Vol 10, No 4 (2020)

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Full Issue


Neutrophil granulocytes: participation in homeostatic and reparative processes. Part I

Dolgushin I.I., Mezentseva E.A.


After exiting from the bone marrow (BM) into the circulation, mature neutrophil granulocytes undergo a set of sequential phenotypic and physiological changes collectively called “aging” in the absence of inflammation, by constitutively sensing prime signals from commensal microbiota and acquiring higher functional alertness in case of activation upon tissue damage or pathogen invasion. Physiological aging of blood neutrophils and their subsequent return to the BM result in signals modulating size and function of the hematopoietic niche. Circadian physiological infiltration of BM by neutrophils contributes to maintaining baseline level of circulating hematopoietic progenitor cells capable of regeneration and immune surveillance. Apart from the BM, neutrophils actively enter other healthy tissues, probably exerting some effects on their baseline physiologic state. Using lung tissue, it has been shown that neutrophils can “govern” action of gene set regulating cell growth, migration, proliferation, differentiation, and carcinogenesis. Neutrophils participate in destruction of endometrial tissues during desquamation phase as well as subsequent repair and physiological angiogenesis during proliferative phase of the menstrual cycle; promote wall rupture of the preovulatory ovarian follicle and oocyte exit; contribute to degradation and resorption of the corpus luteum in pregnancy failure; play an important physiological role in vascular remodeling in pregnant uterus and developing maternal immune tolerance to semi-allogeneic fetus. Neutrophils actively migrating to the surface of intestinal epithelium during local infection and/or damage stimulate epithelial restitution and recovery of its barrier function. On the other hand, neutrophils recruited into the oral cavity regulate quantitative and qualitative composition of microbial communities in oral biofilms, and ensure healthy state of periodontal structures. Being a major player and regulator in healing of skin wounds at early stage, inflammation, neutrophils not only destroy potential pathogens, but also participate in cleansing wounds from cell debris, produce cytokines, enzymes, and growth factors affecting further stages in repair process. Both apoptosis and NETosis underlying neutrophil death greatly contribute to wound healing. However, dysregulation and imbalance in both apoptosis and NETosis may lead to unfavorable consequences as well as developing chronic non-healing wounds.

Russian Journal of Infection and Immunity. 2020;10(4):609-624
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Cytokines and neuron-specific proteins in pediatric viral encephalitis and convulsive syndrome. I. Viral encephalitis

Alekseeva L.A., Zheleznikova G.F., Gorelik E.Y., Skripchenko N.V., Zhirkov A.A.


Convulsive syndrome in children is manifested in the three forms: febrile convulsions in acute infections, symptomatic convulsions during acute neuroinfection, as well as onset of epilepsy requiring careful differentiation to prescribe adequate therapy. A threat of convulsive syndrome spreads beyond complications related to ongoing infection, because its development is associated with the risk of emerging symptomatic epilepsy in the future. Postencephalitic epilepsy developing in children within the first years after viral encephalitis has been specifically highlighted. A necessity to identify groups at risk of developing epilepsy gave a momentum to seek out for biomarkers of epileptogenesis reflecting the features of systemic and local inflammatory process in the central nervous system during the immune response to infection. Cytokines mainly mediating inflammation are currently examined being studied as candidate biomarkers of the risk of epilepsy. On the other hand, neuron-specific proteins known as inflammation biomarkers identified in various diseases of the central nervous system are being investigated to reveal brain cell injury in neuroinfections and epilepsy. Here we review publications assessing a potential to use inflammation biomarkers (cytokines and neuron-specific proteins) to diagnose and monitor pediatric neurological diseases associated with convulsive syndrome. The first part of the review describes the results of determining the inflammation biomarkers in the blood and cerebrospinal fluid during acute viral encephalitis/encephalopathy associated with various neurotropic viruses (herpes viruses, flaviviruses, enteroviruses). A significance of diverse biomarkers in predicting an outcome and long-term disease consequences are discussed.

Russian Journal of Infection and Immunity. 2020;10(4):625-638
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Аntibacterial inorganic agents: efficiency of using multicomponent systems

Meleshko А.A., Afinogenova A.G., Afinogenov G.E., Spiridonova A.A., Tolstoy V.P.


Metal and metal oxide nanoparticles (NPs) are promising antibacterial agents. They have a broad antimicrobial activity against both Gram-positive and Gram-negative bacteria, viruses, and protozoans. The use of NPs reduces the possibility of the microbial resistance development. This review briefly shows the general mechanisms and the main factors of antibacterial activity of NPs. In this article, a comprehensive review of the recent researches in the field of new antimicrobial agents with superior long-term bactericidal activity and low toxicity is provided. The review gives the examples of synthesis of double and triple nanocomposites based on following oxides: CuO, ZnO, Fe3O4, Ag2O, MnO2, etc. including metal and nonmetal doped nanocomposites (for example with Ag, Ce, Cr, Mn, Nd, Co, Sn, Fe, N, F, etc.). Compared with bactericidal action of individual oxides, the nanocomposites demonstrate superior antibacterial activity and have synergistic effects. For example, the antimicrobial activity of ZnO against both Gram-positive and Gram-negative bacteria was increased by -100% by formation of triple nanocomposites ZnO—MnO2—Cu2O or ZnO—Ag2O—Ag2S. Similar effect was showed for Ce-doped ZnO and Zn-doped CuO. The present article also provides the examples of nanocomposites containing NPs and organic (chitosan, cellulose, polyvinylpyrrolidone, biopolymers, etc.) or inorganic materials with special structure (graphene oxide, TiO2 nanotubes, silica) which demonstrate controlled release and longterm antibacterial activity. All of the considered nanocomposites and their combinations have a pronounced long-term antimicrobial effect including against antibiotic-resistant strains. They are able to prevent the formation of microbial biofilms on biotic and abiotic surfaces, have low toxicity to eukaryotic cells, demonstrate anti-inflammatory and woundhealing properties in compositions with polymers (sodium alginate, collagen, polyvinylpyrrolidone, etc.). The use of nanoscale systems can solve several important practical problems at the same time: saving of long-term antimicrobial activities while reducing the number of compounds, creation of new antimicrobial agents with low toxicity and reduced environmental impact, development of new biocidal materials, including new coatings for effective antimicrobial protection of medical devices.

Russian Journal of Infection and Immunity. 2020;10(4):639-654
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The COVID-19 pandemic: a systematic review of the current evidence

Ghomi R., Asgari N., Hajiheydari A., Esteki R., Biyabanaki F., Nasirinasab F.


Introduction. An epidemic of Coronavirus Disease 2019 (COVID-19) begun in December 2019 in China, causing primary concern. One of the important issues is its rapid spread around the world. Among the questions raised, disease epidemiology, clinical, laboratory symptoms and radiological findings and treatment of COVID-19 disease have been identified in some studies. But no systematic review on current evidences about COVID-19 has been published.

Objective. The aim of this study was to determine the COVID-19 epidemiology, clinical features, diagnosis and treatment.

Data sources. We performed a systematic review of the literature, using the keywords: “coronavirus” and “2020”, “COVID-19” in databases: Science Direct, PubMed, Springer and Scopus during January 1, 2020 to February 23, 2020.

Study Selection. All observational studies, as well as case reports and editorial that published in English were include. Data Extraction. Data on the disease control methods of COVID-19 were extracted by multiple observers.

Results. 131 articles were retrieved. After screening by abstract and title, 58 articles were selected for full-text assessment. Of them, 43 were finally included for review. The COVID-19 has spread rapidly and can be transmitted via close human-to-human contact via nasopharyngeal or oropharyngeal droplets. The COVID-19, causing considerable problems, especially in patients with comorbidities and old patients. Fever, cough, sore throat and diarrhea are the main clinical features of this emerging disease. The most common radiological finding is bilateral ground-glass view and Lopinavir and Ritonavir are among the antiviral drugs used.

Conclusion. COVID-19 is a new clinical infectious disease and can be a serious problem for health systems. Additional research is needed to elucidate factors that may mediate the pathogenesis of the severe and fatal associated disease.

Russian Journal of Infection and Immunity. 2020;10(4):655-663
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Strongyloidiasis in clinical practice: challenges in diagnostics and treatment (brief review and clinical observations)

Tokmalaev A.K., Kozhevnikova G.M., Zavoikin V.D., Tumolskaya N.I., Polovinkina N.A., Konnov V.V., Golub V.P., Kharlamova T.V., Emerole K.C.


High priority of soil-transmitted helminths worldwide and in the Russian Federation is due to their vast distribution and the severe pathological features they induce in humans. Recently, it was observed that awareness of clinicians regarding this disease category was markedly decreased, although no significant decline of the disease occurrence has been recorded, whereas rate of imported cases of parasitic diseases including soil-transmitted helminths like strongyloidiasis mainly originating from subtropical or tropical countries rose in non-endemic regions. Lack of alertness on diseases like strongyloidiasis impedes timely diagnostics and treatment. Global prevalence of strongyloidiasis was estimated to range within 30—100 million people, however the World Health Organization (WHO) suggests that it was underestimated as precise data in endemic countries remain unknown. The occurrence of these helminths has been recorded in regions of temperate-continental climate: Western Ukraine, Belarus, Moldova, the Caucasus, Central Asia, as well as in Eastern Europe and the Mediterranean region. In the Russian Federation locally acquired infections are frequently recorded in the Krasnodar Territory and Rostov Region. Here, based on multi-year experience in management of patients with strongyloidiasis we present our data and brief review of publications and systematic literature related to the challenges of its clinical picture, diagnostics and treatment. Life cycle, basic biological parameters of free-living helminth in nature and distinctive features of autoinfection related to strongyloidiasis were reviewed. Special attention was paid to the risk of developing severe forms (hyperinfection and disseminated strongyloidiasis) especially in immunocompromised hosts: HIV infection, radiotherapy followed by chemotherapy, long-term corticosteroid use. Difficulties in diagnosing Strongy-loides stercoralis infection are due to its polymorphic and non-specific clinical manifestations, as well as the lack of clinical knowledge and awareness about the disease. Clinical importance of parasitological methods for larvae detection was underlined. It was noted that the drug of choice in therapy of strongyloidiasis is ivermectin unapproved yet in Russia, whereas albendazole as an alternative drug exerts poorer efficacy, justifying a need to repeat treatment courses to establish full recovery from the disease.

Russian Journal of Infection and Immunity. 2020;10(4):664-670
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Salmonella-induced changes in the level of key immunoregulatory bacteria affect the transcriptional activity of the Foxp3 and RORgt genes in the gut-associated lymphoid tissue of rats

Bukina Y.V., Fedoniuk L.Y., Koval G.D., Shekhovtsova Y.O., Kamyshnyi A.M., Gubar A.O., Gubka V.O.


Intestinal microbes involved in many physiological processes owner, contributes to the formation and maintenance of immune homeostasis by regulating immune responses to protect against colonization by pathogens. A special role in the differentiation of various subpopulations of T-lymphocytes play the segmental filamentous bacteria (Segmented filamentous bacteria, SFB), capable of inducing a gut-associated lymphoid tissue (GALT) differentiation proinflammatory Th17-cells and members of the genus Clostridium (cluster IV and XIVa) and Bacteroides fragilis (polysaccharide A [PSA]), stimulating the formation of regulatory T-cells (Treg) and production of suppressor of cytokine IL-10. Important metabolites of B. fragilis are short-chain fatty acids (SCFA), which are able to activate GALT cells through the FFAR2 receptor. Lowering of the SCFA concentration leads to the reduction of the number of Treg in the intestine and breaks Th17/Treg balance. These changes lead to direct reducing of mRNA FFAR2, Foxp3 expression and increasing in RORyt GALT. Therefore, the goal was to determine the level of the key in the edge immunoregulatory bacteria intestinal microflora rats and their effects on the transcriptional activity of the genes Foxp3 and RORyt in GALT with Salmonella-induced inflammation and during administration of vancomycin and B. fragilis. To determine the genus and species of bacteria, as well as their number in the microflora of rats, was used the method of polymerase chain reaction (PCR-RV) with their identification by 16S rDNA genes. To study the transcriptional activity of genes using polymerase chain reaction reverse transcription real-time (RT-PCR). During the experiment with the introduction of animals vancomycin and Salmonella there was an increase in the level of SFB and a decrease in A. muciniphila, F. prausnitzii. Also, during infecting rats with S. Enteritidis and S. Typhimurium on the background of pre-treatment with vancomycin, there was an increase in the number of SFBs against the background of a pronounced decrease in Bacteroides—Prevotela group, A. muciniphila, Clostridium spp. clusters XIV, IV, and F. prausnitzii, which led to a decrease in the expression level of Foxp3+ mRNA and an increase in RORyt+, respectively. However, administration of B. fragilis to animals receiving S. Enteritidis or S. Typhimurium against pretreatment with vancomycin caused a decrease in the level of SFB and mRNA RORyt+, and, conversely, increased the number of Bacteroides—Prevotela group, A. muciniphila, Clostridium spp. clusters XIV, IV, F. prausnitzii and expression of Foxp3+ genes, which indicates the restoration of the homeostasis of the intestinal microbiome. The obtained results showed that B. fragilis can be successfully used in the treatment of inflammatory bowel diseases or diseases with impaired intestinal barrier function.

Russian Journal of Infection and Immunity. 2020;10(4):671-685
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Meta-analysis of the effectiveness of pentavalent live oral vaccine for the prevention of severe forms of rotavirus gastroenteritis in children

Kosova A.A., Bashkirova E.S., Mashin T.I., Chalapa V.I.


Rotavirus infection is ubiquitously distributed and represents a global public health problem. Some studies showed that vaccination with pentavalent oral live vaccine was effective in prevention of severe forms of rotavirus gastroenteritis among children up to 3 years of age. Previous randomized placebo-controlled studies assessing this issue were repeatedly conducted. However, due to the features of the epidemiology of pediatric rotavirus infection in Russia, a metaanalysis was conducted in the risk group — children under the age of 3 years by administering a full vaccination course for a single vaccine registered in the Russian Federation. A search was performed by two independent reviewers covering 1994 to February 2019, without restrictions on language, in five databases on medical and biological publications: Russian Science Citation Index, PubMed, Web of Science, MEDLINE, Scopus, and in contents of thematic journals and bibliographic lists. The meta-analysis included multicenter randomized controlled trials comparing the efficacy of placebo and completed full vaccination course with pentavalent live oral rotavirus vaccine in children under 3 years of age. The primary endpoint of the study was the incidence of severe gastroenteritis among children according to the Vesikari evaluation system. Data processing and generation of forest-plots to evaluate summarized results were carried out by the RevMan 5.3 free software distributed on the Cochrane Community website. The implementation of the “trim and fill” method was performed by using Stata 14.2 software. The meta-analysis consisted of 7 original publications performed as multicenter randomized, placebo-controlled double-blind studies. In the experimental and control group there were enrolled 19,384 and 19,425 subjects, respectively. Three-dose vaccination protocol markedly reduced a risk of infection with severe rotavirus gastroenteritis in the experimental group compared to control group, the odds ratio was 0.34 [95%, CI 0.19—0.60]. Cluster analysis also confirmed the protective effect of the full vaccination course. Group assessment of the vaccination effectiveness against rotavirus infection in countries of Africa and Southeast Asia showed significant protection, the odds ratio was 0.60 [95%, CI 0.52—0.70]. While evaluating the effectiveness of vaccination against rotavirus infection in Finland, the odds ratio was set at the level of statistical significance and reached 0.07 [95%, CI 0.04—0.11]. Thus, a full vaccination course with pentavalent live oral vaccine against rotavirus infection lowers a risk of developing severe rotavirus gastroenteritis in young children.

Russian Journal of Infection and Immunity. 2020;10(4):686-694
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Bioinformatics analysis of putative causes for сross-reactive antibodies interacting with antigens derived from various pathogenic human papillomaviruses

Stolbikov A.S., Salyaev R.K., Rekoslavskaya N.I.


Human papillomaviruses (HPVs) belong to highly abundant resulting in sexually transmitted virus infections, and cause cervical cancer holding place 4 among most common cancer types in women. In 2012, there were registered 266,000 death cases and 528,000 new cases. At present, three HPV prophylactic vaccines were generated worldwide: bivalent Cervarix, quadrivalent Gardasil and nonavalent Gardasil-9. Examining such vaccines uncovered that they are able to induce anti-HPV antibody production against viral antigens lacked in vaccine formula. The mechanism of such crossneutralizing antibodies recognizing antigens derived from various HPV pathogenic types remains unknown. In our study we attempted to uncover putative basis underlying cross-reactive interaction between vaccine-induced antibodies and non-vaccine antigens by bioinformatical approaches, that might allow optimize generation of future candidate vaccines and obtain more effective polyvalent immunobiological preparations against HPV. We used amino acid sequences of L1 coat protein of four top high-risk oncogenic HPV types (16, 18, 31 and 45) in the study. Work sequences were retrieved from the International Data Base of NCBI (National Center for Biotechnology Information) and aligned by using Clustal Omega’ and BioEdit software. A search and analysis of distinct antigenic determinant (epitopes) were performed by using software suite BepiPred-2.0: Sequential B-Cell Epitope Predictor, DiscoTope 2.0 Server, and SYFPEITHI. Bioinformatics data revealed pronounced potential of cross-neutralizing vaccine-induced antibodies and non-vaccines antigens derived from high-risk pathogenic types HPV 16, 18, 31 and 45 owing to the similarity in antigenic determinants (epitopes). Common linear determinants for T- and B-cells were found in all four types of L1 protein counterparts. In addition, similar three-dimensional B-cell determinants were discovered in HPV16 L1 and HPV18 L1. Antigenic determinants derived from HPV16 L1 and HPV31 L1 exhibited most close similarity. Hence, while immunizing with HPV16 L1, a more pronounced and moderate cross-reactive antibodies interacting with HPV31 L1 as well as HPV18 L1 and HPV45 L1 antigens, respectively, should be expected. Inversely, immunization with HPV18 L1might elicit active and less efficient crossneutralizing response with HPV45 L1 as well as HPV16 L1 and HPV31 L1, respectively.


Russian Journal of Infection and Immunity. 2020;10(4):695-706
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Determining molecular and genetic markers for severe EBV-mononucleosis

Filatova E.N., Sakharnov N.A., Utkin O.V., Kulova E.A.


Epstein—Barr virus (EBV) is one of the etiological agents causing infectious mononucleosis. A severe form of the disease can result in developing serious complications, which risk might also depend on the state of patient’s immune system. To date, no specific tests for assessing a risk of developing severe disease form are available. Our study was aimed at identifying molecular genetic markers of severe EBV-infectious mononucleosis (EBV-IM) in immunocompetent peripheral blood cells. Expression of 483 genes and gene transcripts regulating apoptosis, proliferation and differentiation of immunocompetent cells was measured in the peripheral blood leukocytes from patients with severe and moderate EBV-IM as well as apparently healthy donors. A DNA-microarray designed by us and subsequent data processing were carried out by using custom-made “MiDA” software. To identify markers of a severe form of the pathology, expression of each gene and transcript was compared in EBV-IM patients and apparently healthy donors. For each gene and transcript, the level of expression fold change and significance for binary classification were determined. Genes and transcripts, characterized by the maximum values of two determined parameters while comparing patients with severe infection and healthy donors, as well as patients with severe and moderate EBV-IM forms, were selected as markers of severe EBV-IM. Genes and transcripts with differed expression in patients with moderate EBV-IM and healthy donors, were excluded from the list of markers. In addition, sex- and age-linked markers with differed expression were excluded as well. The markers for severe EBV-IM consisted of apoptosis regulators (BCL2L11, BIRC3 genes and XIAP.NM_001167 transcript) and splicing factors (CELF6 gene and SF1.NM_201995 transcript). Compared with donors and patients with a moderate form of the disease, a decreased expression of BCL2L11, BIRC3 genes, transcripts SF1.NM_201995 and XIAP.NM_001167, as well as increased expression of the CELF6 gene were detected in the blood of patients with severe EBV-IM. The functional role of identified molecular markers suggests that severe EBV-IM is characterized by suppressed mitochondrial and activated TRAF-dependent apoptosis pathways in immunocompetent cells. The expression pattern for select markers is specific for severe EBV-MI, not associated with patient sex and age. Thus, study data may be used to develop specific tools for assessing a risk of developing complications of EBV mononucleosis.

Russian Journal of Infection and Immunity. 2020;10(4):707-716
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Evaluation of age-related distribution of measles cases with primary and secondary immune response in Russian Federation, 2010-2016

Mamaeva T.A., Zheleznova N.V., Bichurina M.A., Naumova M.A., Govoruhina M.V., Toptygina A.P.


In 2010—2016, blood serum samples were examined from 5539 patients, aged < 1—60 years, with clinically and laboratory confirmed measles. Primary or secondary type of immune response was determined for all measles cases. Studies were performed with children aged < 1—14 years (2381), adolescents, 15—17 years old (189), and adults aged 18—60 years (2969). Serum measles-specific IgM antibodies were measured by “VektoKor’ IgM” ELISA test system (Russia), concentration and avidity of specific IgG — by using “Anti-Measles Viruses ELISA/IgG” and “Avidity: Anti-Measles Viruses ELISA/ IgG” (Euroimmun, Germany). Primary immune response was identified based on the presence of serum measles-specific low avidity IgM and IgG antibodies, whereas secondary immune response was characterized by detecting high avidity IgM and IgG antibodies at concentration of ≥ 5.0 IU/ml. Analyzing measles-specific IgM antibodies in 2010—2016 demonstrated that measles morbidity was mainly due to children, aged 1—2 years reaching up to 39.9% of the total number of children with measles aged < 1—14 years as well as adults aged 18—40 years old comprising as high as 80.1% total number of patients aged 15—60 years. Serum measles-specific IgG testing showed that in 15.0% of cases they were detected at concentration of ≥ 5.0 IU/ml. Further serum dilution resulted in finding IgG titer ranging within 8.5—45.0 IU/ml (21.4+0.36) and high avidity antibodies in 80—100% (92.5+0.2) cases. The remaining 85.0% cases found low avidity measles-specific IgG antibodies (< 30%) at concentration of 0.2—3.46 IU/ml (1.73+0.03). An age-related analysis of our data demonstrated that all children under 14 with laboratory-confirmed measles developed primary immune response. Moreover, in 73.7% of measles patients aged 15—60 with primary immune response measles might be prevented by timely vaccination, whereas persons with “vaccine failure” comprised 26.3%. In 2010 (0.09 per 100,000 subjects) and 2016 (0.12 per 100,000 subjects), frequency of patients with “vaccine failure” during relative epidemic well-being was 35.3% and 18.2%, respectively, exceeding 9.9% (p < 0.001) serving as a hallmark 2014 high measles incidence rate (3.24 per 100,000 subjects).The data obtained indicate that measles virus circulate among people with “vaccine failure,” which may account for potential to spread and infect unprotected population cohorts as well as cause measles outbreaks during periods of epidemic well-being.

Russian Journal of Infection and Immunity. 2020;10(4):717-728
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Rise in 2017-2018 measles morbidity in Serbia and Northwest Russia

Stoiljkovic V.D., Bichurina M.A., Lavrentieva I.N., Filipovic-Vignjevic S.B., Bancevic M.D., Zheleznova N.V., Antipova A.Y.


In 2017, the WHO registered 23,927 measles cases in 44 out of 53 countries in the European region. In 2018, measles incidence rate increased up to 82,599 cases registered in 48 countries of the region, with a large number of measles-associated deaths. Overall, 72 measles fatalities were registered in 10 European countries, including Serbia (15 cases).

Aim of the study: to characterize 2017—2018 epidemiological upsurge of measles incidence rate observed in the Republic of Serbia (RS) and the Northwestern Federal District (NWFD) of the Russian Federation.

Materials and methods. During the 2017—2018 season, 944 serum samples were collected from patients with measles, rubella, or exanthematous diseases in the NWFD and tested in the Laboratory of Virology at the St. Petersburg Regional Centre for Measles Surveillance (SPbRC). In 2017—2018, 2,946 serum samples from the Republic of Serbia were analyzed in the SPbRC by using ELISA with IgM measles test system (Vector-Best, Russia; or Siemens, Germany). Urine and swab samples were examined by RT-PCR and used for isolation and genotyping of measles viruses.

Results. From 2017 to 2018, 5,798 measles cases were registered in the RS, among which 2,946 were laboratory-confirmed (serological testing and/or PCR). Unvaccinated subjects or those with unknown vaccination status accounted for majority of the cases. Children under 5 years of age and adults aged 30 years and over dominated among measles patients. During this season, 15 deaths were reported. Several genotypes of measles virus circulated in the RS, e.g. В3 Dublin, D8 Gir Somnath, and D8 Herborn. In 2018, 109 measles cases were recorded in the NWFD, 5 of which were imported from abroad. Among patients, adults comprised 64.2%, wherein 74.3% were covered by unvaccinated subjects or those with unknown vaccination status. Rise in measles incidence rate linked to multiple importations of various measles virus genotypes: В3 Kabul; B3 Dublin; D8 Frankfurt; D8 Cambridge; and D8 Gir Somnath.

Russian Journal of Infection and Immunity. 2020;10(4):729-734
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VNTR loci as indicators of proline-dependent plague microbe strains (Yersinia pestis) in the central caucasian mountain natural plague focus

Dubyanskiy V.M., Volynkina A.S., Anisimov A.P.


Y. pestis MLVA typing is used both to seek for similarities and differences between individual isolates upon conducting epidemiological investigations as well as for clonal clustering of intraspecies phylogenetic groups while analyzing microevolution and taxonomy issues. It cannot be ruled out that the most variable loci may be indicators allowing to approximate the unique strain-related properties circulating in certain natural plague foci. The Central Caucasian Highland Natural Plague Focus distinguished by heterogeneity of the circulating strains therein, including proline pro- and auxo-trophy, may represent a convenient model for testing this hypothesis. The purpose of our work was to assess the frequencies of the VNTR alleles associated with proline dependence among the Y. pestis strain VNTR loci, determined during previous MLVA-25 typing in the Central Caucasian Highland Natural Plague Focus. The main task was to identify the most informative sets of VNTR loci suitable for predicting proline pro— and auxotrophy (pro+, pro—). It was found that the loci ms45, ms56, ms46, ms07, ms69, ms62 displayed peak variability by allele frequencies and/or exhibited significant differences of mean allele frequencies in the pro— and pro+ strains. In particular, it was showed that the alleles of the ms45 locus contained 6 tandem repeats suggesting probability for pro+ reaching 0.944, whereas the alleles of the ms45 locus contained 7 tandem repeats with expected probability for pro— reaching 0.783. Moreover, the ms56 and ms46 contained 9 and more than 18 tandem repeats, respectively, thereby pointing at probability for pro+ equal to 0.933 and 0.818, respectively. Diagnostics for pro+/pro— phenotype by using specific statistical methods demonstrated statistical error 13.33% and 26.67% for the pro— and pro+ strains, respectively. All pro+ strains bearing a 6 tandem repeat complex from the ms45 locus, 9 tandem repeats derived from the ms56 locus and ms46 locus-derived 29—30 tandem repeats were accurately diagnosed solely based on these 3 loci. Thus, it is possible to predict some properties of Y. pestis strains based on determining the allele frequencies. While the number of MLVA typed plaque strains isolated in such natural focus has been progressively increased, it may be expected that opportunities for prognosing their properties based on determining locus tandem repeat composition having diagnostic value would be elevated.

Russian Journal of Infection and Immunity. 2020;10(4):735-740
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State of lipid peroxidation and antioxidant defense in chronic gastritis associated with Helicobacter pylori-infection in middle-aged males

Smirnova O.V., Sinyakov A.A., Titova N.M.


Helicobacter pylori is the most widespread human pathogen, with prevalence reaching up to 20—40% and 80— 90% of adult infection in developed and developing countries, respectively. Many authors consider this infection as a major factor in the development of gastric cancer. In case of H. pylori infection, free homogeneous oxidation is augmented, that elevates the blood amount of POL products. Hyperproduction of reactive oxygen species stimulates free radical POL, accompanied by membrane destruction, damage to proteins, lipids, and DNA. Thus, the destruction of the intracellular and cell outer membranes occurs resulting in cell death. In diseases associated with H. pylori infection, there is a dysregulation of the lipid peroxidation system — antioxidant defense contributing to inconsistency in the regeneration phases triggering disease progression. The aim of our work was to study indicators of POL (diene conjugates, malonic dialdehyde) and antioxidant protection (AOP) (superoxide dismutase enzymes, catalase) in chronic gastritis and chronic atrophic gastritis associated with H. pylori infection. In patients with CG associated with H. pylori as well as CAG and CAG associated with H. pylori they were featured with increased amount of primary (↑DC) and end TBA-active products of lipid peroxidation (↑MDA), whereas activity of superoxide dismutase was decreased, additionally highlighted with reduced catalase activity (↑CAT) in CAG and CAG associated with H. pylori. H. pylori just triggers the mechanisms of ROS generation in host cells. The energy of redox reactions is used by the microorganism to carry out its physiological functions and serves as a factor in its own pathogenicity, the ROS generated in such reactions can have a damaging effect on the structure of gastric mucosa. In addition, examining H. pylori genome has shown that it bears the genes encoding oxidative metabolism enzymes, such as SOD, catalase, nitroreductase, flavodoxin oxidoreductase. Long-term persistence of H. pylori in the gastric mucosa paralleled with its increased biomass accounts for it being the main source of ROS production able to augment lipid peroxidation and cause damage to the membrane structures and DNA of gastric epithelium cells.

Russian Journal of Infection and Immunity. 2020;10(4):741-746
pages 741-746 views

The role of infectious agent in development of tooth decay

Liubimova A.V., Brodina T.V., Goncharov A.E., Silin A.V., Zueva L.P., Klimova E.A., Belova L.V.


Aim: to assess the relationship between colonization of the oral cavity with S. mutans and different genotypic characteristics and the degree of tooth decay in children.

Materials and methods. 274 children aged 5 to 17 years (153 girls and 121 boys) who received a preventive dental checkup were included in the study. The dental caries experience was assessed by the DMFT index (number of decayed, missing due to caries, and filled teeth), according to WHO recommendations. The plaque was collected with sterile wooden toothpicks from the buccal gingival margin or from fissures of the first molars and placed in 1.5 mL Eppendorf tubes, and then plated on Mitis Salivarius Agar medium (HiMedia, India). 481 strains of S. mutans were selected for further study. DNA was extracted by an express method. Amplification was performed in the CFX-96 thermal cycler (Bio-Rad, USA). Serotyping was performed by multiplex PCR. PCR products were analyzed by gel electrophoresis in 1.5% agarose gel with ethidium bromide (10 mg/mL) manufactured by Helicon, Moscow, and visualized in UV light in transilluminator UVT1 by Biokom. Genotyping was performed according to the methodology (Saarela et al., 1996) with the oligonucleotide primer OPA-02 (5’-TGCCGAGCTG-3’). Strains of S. mutans were studied for the presence of the following genes: gtfB, spaP, cnm, fruA, gtfB, htrA, comE, mutA x(I), mutA (II), mutA (III), nlmAB (IV), adcA, Smu.399, Smu.583, Smu.761, Smu.940c, Smu.1449, Smu.2130.

Results. S. mutans was isolated from all the examined children. Dental decay was detected in 82.4% of the children. Among the strains studied, all 4 serotypes were found: in children with a DMFT = 0 only serotypes k and f were detected; the predominant serotype in children with tooth decay was serotype c (74.7%). 19 genotypes of S. mutans were identified. In children without caries (DMFT = 0), S. mutans did not contain the genes spaP, comE, adcA, Smu.2130, Smu.1449, gtfB, htrA. With the increase in the DMFT index, the frequency of their detection increased. 9 genotypes of S. mutans had all 7 virulence factors. In 94.9% of children colonized by these “virulent” genotypes, high DMFT index scores were observed.

Conclusion. The data obtained indicate that only a limited number of specific strains have a cariogenic potential. Strains of S. mutans belonging to serotypes e and c with a combination of virulence genes spaP, gtfB, comE, adcA, Smu.2130, Smu.1449, and htrA were isolated from children with tooth decay. Strains without these factors did not cause any damage to the teeth. The degree of tooth decay increases with colonization by several genotypes with the combination of virulence factors described above.

Russian Journal of Infection and Immunity. 2020;10(4):747-754
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Infiornativity lacrimal fluid interleukins in diagnostics and development of angle-closure glaucoma in elderly subjects

Chukhraiev A.M., Agarkov N.M., Konyaev D.A., Popova E.V., Yablokov M.M., Kulabukhov A.S.


An increased percentage of the elderly subjects in pattern of contemporary society, along with other causes and risk factors, is accompanied by rise in the incidence of glaucoma. By 2020, according to international studies it is expected that prevalence of glaucoma patients in the world would increase up to 80 million subjects. Among the elderly, glaucoma is a common pathology, which development is associated with local disturbances in interleukin profile. However, the features of the latter in patients with primary closed-angle glaucoma in the elderly were poorly examined. Studies of local interleukin status were conducted mainly in patients with suspected or initial manifestations of primary open-angle glaucoma. The features of lacrimal fluid interleukin shift in a target group of elderly patients suffering from stage II primary closed-angle glaucoma virtually gained no attention. In addition, a limited range of local interleukins in patients with such pathology in previous studies was examined. In addition, informativity of lacrimal fluid interleukins in elderly glaucoma patients was not assessed too based on objective methods. The aim of the current study was to outline features and informativity of local interleukin profile indicators in 58 elderly patients with primary closed-angle glaucoma stage II, aged 60—74 years (main group) and 27 age-matched elderly subjects lacking such pathology. The level of interleukins in the lacrimal fluid was determined with the enzyme immunoassay “Multiscan” analyzer (Finland) by using sandwich ELISA (R&D Diagnostic Inc., USA). Informativity of measuring various interleukins was calculated according to the generally accepted formula. It was found that local interleukin profile in elderly patients with primary closed-angle glaucoma was mainly featured with increased amount of IL-2, IL-17, IL-8, but decreased IL-10. Hence, such local interleukins displayed peak informativity. The data obtained should be used in the diagnostics and treatment of such pathology, as well as of applied importance to unveil novel mechanisms behind development, diagnostics and corroboration for selective immuno-tropic therapy of primary closed-angle glaucoma.

Russian Journal of Infection and Immunity. 2020;10(4):755-761
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Assessing cytokine status of patients with chronic endometritis combined with endometrial hyperplastic processes in reproductive period

Tkachenko L.V., Sviridova N.I., Zharkin N.A., Burova N.A., Belan E.B.


The goal of our study was to examine local and serum cytokine level involved in regulating inflammation in patients with chronic endometritis combined with endometrial hyperplastic processes. On admission, all patients underwent hysteroscopy with separate diagnostic curettage followed by histological examination of samples isolated from the uterine and cervical canal mucosa. Such manipulations were indicated due to abnormal uterine bleeding as well as suspected endometrial pathology based on ultrasound examination. According to the histological examination data of the endometrial samples, all patients were divided into two groups: group I contained 45 women with CE combined with PEG without atypia; group II — 38 patients with morphologically verified CEE combined with AEG without atypia. Level of IL-1P, IL-2, IL-6, IFNy, TNFa in biological fluids (aspirate from the uterus; serum) was measured by using enzyme-linked immunosorbent assay. We found that in both groups (91.1% and 89.6%, respectively) the vast majority of patients was hospitalized due to abnormal uterine bleeding. Oligomenorrhea alternated with intermenstrual bleeding (66.7% and 71.2%, respectively) and dominated in pattern of menstrual cycle disorders in the examined patients, whereas 11 (24.4%) and 7 (18.4%) patients from group I and II, respectively, were noted to suffer from severe menstrual bleeding. Overall, analyzing the data on cytokine level both in the uterine aspirate and serum evidences about ongoing inflammatory process found at examination time point. Upon that, such process was not only local, but also exhibited signs of a systemic inflammatory response. The data on cytokine level in the uterine aspirate from patients with CE coupled to PGE or CGE without atypia point at local inflammatory process characterized by significantly increased concentration of IL-ф, IL-2, IL-6, TNFa and IFNy. At the same time, higher level of IL-ф and IFNy in patients from group II might indicates that degree of morphological changes in the endometrium could affect the level of local cytokine production. Thus, the data obtained evidence that immune changes in chronic endometritis combined with non-atypical endometrial hyperplastic processes mostly occur locally. In this regard, measuring cytokine concentration in the uterine aspirate is a diagnostic predictor and serves as a sign for monitoring therapeutic effectiveness of therapy in this cohort of patients.

Russian Journal of Infection and Immunity. 2020;10(4):762-768
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HIV-1 CRF63_02A6 models as a tool for evaluating efficacy of developing antiretroviral drugs

Zyryanova D.P., Bogacheva N.V., Totmenin A.V., Gashnikova N.M.


Highly active antiretroviral therapy (HAART) allows not only to control the infection process in certain patient, but also to reduce a risk of HIV infection spreading in general, so that one of the goals for international community fighting against HIV-spread is to maximize coverage of infected subjects with HAART. Antiretroviral therapy in HIV infection is administered lifelong, so that therapeutic efficacy may be lowered due to emergence of resistant HIV-1 variants. Currently, development of new antiretroviral drugs is currently underway throughout the world, therefore standard HIV-1 models are demanded to evaluate antiviral efficacy of promising drugs. To reliably assess drug efficiency regarding Russiawide HIV-1 variants, HIV-1 genovariants widespread in Russia should be used as a virus model. A recently emerged recombinant form of CRF63_02A6 HIV-1 is spread in Russia being currently a dominant variant detected among HIV-infected individuals in an extended region of the Siberian Federal District: in the Novosibirsk, Tomsk, Omsk, Kemerovo Regions, Krasnoyarsk and Altai Krai. We have obtained CRF63_02A6 infectious isolates of HIV-1, one of which contains mutations, reducing the sensitivity to the applied inhibitors of the virus reverse transcriptase. In addition, we constructed infectious molecular clones based on HIV-1 CRF63_02A6 variants with an affinity for CCR5 coreceptors and CXCR4. Infectious isolates and molecular clones CRF63_02A6 tested as models for assessing efficacy of antiretroviral drugs using the example of the drug “Efavirenz”. The fifty percent inhibitory concentration determined on the models of HIV-1 infectious molecular clones and HIV-1 isolate 18RU7056 ranged from 0.00027 pg/ml to 0.00046 pg/ml being in agreement with data published elsewhere. Concentrations of “Efavirenz” used in the study did not suppress the replication of HIV-1 12RU6987, which is resistant to non-nucleoside reverse transcriptase inhibitors, which confirms the decrease in the sensitivity of HIV-1 12RU6987 to “Efavirenz” by no less than 10,000 times. Thus, our data demonstrate that CRF63_02A6 HIV-1 isolated strains and infectious molecular clones are relevant and complementary tools for assessing efficacy of developing drugs aimed at suppressing HIV-1, including non-nucleoside-resistant virus reverse transcriptase inhibitors.

Russian Journal of Infection and Immunity. 2020;10(4):769-774
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Clinical and immunological characteristics of bacterial pneumonia associated with HIV infection coupled to drug addiction

Puzyreva L.V., Mordyk A.V., Paneva M.A.


Bacterial pneumonia holds the second place after respiratory tuberculosis in patients with HIV infection. In recent years, sexual transmission of HIV was replaced by injection drug route. It seems of high relevance to advance medical aid to patients with HIV infection and bacterial pneumonia depending on psychoactive substance use.

Aim of study — assessment of clinical and immunological manifestations of bacterial pneumonia coupled to HIV infection with respect to verified injection drug use.

Materials and methods. Clinical and immunological data collected from 224 patients with HIV infection and pneumonia were retrospectively analyzed: group 1 group — 70 patients with HIV infection, IDU, verified bacterial pneumonia; group 2 — 16 injecting drug users (IDU) with HIV infection and pneumonia of unverified etiology; group 3 — 65 patients with HIV and bacterial pneumonia of verified etiology without injection drug use, group 4 — 73 patients with HIV infection and bacterial pneumonia of unverified etiology, without injection drug use. The data obtained were analyzed by using software Statistica 13.3. Methods of descriptive statistics with calculation of nonparametric criterion — the Kruskall—Wallis test (H-criterion) and χ2 test — were used.

Results. Immunological manifestations of HIV infection and bacterial pneumonia were characterized by decreased count of CD4+ cells paralleled with increased count of CD3+ and CD8+ cells at higher magnitude without injection drug use being also featured with peak viral load upon developing pneumonia. Bacterial pneumonia coupled to HIV infection showed clinical manifestations similar both in injecting drug users and non-users, proceeding in 10% cases during normothermia. Injection drug user patients often demonstrated clinical picture of pneumonia resembling those found in sepsis such as pain in the body, muscles, bone aches untypical to HIV-sexually infected subjects. In addition, systolic murmur on a heart top was more often auscultated in this patient group.

Conclusion. Subjects self-considered healthy being at risk of sexually transmitted infections should examined for HIV. All subjects manifested with symptoms of the lower airway tract infections in admission department should not be rejected to be hospitalized and undergo chest X-ray examination.

Russian Journal of Infection and Immunity. 2020;10(4):775-781
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Comparative prevalence of atopic sensitization in the border areas between Russia and Finland

Markelova O.A., Vezikova N.N., Zilber E.K.


Current century has been highlighted with rise in allergic pathology, and environment markedly affects it via epigenetic mechanisms. Allergy research in Russia and Finland has been conducted for many years, of larger scale recorded in the latter, still being maintained over time. Atopy prevalence was studied in the border areas in both countries. The level of total, dietary, inhaled IgE level, as well as dietary and inhalation range were examined. The Phadiatop® radio allergen sorbent test was used (UniCAP 1000 v.2; Pharmacia Upjohn, Uppsala, Sweden), with cut-off point: IgE > 110 kUA/l and sIgE > 2.5 kUa/l and 0.35 kUA/l. The study was subdivided into 2 stages conducted during 2003 and 2010/2012 timeframe. Stage 1 was performed with children from Finland (n = 344), Russia (n = 427), aged 7—15 years, whereas stage 2 — 180 subjects (Finland, n = 98, Russia, n = 82). Results. It was found that total IgE level was higher in children from Finland. The inhaled sIgE in 2003 and 2010/2012 was higher among children from Finland, p = 0.019 and p = 0.027, showing temporal elevation. In 2003, dietary sIgE was higher among those from Finland (27.6% and 18.3%), p = 0.142, whereas in 2010/2012 it was decreased by 2- and 3-fold in subjects from Finland and Russia, respectively. In 2003, high atopy rate against dust mites, cats, timothy, birch, and dogs was found in Russia, which was increased at stage 2. Such parameter was most evidently elevated for timothy — by 2-fold, p = 0.176, wormwood — by 2-fold, p = 0.312, equine allergens — by 2-fold, p = 0.563, canine allergens — by 1.5-fold, mite — by 1.5-fold, p = 0.220. In 2003, atopy rate in Finland to canine allergens reached 26.5%, timothy — 24.5%, birch — 20.4%, feline allergens — 20.4%. In 2010, it was noted rise in atopy rate mainly to dust mites — by 2-fold, equine allergens — by 2-fold. In 2003, atopy rate in Russia to egg, milk, and wheat prevailed, whereas in Finland it was mostly found against milk, nuts, wheat, eggs, in both cases declined in dynamics. Interestingly, no sensitization to fish in subjects from Russia and Finland was observed at both stages. Finally, at the stage 2 dietary atopy rate was declined in both countries. Differences in atopic sensitization as well as during 7—9 year follow-up observation were preserved between both subject cohorts from Finland and Russia.

Russian Journal of Infection and Immunity. 2020;10(4):782-788
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Parthenolide: suggested drug for COVID-19

Nemati M., Danesh Pouya F., Roshani Asl E., Rami Y.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the 2019 novel coronavirus (2019-nCoV) that causes acute respiratory distress syndrome (ARDS) which is the main reason for patients mortality. One of the effective treatments to reduce the effects of this virus is parthenolide (PN). Parthenolide is a sesquiterpene lactone found in medicinal plants. It can inhibit several pro-inflammatory signaling pathways, in particular the ATPase activity of NLRP3. Based on its ability to suppress inflammatory signal transduction and elevated level of serum IL-1β (a surrogate marker for NLRP3 activation) in COVID-19 patients, we suggest that PN could be potentiallyeffective for the treatment of COVID-19.

Russian Journal of Infection and Immunity. 2020;10(4):789-791
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An accelerated method for determining «self/non-self» microorganisms in the agglutination reaction

Bukharin O.V., Perunova N.B., Chainikova I.N., Ivanova E.V., Andryushchenko S.V.


A simple accelerated method for determining «self/non-self» microorganisms by using the agglutination reaction (RA) and therapeutic/prophylactic serum (Immunoglobulin complex preparation, lyophilized IgG, IgA, IgM immunoglobulins, developed by CSC Immuno-Gem, Moscow) is proposed to test for pathogenic, opportunistic and dominant probiotic Bifidobacteria spp. In parallel, all the microbial cell cultures examined were registered in the databases of Russia-wide and international collections and tested by the intermicrobial “self/non-self” recognition method, previously developed by us. 16 collection strains of various microorganisms were assessed by the RA with relevant therapeutic and prophylactic serum. Biological samples were obtained from the collection bacterial strains of Bifidobacterium bifidum 791, Escherichia coli LEGM-18, Klebsiella pneumoniae 278, Lactobacillus fermentum 90T-C4, Bifidobacterium longum MC-42, Escherichia coli M-17, Shigella sonnei 177b, Shigella flexneri 170, Escherichia coli 157, Staphylococcus aureus 209, Candida albicans 10231 and Salmonella serovar Enteritidis ATCC 10708. In addition, cell cultures obtained from the Museum of the Institute of Cellular and Intracellular Symbiosis UB RAS such as Bifidobacterium longum ICIS-505, Lactobacillus acidophilus ICIS-1127, Bifidobacterium bifidum ICIS-202, Bifidobacterium bifidum ICIS-310 were also included into the study. To assess microbial peptidoglycan foreignness, the intermicrobial “self/non-self” recognition method was also used based on inducing metabolites produced by the “dominant” test strain Bifidobacterium longum MC-42 after pre-incubation with metabolites collected from the studied cell cultures (“associates”) followed by established “dominant-associate” feedback loop. The data were evaluated by assessing change-fold in reproduction (growth/replication) and adaptation (biofilm formation and anti-lysozyme test) of microbial cultures in accordance with the described technique followed by comparing these two methods for intermicrobial “self/non-self” recognition. All the RA data were found to fully agree with those obtained after previous studies by using intermicrobial “self/non-self” recognition method coupled to “dominant-associate” system. Moreover, compared to analogous “intermicrobial recognition” method (5 days), ease of use and test timeframe (24 hours) allow to consider RA attractive for screening studies to select strains for scientific and industrial purposes.

Russian Journal of Infection and Immunity. 2020;10(4):792-796
pages 792-796 views


In memory of valentin V. Pokrovskiy


Russian Journal of Infection and Immunity. 2020;10(4):797-798
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