the order Nidovirales — were discovered in the first half of the last century. The first human coronavirus, HCoV-B814, was isolated in 1965 that was not preserved in available virological collections. Over the last time, old-fashioned names and terms have been overlapped. By the beginning of the XXI century coronaviruses posed a serious veterinary problem but it was believed that epidemic coronaviruses were not among highly dangerous viruses. Scientific community had to revise such views first in 2002 when SARS-CoV (Severe acute respiratory syndrome-related coronavirus) was transferred to human population in the Southeast Asia from bats, and then in 2012 when natural foci of the MERS-CoV (Middle East respiratory syndrome-related coronavirus) were found on the territory of the Arabian Peninsula. Due to an increased interest in coronaviruses, a large number of new Coronaviridae members was discovered in the first two decades of the XXI century, which required to revise its taxonomic structure several times. This review is aimed at outlining a history of investigating coronaviruses and their current classification that was shaped in early 2020 in accordance to the last recommendations of the International Committee on Taxonomy of Viruses.
Russian Journal of Infection and Immunity. 2020;10(2):221-246
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COVID-19: an updated review

Isihak F.A., Hamad M.A., Mustafa N.G.


COVID-19 is a zoonotic disease that showed higher levels of transmissibility in humans. Coronavirus has the largest recognized genome (28–33 kb) of a positive-sense single stranded RNA. The genome composed of 5′-end, the translationable mRNA sequences for the key proteins; replicase, spike, envelop membrane, and nucleocapsid and 3′-end (polyA tail). This highly contagious virus may impair the immune system in the early phase of the disease, hence the symptoms of the disease appear very rapidly. Importantly until now, there is no efficient strategy for containing the disease. So, all the world scientists today are in a race against time to find a vaccine or treatment to COVID-19, which requires a deeper understanding.
Russian Journal of Infection and Immunity. 2020;10(2):247-258
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Innate immunity in coronavirus infection

Smirnov V.S., Totolyan A.A.


Coronaviruses (CoVs) comprise a polymorphic group of respiratory viruses causing acute inflammatory diseases in domestic and agricultural animals (chicken, pig, buffalo, cat, dog). Until recently, this infection in humans was mainly observed during the autumn-winter period and characterized by a mild, often asymptomatic, course. The situation changed dramatically in 2003, when SARS outbreak caused by pathogenic CoV (SARS-CoV) was recorded in China. A decade later, a new CoV outbreak occurred in the form of the Middle East respiratory syndrome (MERS-CoV), whereas in December 2019, SARS-CoV-2 (COVID-19) cases were recorded, which transformed within the first months of 2020 into the pandemic. In all three cases, CoV disease led to severe bronchopulmonary lesions, varying from dry, debilitating cough to acute respiratory distress syndrome (ARDS). At the same time, multiple changes in innate immunity were noted most often manifested as a pronounced inflammatory reaction in the lower respiratory tract, featured by damaged type II pneumocytes, apoptosis, hyalinization of alveolar membranes, focal or generalized pulmonary edema. Destructive processes in the respiratory tract were accompanied by migration of monocytes/macrophages and granulocyte neutrophils to the inflammatory focus. Such events were accompanied by production of pro-inflammatory cytokines, which magnitude could ascend up to a cytokine storm. SARS-CoV is characterized by symptoms of secondary immunosuppression, manifested by the late onset of interferon production and activation of NLRP3 inflammasomes – the key inflammatory factor. The reason for such reaction may be accounted for by CoV arsenal containing extensive set of structural and non-structural proteins exerting pro-inflammatory and immunosuppressive properties. Delayed IFN production allowed CoV to replicate actively and freely, and when type I IFN synthesis was eventually triggered, its activity was detrimental and accompanied by an aggravated infection course. Thus, SARS can surely be referred to immune-dependent infections with a marked immunopathological component. The purpose of this review was to describe some mechanisms underlying formation of innate immune response to infection caused by pathogenic coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 (COVID-19).
Russian Journal of Infection and Immunity. 2020;10(2):259-268
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Heterologous immune responses in health and disease

Toptygina A.P.


Immunological memory and tolerance represent major achievements and advantages of adaptive immunity. Organisms bearing adaptive immunity display prominent competitive advantages in the fight against infections. Memory immune cells are preserved for decades and are able to repel a second attack of an infectious agent. However, studies performed in the XXI century have shown that even unrelated pathogens may be quickly and effectively destroyed by memory cells. This type of response is called heterologous so that heterologous immune response is mainly typical to viral infections and other intracellular infections, where T-cells play a lead role in protection. This review will discuss various mechanisms involved in implementing T-cell cross-reactivity, describe molecular prerequisites for heterologous T-cell responses. Experimental evidence of memory T-cell potential to heterologous immune response in mouse models and in human infections are also discussed. Heterologous immune response is an important immune arm in adults and the elderly when the yield of naive cells to the periphery declines due to thymus involution. Along with obvious advantages, heterologous immune response leads to imbalanced memory T-cell repertoire, replacement of immunodominant epitopes with minor ones allowing viruses to evade immune response that results in virus persistence, or, conversely, fulminant infection course. Another threat of heterologous immune response due to switch in dominant repertoire of recognizable epitopes is presented by random self-epitope recognition, which can lead to development of autoimmune pathology. Heterologous immunity can also disrupt drug-induced tolerance in organ and tissue transplants and lead to graft rejection. Heterologous immune response should be taken into consideration while developing and using new vaccines, especially in adults and the elderly.
Russian Journal of Infection and Immunity. 2020;10(2):269-276
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An early assessment of the efficacy of medicines in the treatment of patients with COVID-19

Kolbin A.S.


Coronavirus infection 2019 is considered a modern challenge to the world community. In the absence of vaccines and antivirals, effective and safe medicines are an urgent request from the healthcare system. We have evaluated the medical technologies for COVID-19 which are being examined. The search was conducted on the СlinicalTrials.gov at the beginning of April 2020. As a result it was shown that the growth of new clinical trials in the world devoted to COVID-19 is growing by 65% per week. More often, interventional clinical trials of the II and III phases are carried out. Most studies are planned or conducted in Western Europe (n = 92), China (n = 79), and the United States (n = 51). Surrogate points are usually evaluated, such as: clinical recovery, symptom-based disease relief (fever, cough, diarrhea, myalgia, shortness of breath), lack of progression of shortness of breath, rate of artificial ventilation, rate of admission to the intensive care unit, etc. It is antimalarial drugs that are mainly studied. Currently, it is not possible to discuss the efficacy and safety of a drug in the treatment of COVID-19, as most studies have just begun. The therapeutic regimens proposed now in clinical recommendations have no evidence base, and the studies indicated in them are at best considered hypothesizing.

Russian Journal of Infection and Immunity. 2020;10(2):277-286
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Ethical comments on COVID-19

Kubar O.I.


Over decades, the St. Petersburg Pasteur Institute has been conducting research on Ethical and legal aspects of infectious diseases. One of the areas in this study focuses on ethical issue in the planning and management during epidemics and pandemics. This concept becomes extremely relevant in the situation of the COVID-19 coronavirus pandemic, which has determined the urgent need for rapid updates on this issue and analyzing compliance of decisions and actions undertaken to ethical and legal regulations in Russia and abroad. The rational and practical side of following the global ideology of ethical commitment during worldwide threats due to spread of infectious diseases is aimed to facilitate in preventing violated integrity of anti-epidemic measures, formation of social unity and, finally, to ensure stability of human values, which will be discussed in this study.

Russian Journal of Infection and Immunity. 2020;10(2):287-294
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Examining immune arms in mice immunized with site-specific influenza virus mutants

Markushin S.G., Akhmatova N.K., Stolpnikova V.N., Akopova I.I., Rtishchev A.A., Kalinichenko E.O.


Site-specific mutants as candidates for live influenza vaccines were resulted from directly introducing into the genome of the pathogenic influenza virus A/WSN/33 (H1N1) strain ts mutations derived from the genes encoding the polymerase complex proteins from some cold-adapted strains serving as attenuation donor. Here we present the data of a comparative study examining immune system arms in mice immunized intranasally with influenza virus mutants and classical cold-adapted reassortant obtained by crossing cold-adapted strain Donor A/Krasnodar/101/35/59 (H2N2) with strain A/WSN/33 (H1N1) bearing surface antigens (hemagglutinin and neuraminidase) similar to mutants. Immunophenotyping mononuclear leukocytes from immunized mice indicated at moderate suppressive effect after using site-specific mutant and the HA reassortant viruses on some immune cell subsets. All viruses in immunized mice resulted in activation of certain lymphocyte subsets including MHC II-positive cells, CD45+/CD19+ B lymphocytes and natural killer cells (CD16/32+/CD3). Timescale and magnitude of activation markedly differed for each cell subsets. Mice immunized with mutants M26 and U2 peaked with count of CD16/32+/CD3 expressing cells on day 2 after the second immunization compared with control (p < 0.05) that may suggest about an important role for NK cells in activating immune response. In contrast, no significant changes were observed during the study in percentage of CD4+/CD25+/Fox P3 regulatory T cells, CD4+ T helpers and CD8+ cytotoxic cells, except for a sharply decreased count of activated CD4+/CD25+ cells (4-fold) on day 7 after immunization with mutant virus M26. Moreover, mutants U2 and M26 more moderately increased percentage of TLR2- and TLR4-positive cells. The viruses studied ambiguously affected count of TLR9-expressing cells in immunized animals. All viruses increased phagocytic activity in monocytes, but not neutrophils. Despite the moderate activation of innate and adaptive immunity arms, site-specific mutants more profoundly affected humoral reactions inducing increased antibody titers, so that immunogenicity of mutant viruses was higher than that of the cold-adapted reassortant. Thus, the findings hold a promise of using site-specific mutants as live influenza vaccines.

Russian Journal of Infection and Immunity. 2020;10(2):295-304
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Mimicry between respiratory virus proteins and some human immune proteins

Zhilinskaya I.N.


A comparative analysis on search for amino acid sequences in viral proteins causing respiratory infections (or respiratory infections syndrome) homologous to amino acid sequences from some human immune proteins was performed. The following viruses were used for comparative computer analysis: coronavirus (SARS-CoV), serotype C subgroup adenovirus C (adenoid 71 strain), measles virus (ICHINOSE-BA strain), rubella (Therien strain) and respiratory syncytial (B1 strain) virus. The search for homologous sequences in viral and human immune proteins was carried out by computer comparison of 12 amino acid fragments, which were assigned as homologous at identity in ≥ 8 positions. The data obtained showed that viral proteins contained homologous motifs in several host immune proteins involved in regulating both the inflammatory response and immune response. Mechanistically, all viruses studied were characterized by sequences homologous to host immune proteins such as complement system proteins, integrins, apoptosis inhibitory proteins, interleukins, and toll-like receptors. Such cellular proteins are actively involved in regulating host inflammatory process and immune response formation. Upon that, a set of host immune proteins, to which homologous fragments were found in viral proteins, was individual for each virus. Interestingly, the largest amount of homologous fragments (up to 20) was mainly concentrated in viral proteins with polymerase and protease activity suggesting that these proteins apart to their major role were involved in production of viral nucleic acids and might participate in regulating host immune system. Envelope, internal and non-structural viral proteins, homologous fragments were detected in much smaller quantities (from 1 to 4). In addition, two fragments homologous to various motifs of the same cellular protein were detected in some viral proteins. Thus, the data obtained further support our understanding that signs of immune system disorders in viral infections can result from multi-layered processes associated with modulation of host innate and adaptive immune system, and open up new approaches to study interaction of viruses with host immune system and identify new functions of viral proteins.
Russian Journal of Infection and Immunity. 2020;10(2):305-314
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Expression analysis of apoptotic and survival genes in blood leukocytes of children with various forms of HHV-6 infection

Sakharnov N.A., Utkin O.V., Filatova E.N., Knyazev D.I., Kulova E.A., Presnyakova N.B.


Despite that human herpes virus type 6 (HHV-6) is extremely spread worldwide, molecular mechanisms of behind HHV-6 infection pathogenesis remain largely unexplored. No molecular markers were found linked to unfavorable course of HHV-6 infection which could allow to ease up selecting proper therapy and preventing development of complications. The aim of the study was to analyze expression of apoptosis and survival-related genes in blood leukocytes from 7–17-year-old children upon various forms of HHV-6 infection. The analysis was carried out by using DNA microarrays developed by us allowing to assess changes in expression level both of individual mRNAs and total gene set (-Σ). It was shown that during the acute phase of HHV-6 infection mRNA level was shifted toward pro-apoptotic factors. In the convalescence phase, most altered mRNA levels returned to normal. We have identified a set of mRNAs and genes whose expression level was significantly changed in acute disease phase. According to available data, these factors play an important role in regulation of studied signaling pathways. In order to search for HHV-6-associated factors, which markedly affect disease pattern of severe herpesvirus mixed infection, we analyzed significant changes of mRNA and genes expression levels in patients with severe HHV-6+EBV+CMV mixed infection and EBV+CMV mixed infection of moderate severity compared with healthy donors. The levels of 5 mRNAs (FAF1-NM_007051, DAPK2-NM_014326, CASP8AP2-NM_001137667, CASP8-NM_033356, BTK-NM_001287345) and 3 genes (FAS-Σ, Puma/BBC3-Σ, ITCH-Σ) were significantly increased in severe mixed infection comorbid with HHV-6 (EBV+CMV+HHV-6) but without HHV-6 (EBV+CMV) compared with healthy donors. Most of detected factors belong to Fas-mediated apoptosis pathway, and may be considered as candidate prognostic development factors of severe herpes virus infection involving HHV-6. This study profoundly extends existing understanding on molecular pathogenesis of HHV-6 infection involving apoptosis and pro-survival signaling pathways. Marked changes of mRNA and gene levels most likely contributed to the pathogenesis of HHV-6 as well as severe HHV-6+EBV+CMV mixed infection.
Russian Journal of Infection and Immunity. 2020;10(2):315-328
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Neuropeptide system parameters in acute herpes zoster

Knysh S.V., Markelova E.V., Simakova A.I., Karaulov A.V.


The neuropeptides comprise an important part in the nervous system interacting with endocrine and immune systems. Peptide regulators are responsible for the continuity of communicating elements, which support homeostasis, however, despite abundant research examining neuropeptides, not all specific mechanisms and features of interacting proteins with cells and immune components have been uncovered. Objective: to perform a comprehensive assessment of neuropeptide system in patients with herpes zoster. Materials and methods: 106 in-hospital patients were examined diagnosed with herpes zoster within 2016–2019 period. Control group consisted of 30 healthy age- and sex-matched volunteers. Blood serum was collected after verifying diagnosis on day 1. After discharge, patients were monitored for signs of pain syndrome and overall state within 3 months. It allowed to divide patients into 3 groups retrospectively. Group 1 — patients with herpes zoster, accompanied by mild or moderate pain syndrome; group 2 — patients with herpes zoster, accompanied by severe pain; group 3 — patients with herpes zoster, complicated by postherpetic neuralgia. Level of serum protein s100B, myelin basic protein, nerve growth factor, brain-derived neurotrophic factor, neuron specific enolase was measured by using specific reagents purchased from “R&D Diagnostics Inc.” (США). Results. it was found that level of serum protein S100B in all groups was significantly increased compared to control group, showing no inter-group differences. Amount of myelin basic protein in all study groups vs. control was significantly higher. Moreover, level of these parameters in group 2 vs. group 1 and 3 was significantly elevated. In addition, level of nerve growth factor was significantly increased in group 1 vs. groups 2 and 3, whereas in group 3 it was significantly lower than in control and group 2. Brain-derived neurotrophic factor was significantly decreased in all the study groups compared to control, showing no significant intergroup differences. Level of neuron-specific enolase was significantly increased in group 3 vs. control as well as group 1 and 2. The data obtained allowed to identify two parameters for assessing a risk of postherpetic neuralgia in acute herpes zoster, as well as provided deeper insights into the pathogenesis of neuroimmune disorders accompanying herpes zoster.
Russian Journal of Infection and Immunity. 2020;10(2):329-337
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Clinical diagnostic criteria of efficiency for combined etiopathogenetic therapy in patients with chronic Epstein–Barr virus infection

Zurochka V.A., Zabkov O.I., Dobrynina M.A., Gritsenko V.F., Davydova E.V., Chukichev A.V., Zabokritskii N.A., Sarapultsev A.P., Zurochka A.V.


Treatment of chronic viral infections accompanied by permanent virus persistence in the target epitopes of the oral cavity, skin, urogenital tract is complicated by virtual lack of available drugs exerting combined systemic virulicidal and immunomodulatory effects. Here we demonstrate clinical and immunological efficacy of combined therapy in treatment of Epstein–Barr virus (EBV)-associated chronic infections. The aim of the study was to evaluate the clinical and immunological efficacy of combined etiopathogenetic therapy using the Acegram cosmetic product in patients with EBV-associated chronic infections. Materials and methods. There were enrolled 40 patients monitored before treatment as well as 20 patients followed up after combination therapy (cycle therapy consisted of oral valaciclovir (Valtrex) applied at dose of 500 μg twice a day for 10 days, glucosaminylmuramyldipeptide (Licopid) — 10 mg 2 twice a day for 10 days, topical irrigation for mucous membranes with granulocyte-macrophage colony-stimulating factor active center-derived peptide (Acegram-spray) 3 times a day for 10 days. If necessary, treatment courses were repeated 20 days after the onset. All patients were examined for the presence of EBV genomes in the oral fluid and blood using the qualitative and quantitative polymerase chain reaction (PCR) using the DNA technology test system (Russia) on a DT-Lite device prior treatment and 30, 60 days post-therapy time points. In addition, serum samples were analyzed for level of class G immunoglobulins specific to the EBV nuclear and capsid antigens by using enzyme immunoassay (test systems manufactured by CJSC Vector Best, Russia) as well as immune status (clinical methods, enu flow cytometry evaluation of the phagocytic activity of neutrophils, ELISA method). Results. Use of single or two course combination therapy in subjects with fully eradicated EBV carriage associated with reversed clinical symptoms was accompanied by recovered immune system status (T and B cells, T-helper cells, CD3+ CD25+  cells, phagocytosis parameters). A non-invasive approach proposed for controlling virus elimination in the oral fluid by using polymerase chain reaction method may serve as to objectively monitor therapeutic efficacy.
Russian Journal of Infection and Immunity. 2020;10(2):338-346
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Epstein–Barr virus LMP1 oncogene polymorphism in tatar and slavic populations in Russian Federation impacting on some malignant tumours

Gurtsevitch V.E., Smirnova K.V., Botezatu I.V., Dushenkina T.E., Lubenskaya A.K., Dubar E., Senyuta N.B., Lichtenstein A.V., Petrov S.V.


Objective: To compare genetic structure of the main Epstein–Barr virus (EBV) oncogene, latent membrane protein 1 (LMP1), in EBV strains circulating in two genetically distinct ethnic populations in Russian Federation, Tatars and Slavs, as well as assess an impact of diverse LMP1 variants on incidence and mortality rate for some malignant tumors partially associated with EBV infection. Materials and methods. Oral washing samples were collected from 60 ethnic Kazan Tatars and 65 ethnic Moscow Slavics. Carboxy-terminal nucleotide sequences (41 and 40 sequences, respectively) derived from hypervariable LMP1 gene region were amplified from EBV DNA samples. Next, final nucleotide sequences were translated into amino acid sequences and analyzed according to classification by Edwards et al. Results. Analysis of 41 and 40 LMP1 samples obtained from ethnic Kasan Tatars and ethnic Moscow Slavics, respectively, revealed significant difference in relevant amino acid structures. In particular, all LMP1 samples derived from Moscow Slavics were found to belong to the four protein variants: B95.8/A, Med–, China1 and NC. Among them, low-transforming variant B95.8/A was dominant (82.5%). In contrast, solely 21 out of 41 LMP1 samples derived from ethnic Tatars were classified as B95.8/A, Med– and China1 variants. Importantly, the percentage of low-transforming B95.8/A variant among ethnic Tatar samples was significantly lower compared to that one found in Moscow Slavics (29.3% vs. 82.5%). On the other hand, seven (17.1%) out of 20 other samples formed a unique protein mono group characterized by LMP1 amino acid sequence differed from that one available in the GenBank database. Such group of variants was designated as LMP1-TatK. The remaining 13 samples (31.7%) did not match either protein variants, thereby forming the “beyond classification” (LMP1-TatBC) group. Conclusion. The data obtained suggest that various LMP1 variants exist in EBV strains persisting in ethnic Tatrs and ethnic Slavics examined in Russian Federation. It was also found that EBV strains isolated from ethnic Tatars contained a unique LMP1 gene variant encoding protein LMP1-TatK lacked in EBV strains derived from ethnic Moscow Slavics. Taking into account the genealogy of Tatars, it cannot be ruled out that EBV strain bearing LMP1-TatK variant represented ethnically specific EBV strain that might circulate many centuries ago among their historical human predecessors called Mongol-Tatar tribes. In addition, it was shown that the LMP1 variants in EBV strains isolated from ethnic Kazan Tatars and ethnic Moscow Slavics did not affect the incidence and mortality of different forms of cancer consisting of EBV-associated cases.
Russian Journal of Infection and Immunity. 2020;10(2):347-358
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A role of oropharyngeal microbiota in developing acute and chronic diseases of the upper respiratory tract

Ababii I.I., Danilov L.A., Maniuc M.K., Ababii P.I., Ghinda S.S., Trofimciuc M.G., Kostinov M.P., Poddubikov A.V.


Currently, a rise in incidence of polyethological inflammation of the upper respiratory tract mucosa paralleled by altered resident and transient microbiota displaying in many cases increased antibiotic resistance has been noted. Opportunistic microbes play a major role in developing inflammatory process in Pirogov–Waldeyer’s ring. An inflammatory process occurring in the tonsillar lymphatic tissue results in host systemic complications. Fighting against acute and chronic infections of the upper respiratory tract holds the main task in pediatric otorhinolaryngology, as they can consequently elicit the cardiovascular, genitourinary and musculoskeletal complications. The results of studies examining this issue remain very contradictory, which accounted for a need to conduct our study on the territory of Moldova featured with mixed climatic conditions. Here, we wanted to study a role of microbial factor in etiopathogenesis of chronic tonsillitis in children. Bacteriological microbiota data for superficial palatine tonsils were obtained form 608 children subdivided into 5 groups: group I — 333 children with compensated chronic tonsillitis; group II — 87 children with decompensated chronic tonsillitis; group III — 91 children with acute upper respiratory tract infections (comparison group); group IV — 48 children with acute upper respiratory tract infections treated with antibiotic therapy; group V — 49 apparently healthy children (control group). It was found that β-hemolytic streptococcus exerting high sensitivity to virtually all antibiotics groups was detected in 17.4% of children with acute tonsilar inflammatory processes and decompensated defense in the lymphatic pharyngeal ring compared to 3.5% in control group. Streptococcus pneumoniae was isolated in all study groups ranging within 4.8–21.7%, including 14% in apparently healthy children characterized by reduced antibiotics sensitivity. The data obtained suggest that sickly children with acute and chronic upper respiratory tract infections constitute a risk group for developing somatic diseases. The high incidence of Streptococcus pneumoniae indicates a need for performing immunoprophylaxis, use of therapeutic vaccination as a up-to-date, combined approach in treatment of such pediatric cohort.

Russian Journal of Infection and Immunity. 2020;10(2):359-367
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The local interferon-corrective therapy in children with congenital cleft lip and palate, suffering from the recurrent respiratory infections

Nesterova I.V., Mitropanova M.N., Chudilova G.A., Kovaleva S.V., Khalturina E.O.


It is known that children with congenital cleft lip and palate are suffering from recurrent respiratory infections, which worsen the state of their health, and also complicate the results of reconstructive surgical treatment. The aim of the study was to detect defects of mucosal immunity in children with congenital cleft lip and palate, suffering from recurrent respiratory infections, and to create the program of local interferon corrective therapy with an assessment of its effectiveness. The studies included 56 children from the age of 1 to 3 years. Three groups of children were formed: group 1 – 26 children with congenital cleft lip and palate (antibiotic therapy); group 2 — 30 children with congenital cleft lip and palate (antibiotic therapy + local interferon therapy), group 3 — the control group. The clinical examination included a medical history, an assessment of the symptoms of recurrent episodes of acute respiratory infections and exacerbations of chronic infections. Microbiological studies were performed using standard methods. The status of local immunity was detected: the concentrations of secretory IgA, cytokines IL-17, IL-4, IL-6, IL-1β, IFNγ in the oral fluid were tested by ELISA. Results of the study established that in group 1 and group 2 clinical criteria of immunodeficiency with an infectious syndrome were revealed: repeated acute respiratory viral infections from 10 or more times a year, complicated by frequent exacerbations of chronic bacterial infection (up to 10 or more per year). Assessment of the state of local immunity in children with congenital cleft lip and palate revealed a lack of sIgA compared with the control group. Before treatment in group 2 oral fluid level of IL-17, IL-6 were statistically significant increase (p < 0.05); the results of the study also established increase in the level of IL-1β and a decrease in anti-inflammatory IL-4 and regulatory IFNγ relative to the control group (p > 0.05). After complex treatment with the inclusion of local interferon therapy in group 2 the appearance of sIgA, increase in the concentration of IL-4, IL-1β and a decrease IL-17 in oral fluid were observed (p > 0.05). The concentrations of IL-6, IFNγ did not change (p > 0.05). After treatment in group 2 there were a decrease in exacerbations of chronic upper respiratory tract infection and in frequency of acute respiratory viral infections compared with group 1 (p < 0.05). Positive clinical efficacy of local interferon therapy (the gel of recombinant IFNα2b in combination with oxidants — Viferon gel) in the process of staged rehabilitation of children with congenital cleft lip and palate has a protective clinical effect in reducing the frequency of acute respiratory viral infections, reducing the number of postoperative complications, reducing hospital stay, duration of antibacterial therapy and the number of exacerbations of chronic bacterial infection.

Russian Journal of Infection and Immunity. 2020;10(2):368-374
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Pattern of resilient age-related measles immunity

Sonis A.G., Gusyakova O.A., Gilmiyarova F.N., Ereshchenko A.A., Ignatova N.K., Kuzmicheva V.I., Borodina I.A., Nenjajkin S.S.


Epidemiological situation describing global measles spread is ambiguous. Along with countries succeeded in measles eradication, there are those wherein measles rate remains at quite high level. Because measles is a vaccine-preventable infection, it may then be eradicated solely by ensuring sufficient population coverage with preventive vaccination. The aim of our study was to assess level of measles immunity in medical workers at the Clinics of Samara State Medical University as well as the Samara State Medical University. There were enrolled 1503 subjects (aged 18–79 years), among which all individuals under 55 (77.58%) but not older counterparts provided with medical record on previous measles vaccination or measles infection. Level of serum measles virus-specific IgG antibodies was measured by using ELISA (VektoKor-IgG, JSC Vector-Best, Novosibirsk), with mean concentration ranging in general population within 1.02±0.02 IU/ ml. Positive results were observed in 72.52% of the examined individuals. Average vs. high measles virus-specific IgG level was detected in 52.90% (mean age — 41.4±0.5 years) and 19.62% (mean age — 54.2±0.72 years) of individuals, whereas at level below threshold — in 27.48% of subjects (mean age — 33.25±0.53 years). Thus, in 34.16% of the surveyed vaccinated individuals mostly presented by young subjects contained anti-measles virus-specific antibodies below protective level. Older age groups were shown to increase in average IgG amount with age. Interestingly, age-related measles immunity pattern was observed: percentage of subjects with high vs. low measles virus-specific IgG level increases and decreases, respectively. Taking into consideration a large percentage of subjects previously vaccinated against measles among carriers of low measles immunity, it may be concluded that measles virus-specific IgG antibody level must be monitored in young adulthood to decide of whether subsequent revaccination is necessary.
Russian Journal of Infection and Immunity. 2020;10(2):375-380
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A survey of examining herd measles immunity in adults over 35 years old

Rubis L.V.


A high measles incidence rate has been registered in Russia in recent years, with adults being actively involved in the epidemic process (about 40% of patients), thereby underlying relevance of assessing herd immunity in different  age groups to measure its risk. The data on examining serum antibodies to measles virus in 402 residents of Petrozavodsk are shown: 164 and 238 subjects were born in 1948–1968 (51–71 years) and 1970–1983 (36–50 years), respectively. It was found that the second group had significantly higher percentage not only of seropositive persons (94.1±1.5 vs. 77.4±3.3%, respectively), but also frequency of detected high IgG level (5 and more IU/l) reaching 39.7±3.5 vs. 15.4±5.8%, respectively. Analysis of vaccination history showed that of 351 people with protective antibody levels, 20.9% were vaccinated once or twice, 14 of them in childhood and 63 within the 15 years prior to the study. Of the 51 people with no measles antibodies or below protective level, 13.7% were vaccinated: five in childhood, and two within the last 15 years. Among those who was born in 1948–1968, 87.1±2.2% provided no information about previous vaccinations and probably were not vaccinated. In this group, percentage of those examined with a protective antibody level was significantly higher than in the 36–50 years group — 87.1±2.2 and 62.2±4.3%, respectively. In addition, 23 subjects confirmed that they recovered after measles in childhood. Of these, antibodies were detected in 21 subjects, including 9 having serum titer at level of 5 or more IU/ml. Until 1969, the Republic of Karelia registered a high level of measles morbidity (477–2176,0 per 100 thousand). The predominance in the group born before 1969, individuals seropositive to measles mainly at high titer, indicates that intense post-infectious immunity was preserved. The lack of protective level of antibodies to measles virus in 22.6% of persons aged 36–50 years (1969–1983 year of birth), due to the low level of post-infectious and insufficient durability of post-vaccination immunity allowing to definer them as a high risk group for measles infection.

Russian Journal of Infection and Immunity. 2020;10(2):381-386
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Practical aspects on identification, cultivation and characteristics of varicella-zoster virus isolates

Nagieva F.G., Barkova E.P., Lisakov A.N., Sidorov A.V., Zverev V.V., Osokina O.V., Stroeva A.D.


Until now, it has been considered that infectivity of the varicella-zoster virus (VZV) is closely related to target cell, and newly formed virus is not released into the culture medium. It is also known that it is hard to grow VZV in cell cultures, due to its slow replication rate and a limited range of sensitive cell cultures. In addition, VZV isolation depends on type of cell culture used, nature of clinical material, presence of viable virus and transport time. Objectives. To study production of infectious extracellular VZV in various cell cultures. Materials and methods. Eight cell cultures were used, including human embryonic diploid lung cells and human embryonic dermomuscular tissue (KM-27), as well as continuous human and monkey cell lines. Crusts detached from vesicular lesions were used as clinical isolates, which were placed into cryo-vials added with transport medium and transferred in liquid nitrogen. VZV infectivity was assessed in cell cultures by using hemo-adsorption assay with erythrocyte suspension isolated from guinea pig or human zero group blood and confirmed by indirect immunofluorescence with polyclonal sera from varicella or herpes zoster convalescents. Results. There were examined 27 clinical samples consisting of crusts from vesicular lesions isolated from patients with chickenpox, as well as one sample from 63-year old patient with exacerbated recurrent herpes zoster. Primary infection with clinical isolates was performed on diploid human lung embryo cells (HLEC) at low temperature. It was found that clinical samples collected within day 1–18 inclusive after the onset of skin eruption were able to induce cytopathic effects in HLEC cell monolayer such as cytolysis around dermal crusts. Specificity of cytopathic effect was confirmed by using real-time polymerase chain reaction (RT-PCR). Viral antigens were prepared on 7 cell lines infected with the laboratory strain Ellen VZV (USA) to assess the immune sera. A high anti-VZV specificity of mouse sera was detected by ELISA while all the lysates of infected cell lines were used as the solid-phase sorbent. In experiments on VZV reproduction demonstrated that extracellular virus was released into the culture medium starting from day 1 after infection of target cells, and infectivity of the virus-containing fluid ascends during further cultivation.

Russian Journal of Infection and Immunity. 2020;10(2):387-396
pages 387-396 views

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