Vol 11, No 5 (2021)

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A controversial role of neutrophils in tuberculosis infection pathogenesis

Linge I.A., Apt A.S.


Tuberculosis (TB) continues to be an important and unresolved medical problem. About a quarter of mankind is infected with Mycobacterium tuberculosis, and about 5–10% of these people eventually develop TB. Macrophages and CD4+ T cells are considered the key cells providing defense against TB infection. The role of neutrophils in TB is less well defined. Neutrophils are short-lived granulocytes among first migrate into the infectious lung tissue and phagocy tose mycobacteria. On the one hand, there is evidence for protective role of neutrophils in TB released via anti-microbial peptides inhibiting mycobacterial growth, up-regulation of CD4+ T-cell activation, and dendritic cell migration in the lymph nodes. On the other hand, infection of genetically TB susceptible animals leads to an overwhelming lung neutrophil inflammation, development of necrotic granulomata, and a rapid death. Neutrophils act directly or indirectly on mycobacteria by different oxidative or other reactions including neutrophil extracellular traps (NETs) formation. Phagocytosis of mycobacteria by neutrophils is accompanied by the production of pro-inflammatory factors, thus making neutrophils active participants of inflammation in all stages of the infectious process. Finally, neutrophils die by apoptosis or necrosis. Necrosis of neutrophils, which is activated by reactive oxygen species, also prolongs the inflammation. In this way, there is strong evidence that neutrophils are the cells involved in the transition of infection to the terminal stage, participating in lung tissue destruction. Although neutrophils evolutionary developed many ways to resist pathogens, it is likely, that neutrophils do not possess sufficient anti-mycobactericidal capacities due to the development of many adaptations allowing mycobacteria to survive inside the neutrophils. Neutrophils effectively phagocytose but poorly kill mycobacteria, thus hiding bacilli from more efficient killers, macrophages, and playing the role of the “Trojan Horse”. In this review, we summarize the data on the involvement of neutrophils in TB inflammation. We discuss their ambiguous role in pathogenesis which depends upon mycobacterial virulence, host genetics, dynamics of migration to inflammatory foci, and persistence during initial and chronic stages of the infectious process.

Russian Journal of Infection and Immunity. 2021;11(5):809-819
pages 809-819 views

Effect of the natural and climatic factors on epidemiological situation related to natural focal infections

Prislegina D.A., Dubyanskiy V.M., Platonov A.E., Maletskaya O.V.


This article is dedicated to the analysis and generalization of the Russian and foreign research results on natural and climatic factors effect on the intensity of epidemic process manifestations and the natural focal infections pathogens vectors vital activity which are the most widespread in the Russian Federation. Over the past seven years tick-borne infections have been accounting for more than 50 per cent in the natural focal diseases general nosological structure. Among the diseases of this group Lyme borreliosis leads in prevalence and frequency of cases identification. Tick-borne viral encephalitis is still a serious danger for national health. Crimean-Congo hemorrhagic fever epidemiological situation remains unfavorable in the south of the European part of Russia. In addition to the annual patients identification, the demonstrable trend of shifting and expansion of the pathogen’s area in a northerly direction was established. It creates a risk for the spread of the Crimean-Congo hemorrhagic fever virus outside the southern regions of the country. High incidence of the dangerous vector-borne infection — West Nile fever — with the involvement of new subjects in the epidemic process and the emergence of local cases of infection in previously non-endemic territories is registered. Expansion of hemorrhagic fever with renal syndrome natural foci borders, which is the most widespread natural focal zoonosis of viral etiology in the Russian Federation and is the second by the frequency of patients identification after tick-borne infections, is noted. Research data for the dependence of the carriers pathogens number and the dynamics of the natural focal infections incidence on the values of climatic factors, confirmed using various methods of mathematical statistics (time-series analysis, autoregression integrated moving average, logistic regression, correlation analysis, one-way analysis of variance and other) were systematized. It was found that the temperature and humidity of the air and soil, the amount of precipitation, the height of the snow cover are the common abiotic factors for all of investigated infections. The values of these factors can be used for the subsequent epidemiological forecast. The further study of relationship between the incidence rate of the population, the number of arthropod vectors and small mammals with indicators of soil moisture and temperature at different depths, hydrothermal coefficient, normalized relative vegetation index, accumulated values of temperature and precipitation, as well as similar studies on other actual natural focal infections in the Russian Federation will be very promising.

Russian Journal of Infection and Immunity. 2021;11(5):820-836
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Antimicrobial peptides as promising drugs for treatment of primary viral pneumonia

Shchelkanov M.Y., Cybulsky A.V., Dedkov V.G., Galkina I.V., Maleev V.V.


The COVID-19 pandemic which began in March 2020 has again drawn attention to the problem of treating primary viral pneumonia (PVP), wherein damage to the tissues of the lower respiratory tract including functionally important alveolocytes occurs as a result of cell infection by pathogens of the Virae Kingdom. Whereas treatment of bacterial pneumonia is based on the basic approach related to the use of antibiotics (which effectiveness needs to be verified more often than ever due to the “curse of the resistance effect” — that, however, does not cancel the essence of the basic approach), efficient PVP treatment is feasible only in case of available etiotropic, but catastrophically few, drugs. Such drugs in case of the influenza A virus (Articulavirales: Orthomyxoviridae, Alphainfluenzavirus) have been known since the second part of the XXth century. However, no consensus was achieved among clinicians regarding particularly dangerous human coronaviruses (Nidovirales: Coronaviridae, Betacoronavirus) which threat has driven the world epidemiology in the XXIst century: SARS-CoV (subgenus Sarbecovirus), MERS-CoV (Merbecovirus), SARS-CoV-2 (Sarbecovirus). And we should be prepared to the fact that increase in population density and scaling up of anthropogenic impact on ecosystems elevates a probability of overcoming interspecies barriers by natural focal viruses and their penetration into the human population with adverse epidemic consequences. Therefore, PVP therapy should be developed systematically in the nearest future. Antimicrobial peptides (AMP) as the components of non-specific innate immunity against a wide range of infectious pathogens: bacteria (Bacteria), microscopic fungi (Fungi) and viruses (Virae) may serve as a platform for developing such system. Our review justifies a way to select such platform and provides well-known examples of successfully used AMP in treatment of PVP and related pathological conditions.

Russian Journal of Infection and Immunity. 2021;11(5):837-852
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A role of streptokinase in experimental post-streptococcal glomerulonephritis

Burova L.A., Gavrilov E.A., Pigarevsky P.V., Totolian A.A.


Post-streptococcal glomerulonephritis (PSGN) refers to the sequela of the acute infection, caused by Streptococcus pyogenes (group A streptococcus, GAS). This pathology has been studied for a long time, and today attempts are being made to identify the products of their life activity, able to initiate an immunopathological process in kidneys. Most attention has been paid to streptokinase, the enzyme transforming blood plasminogen into plasmin, capable, together with the plasmin receptor (NAPlr), of damaging the glomerular tissue, as well as activating the complement system. The aim of the study was to consider two tasks: to study the ability of the GAS-obtained enzyme to transform plasminogen of different species into plasmin as well as to study its role in the development of PSGN in rabbits having subcutaneously implanted tissue chambers. The animals were infected by inoculating GAS cultures into the chambers. Materials and methods. GAS strains of M types 1, 12, 22 and their ska– isogenic mutants were used in the study. Purified plasminogen preparations were isolated from fresh human, rabbit or mouse plasma by using chromatographic column with Lysine Sepharose 4B. To reveal the ability of streptokinase to activate plasminogen into plasmin, its preparation at a concentration of 1 mg/ml was added to 10 ìg of purified human, rabbit or mouse plasminogen. The concentration of plasmin was defined photometrically using S-2251 (Chromogenix, USA). To reproduce PSGN, four chambers were implanted under the skin in each rabbit; after the complete wound healing animals were infected and observed for three weeks. On day 14, the animals were treated with benzylpenicillin. The kidneys from survived rabbits were subjected to immunohistology analysis. Results. During in vitro experiments, M1, M12 and M22 GAS streptokinase showed distinct functional activity on human plasminogen, transforming it into plasmin: optical density indicators at ë = 405 nm were 0.4–0.7 compared with the negative control (ОD < 0.001). Streptokinase did not activate mouse plasminogen (ОD = 0.001) and exerted quite a weak effect on transformation of the rabbit plasminogen into plasmin (ОD = 0.002). In experiments on PSGN induction in rabbits, we failed to detect streptokinase involvement, because no differences between initiation of glomerulonephritis by wild strains or ska– isogenic mutants were identified. Mutant strains deficient in the gene responsible for streptokinase synthesis but retained ability to bind rabbit and human IgG, caused morphological changes in kidney tissue, specific for PSGN. In addition, a comparative analysis of PSGN “rabbit” and “mouse” models developed by the same technology, was carried out and led to opposing conclusions regarding a role of streptokinase in pathogenesis of experimental glomerulonephritis. The role of IgG Fc-binding activity of GAS in development of experimental PSGN is discussed.

Russian Journal of Infection and Immunity. 2021;11(5):853-864
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Salmonella-induced changes of the rat intestinal microbiota

Bukina Y.V., Polishchuk N.N., Bachurin H.V., Cherkovska O.S., Zinych O.L., Lazaryk O.L., Bezugly M.B.


The gut microbiome profoundly affects the body functioning: it participates in host protection against pathogenic microorganisms, metabolic events, inhibition of inflammatory responses, formation of innate and adaptive immune response in the intestinal mucosa. One of the causes altering microbiota community is due to antibiotics. Therefore, the processes of antibiotics interaction together with Salmonella enteritidis and Salmonella typhimurium with representatives of normal intestinal microflora are of particular interest. Materials and methods. The quantitative and qualitative analysis of the wall microbiota composition in rats was evaluated by bacteriological method, the statistical data analysis was performed using the software StatSoft Statistica v.12. Results and discussion. Inoculation of vancomycin and S. enteritidis, S. typhimurium in groups II, III, IV resulted in quantitatively decreased E. coli level by 10-, 7- and 110-fold, respectively (p ≤ 0.05). The count of P. aeruginosa decreased markedly only in the group III (p ≤ 0.05). The count of Bacteroides spp. members was profoundly decreased by several thousand times (group II) as well as 70- and 87-fold (groups III and IV), respectively (p ≤ 0.05). The count of E. faecalis and E. faecium decreased by 861-, 6- and several thousand times (groups II, III, IV), respectively (p ≤ 0.05). The count of Proteus spp. markedly decreased in group II by 27-fold and rapidly increased in group IV (p ≤ 0.05). Group III revealed a sharp decline in level of Enterobacter spp. and Klebsiella spp. by 847- and 150-fold, whereas in group II they were increased by 7- and 46-fold, respectively (p ≤ 0.05). The count of Staphylococcus spp. decreased by 10-fold only in group II. The level of Clostridium spp. decreased by several thousand times (group II) and by 5,500 times (group IV) (p ≤ 0.05). The count of Lactobacillus spp. decreased by several thousand times (group II). The count of Bifidobacterium spp. members significantly decreased by 10.9-fold and by several thousand times (groups III, IV). The level of Peptostreptococcus anaerobius profoundly decreased in all three study groups (p ≤ 0.05). The level of Salmonella spp. increased in group II by 49 times, but markedly increased in groups III and IV (p ≤ 0.05). Inoculation of Salmonella after vancomycin pretreatment caused dramatic change in the microbiota composition in groups V and VI, namely: increased count of E. coli by 65- and 105-fold, markedly increased level of P. aeruginosa in group V and VI — by 3-fold. In addition, these groups also showed decreased level of Bacteroides spp. by 9- and 10-fold (p ≤ 0.05). The count of E. faecalis and E. faecium decreased dramatically only in group V (p ≤ 0.05). The count of Proteus spp. decreased by 17 times in group V as well as in group VI (p ≤ 0.05). A sharp increase in level of Enterobacter spp. and Klebsiella spp. members was observed in groups V and VI (p ≤ 0.05). However, representatives of Peptostreptococcus anaerobius in groups V and VI decreased by 20 and 9 times, respectively (p ≤ 0.05). The count of Salmonella spp. decreased only in group V by 7 times (p ≤ 0,05). Inoculating experimental animals with B. fragilis conditioned with S. enteritidis, S. typhimurium and pretreated with vancomycin resulted in markedly decreased level of E. coli in group VII and VIII by 538 times (p ≤ 0.05). The count of P. aeruginosa in groups VII and VIII decreased profoundly, whereas level of Bacteroides spp. members was reciprocally increased (p ≤ 0.05). The level of Lactobacillus spp. decreased by 10.3 times only in group VI. The count of E. faecalis and E. faecium increased by 10 and 19 times in groups VII and VIII, respectively, whereas level of Proteus spp. decreased only in group VII by 322 times (p ≤ 0.05). In addition, a sharp decrease in level of Enterobacter spp. and Klebsiella spp. members (p ≤ 0.05) was found in groups VII and VIII. The count of Peptostreptococcus anaerobius and Lactobacillus spp. members was markedly increased by 7-, 12-, several thousand-fold and 40 times (groups VII and VIII, respectively) (p ≤ 0.05). The count of S. enteritidis and S. typhimurium in groups VII and VIII decreased rapidly (p ≤ 0.05). Conclusion. Inoculation of B. fragilis can be used in treatment of inflammatory bowel diseases or disorders with impaired gut barrier function.

Russian Journal of Infection and Immunity. 2021;11(5):865-874
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Results of implementation of viral hepatitis B elimination program in the North-West Russia

Lyalina L.V., Esaulenko E.V., Khorkova E.V., Novak K.E., Ostankova Y.V., Serikova E.N., Vasilyev D.V., Gorziy E.S., Butskaya M.J., Kritskaya I.V., Buts L.V., Grebenkina E.V., Baydakova E.V., Smirnova N.A., Krasnopyorova M.A., Koltsov N.S., Kotovich L.M., Kalinina E.L., Galimov R.R., Kirkhar N.V., Cherepanova E.A., Totolian A.A.


Introduction. Vaccination contributed to reduce the incidence of acute hepatitis B in the territories of the North-West Russia. The urgency of this problem remains due to the high incidence of chronic hepatitis B. This accounted for the need to develop a hepatitis B elimination program in the district discussed that was approved in 2013 by the head of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing. Objective is to characterize the results of the program for the elimination of acute hepatitis B virus implemented in the North-Western Federal District. Materials and methods. The 2010–2020 incidence rate of acute and chronic hepatitis B virus (HBV) infection in the regions of the North-West Russia was carried out. To determine HBV genotypes and subgenotypes, 160 blood plasma samples from patients with acute hepatitis B were studied using molecular genetic methods (PCR, sequencing). The prevalence of latent hepatitis B in various population groups was assessed. The 2016–2020 hepatitis B vaccination coverage and relevant serological monitoring in adults was carried out. Results. While implementing the program, it was found that the incidence rate of acute hepatitis B in the district decreased by 4.5-fold, revealing in 2020 no cases of the disease in 5 regions, with incidence rate in the 6 subfederal units being lower than 1.0 per 100,000 population. Moreover, the incidence rate for chronic hepatitis B decreased by 2.6 times. The 2020 vaccination coverage of children under 17 and adults in all territories comprised more than 95% and 90%, respectively. In addition, it was shown the circulation of genotypes D and A of hepatitis B virus is dominated by genotype D (91.8%), subgenotype D2 (47.8%). The prevalence of latent hepatitis B among migrants was 6.5%, pregnant women — 4.9%, hemodialysis patients — 1.7%. Conclusion. Implementation of the program on elimination of acute viral hepatitis B in the territory of the North-West Russia contributed to raise in the vaccination coverage in adult population and lowered incidence rate of acute and chronic HBV infection.

Russian Journal of Infection and Immunity. 2021;11(5):875-886
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Herd immunity to SARS-CoV-2 among the population of the Republic of Belarus amid the COVID-19 pandemic

Popova A.Y., Tarasenko A.A., Smolensky V.Y., Egorova S.A., Smirnov V.S., Dashkevich A.M., Svetogor T.N., Glinskaya I.N., Skuranovich A.L., Milichkina A.M., Dronina A.M., Samoilovich E.O., Khamitova I.V., Semeiko G.V., Amvrosyeva T.V., Shmeleva N.P., Rubanik L.V., Esmanchik O.P., Karaban I.A., Drobyshevskaya V.G., Sadovnikova G.V., Shilovich M.V., Podushkina E.A., Kireichuk V.V., Petrova O.A., Bondarenko S.V., Salazhkova I.F., Tkach L.M., Shepelevich L.P., Autukhova N.L., Ivanov V.M., Babilo A.S., Navyshnaya M.V., Belyaev N.N., Zueva E.V., Volosar L.A., Verbov V.N., Likhachev I.V., Zagorskaya T.O., Morozova N.F., Korobova Z.R., Gubanova A.V., Totolian A.A.


Objective was to investigate the SARS-CoV-2 collective immunity status of the population of Belarus within the context of the COVID-19 pandemic. Materials and methods. The work was carried out according to the methodology for assessing SARS-CoV-2 population immunity, developed by Rospotrebnadzor Russia and the Ministry of Health of Belarus with the participation of the St. Petersburg Pasteur Institute, taking into account WHO recommendations. The Bioethics Committee of Belarus and the local ethics committee of the St. Petersburg Pasteur Institute approved the study. Selection of participants was carried out using a questionnaire method and online technology (internet, cloud server). Volunteers were randomized into seven age groups (years of age): 1–17; 18–29; 30–39; 40–49; 50–59; 60–69; and 70+. Regional randomization ensured proportional representation of volunteers from each region, and no more than 30 people were included from one enterprise. In accordance with manufacturer instructions, blood plasma samples were analyzed for: IgG antibodies (Abs) to the SARS-CoV-2 nucleocapsid (Nc) using a quantitative ELISA test system; and IgG Abs to the receptor binding domain (RBD) of the SARS-CoV-2 S (spike) surface glycoprotein using a qualitative ELISA test system. Statistical processing was carried out using Excel 2010 and other software. Statistical differences were designated as significant when p < 0.05, unless otherwise indicated. Results. The level of seroprevalence, in terms of Abs to Nc among the Belarusian population, was 38.4% (95% CI 37.6–45.4). The highest Ab levels were found among individuals in older age groups (50-70+ years old). The lowest were found in children 1–17 years old and in young people 18–39 years old The distribution of seroprevalence across Belarusian regions was relatively homogeneous, with the exception of the Minsk Region, where a statistically significant decrease in the indicator was noted. In terms of profession, the largest share of seropositive individuals was found among transportation workers; the smallest was found in business. The moderate COVID-19 incidence has not led to a dramatic increase in the number of contacts. The base reproduction number (R0) was 1.3. In the Republic of Belarus, there was a moderate level of asymptomatic COVID-19 among seropositive individuals (45.3% [95% CI 44.0–46.7]). This form of infection was observed most often among children aged 1–17 years old (65.0% [95% CI 61.3–68.6]). In parallel with seroprevalence assessment, SARS-CoV-2 vaccination was carried out. We used two vaccines: Gam-COVID-Vac (also known as Sputnik V, developed by Gamaleya National Center for Epidemiology and Microbiology, Russia); and BBIBP-CorV (Sinopharm, PRC). Vaccination against SARS-CoV-2 was accompanied by an increase in the level of anti-RBD Abs (95% [95% CI 94.7–96.7]). Taking into account the vaccination of a subset of the population with BBIBP-CorV, the overall herd immunity, inferred from the analyzed indicators (presence of anti-Nc or anti-RBD Abs), was 47.1% (95% CI 46.3–48.0). Conclusion. COVID-19 in Belarus was characterized by a moderately pronounced course of the epidemic process. The threshold level of herd immunity to SARS-CoV-2 has not yet been reached, as a result of which the conditions for progression of the epidemic remain.

Russian Journal of Infection and Immunity. 2021;11(5):887-904
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Epidemiological and etiological aspects of enterovirus infection in Russia and Vietnam

Romanenkova N.I., Golitsyna L.N., Nguyen T.T., Ponomareva N.V., Leonov A.V., Kanaeva O.I., Zverev V.V., Selivanova S.G., Rozaeva N.R., Luong M.T., Bichurina M.A., Novikova N.A.


The epidemic situation and etiological factors of enterovirus infection in Russia and Vietnam were analysed and compared. The identified strains of enteroviruses of 47 types, which circulated in Russia in 2018–2019, belonged to different species: Enterovirus species A (CV-A2, CV-A4, CV-A6, CV-A8, CV-A10, CV-A16, EV-A71), as well as Enterovirus species B and Enterovirus species C. The strains isolated from 87 children from southern Vietnam hospitalised in 2018–2019 into infectious hospitals while having enterovirus infection with exanthema were also studied. All identified strains were represented by Enterovirus species A: EV-A71 — 59 strains, CV-A10 — 20 strains, CV-A16 — 5 strains, CV-A6 — two strains and CV-A2 — one strain. Out of 59 viruses EV-A71, 53 strains belonged to genotype C4 and 6 strains belonged to genotype B5. The sequences of EV-A71 strains of genotype C4 from South Vietnam formed a monophyletic cluster with the sequences of EV-A71 viruses which circulated during 2016–2018 in different provinces of China, and they were very close to EV-A71 strains of the same genotype from the Yunnan Province. These strains were genetically different from Russian viruses and Vietnamese viruses identified in the years 2003–2005 and 2011– 2012. Most of the cases of enterovirus infection from southern Vietnam (78%) caused by EV-A71 virus of genotype C4 were reported in three provinces located in southern Vietnam in the Mekong Delta. The epidemic process and the etiology of enterovirus infection in Russia and Vietnam have common features. At the same time, the epidemic situation in these countries is not the same. The incidence of enterovirus infection is influenced by geographic, climatic, economic and demographic factors that differ in two countries. In the majority of territories of Russia, the climate is temperate or cold, seasonal rises in the incidence rates of enterovirus infection usually occur in the summer, when people go on vacation, spend a lot of time outdoors and swim in open reservoirs. In Vietnam, a constant high-level temperature, a high population density and a large proportion of children determine the higher incidence of enterovirus infection, especially in the southern provinces of Vietnam, compared to Russia. The fact that more than 20% of the Vietnamese population lives in the Mekong Delta, which is the largest river in Indochina, has a significant impact on the epidemic process of enterovirus infection in South Vietnam. The Mekong River which flows through China, Laos, Thailand, Cambodia and Vietnam, and carries huge streams of water, including rainstorm waters and sewages, from all of these countries into the southern provinces of Vietnam, which have the highest incidence rates of enterovirus infection in the country. The results of the research underline the importance of active epidemiological and virological surveillance of enterovirus infection, which plays the key role in informing the public health authorities about the changes in the epidemic situation in order to take appropriate measures and develop the prevention strategies. The goal of anti-epidemic and preventive measures is to reduce the incidence of enterovirus infection and the economic burden of this infection for Russia and Vietnam.

Russian Journal of Infection and Immunity. 2021;11(5):905-916
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El Tor cholera at the contemporary stage of the seventh pandemia: pathogen evolution, clinical and epidemiological features, laboratory diagnostics

Savelyeva I.V., Kulichenko A.N., Saveliev V.N., Kovalev D.A., Taran T.V., Podoprigora E.I., Vasilieva O.V., Shapakov N.A.


The phenotypic and molecular genetic properties of 133 strains of genetically modified (genovariant) Vibrio cholerae O1 El Tor biovar isolated from patients in Dagestan (1993, 1994, 1998), and compared with 246 strains of a typical toxigenic cholera vibrio El Tor biovar isolated in 1970–1990 at the Caucasus Region. It was found that 48.7% of the studied genetically modified strain variants had mixed phenotypic properties of the El Tor and classic biovars that evidences about a need to include the marker genes of the classical biovar (ctxBCl+, rtxC–) and the El Tor biovar (ctxBEl+, rtxC+) into the existing biotyping scheme. The genes of the El Tor biovar, isolated from patients in Dagestan, contain in addition to the El Tor ones, the genes of the classical biovar (ctxBCl and/or rstRCl), as well as the typical toxigenic cholera vibrios of El Tor, islands of persistence (EPI), pathogenicity (VPI-1 and VPI-2) and pandemicity (VSP-I and VSP-II). However, only the El Tor biovar genovariants were found to bear an integrative and conjugative SXT element with antibiotic polyresistance genes. Epidemic cholera outbreaks caused by the El Tor biovar genovariants that occurred in 1993–1998 at the Caucasus Region, correspond to classical (Asian) cholera based on disease severity. The epidemiological features of modern cholera were studied: the main way for transmission via fecal-oral route for typical El Tor cholera vibrio is waterborne, whereas for the El Tor gene variant — household. Primary infections upon water drinking and using domestic water from surface water bodies infected with typical El Tor vibrios occur outside the family hearth. In case of cholera caused by hybrid El Tor variants, infection is transmitted among family members via domestic factors under low sanitary level. The development of laboratory diagnostics and epidemiological surveillance of modern El Tor cholera is based on the development of PCR test systems taking into account the evolutionary genome transformations.

Russian Journal of Infection and Immunity. 2021;11(5):917-926
pages 917-926 views

2019–2020 herd immunity to seasonal influenza viruses prior to epidemic season and rate of severe disease cases

Ilyicheva T.N., Kolosova N.P., Durymanov A.G., Torzhkova P.Y., Svyatchenko S.V., Bulanovich Y.A., Ivanova E.V., Ivanova K.I., Ryzhikov A.B.


The aim was to analyze heard immunity against influenza viruses as well as severe course of influenza infection prior to the 2019–2020 epidemic season. Methods. Blood sera samples were collected prior to and after conducting population-wide influenza vaccination campaign at the sanitary and epidemiological centers in different regions of the Russian Federation as well as at the Siberian Federal District, respectively. Sera samples were tested by using hemagglutination inhibition (HI) assay with vaccine strains A/Brisbane/02/2018 (H1N1)pdm09, A/Kansas/14/2017 (H3N2), B/Colorado/06/2017 (Victoria lineage). Baseline clinical and autopsy materials in case of influenza infection in vaccinated patients or severe and fatal influenza cases were collected to be tested by RT-PCR at the sanitary and epidemiological centers, Rospotrebnadzor. All influenza-virus positive samples were further sent to the SRC VB “Vector”. Results. A total of 7,896 and 600 blood serum samples were collected from subjects at Siberian Federal District prior to and after the populationwide influenza vaccination campaign, respectively. Prior to the epidemic season, the proportion of individuals seropositive for the influenza A virus subtypes A/(H1N1)pdm09 and A/H3N2 exceeded 50% in most of the regions, whereas frequency of those seropositive for the influenza B virus was profoundly lower ranging from 12 to 46% in the Northwestern Federal District and Volga Federal District, respectively. After influenza vaccination, the percentage of seropositive subjects in the Siberian Federal District increased as follows: for influenza subtype A/(H1N1)pdm09 — from 66 up to 79%, influenza subtype A/H3N2 — from 68 up to 78%, and for influenza B/Victoria — from 32 up to 47%. In 2019–2020, influenza B virus more frequently caused severe infection that agrees with the herd immunity data prior to the epidemic season. However, the vast majority of the influenza cases with fatal outcome was associated with influenza virus A A/H1N1pdm09 subtype. Conclusion. Quality of influenza vaccine, especially that one intended to vaccinate risk group subjects remains a crucial issue for contemporary scientific community. The study was conducted within the framework of the State Assignments no. 1/16 and 2/18.

Russian Journal of Infection and Immunity. 2021;11(5):927-933
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Study of features of humoral immune response to the new coronavirus infection COVID-19 among healthcare workers

Reshetnikova I.D., Tyurin Y.A., Agafonova E.V., Kulikov S.N., Gilyazutdinova G.F., Lopushov D.V., Shaуkhrazieva N.D., Isaeva G.S., Ziatdinov V.B.


Relevance. Since the beginning of the epidemic in China, there have been reports of nosocomial cases of SARSCoV-2 infection, including among medical workers. Studies of the intensity of humoral immune response to the SARSCoV-2 virus among medical workers who are much more likely to have professional contact with COVID-19 patients than are of particular importance. The aim is to study the seroprevalence and features of the humoral immune response to SARS-CoV-2 among medical workers. Materials and methods. The study included 61 medical workers from a multidisciplinary hospital in Kazan, which was redesigned to provide medical care to patients with new coronavirus infection, using the method of random sampling. The control group consisted of 60 non-medical workers. For the determination of IgG, a solid-phase ELISA was used. Statistical processing of the results was carried out using MS Excel software. The error of the relative value (M±m) was calculated, and the 95% confidence interval of the frequency of occurrence. To assess the significance of differences, the Student’s test (t-test) was used for independent samples. Results. The proportion of those seropositive to SARS-CoV-2 in the study group was 45.9%, compared with 21.7% in the control group. Among medical workers seropositive to the SARS-CoV-2 virus, the proportion of asymptomatic forms was 18.5%, mild forms — 53.6%, moderate forms and severe forms 25%. Two forms of the formation of a humoral immune response among seropositive ones were revealed: the first is characterized by the gradual elimination of specific IgG antibodies to SARSCoV-2 after 8 weeks from the onset of the first symptoms of COVID-19, the second form is an increase in specific IgG to SARS-CoV-2 and a higher value of the coefficient level of IgM positivity to SARS-CoV-2 after 8–10 weeks from the onset of the first symptoms. The group of seropositive, “raising antibodies”, prevailed over the group of individuals “eliminating antibodies”. Among seropositive medical workers, two forms of the formation of a humoral immune response were revealed: synchronous with the parallel elimination of IgG and IgM antibodies and a parallel increase in IgG and IgM. Conclusion. The study of the level of humoral immunity to COVID-19 in medical workers is important in terms of planning both anti-epidemic measures and predicting the effectiveness of the response to vaccination to SARS-CoV-2.

Russian Journal of Infection and Immunity. 2021;11(5):934-942
pages 934-942 views

Hormone therapy affecting interferon defense in children with infectious mononucleosis

Fedorova I.M., Koteleva S.I., Kapustin I.V., Blyakher M.S., Tulskaya E.A., Zvereva N.N., Ilina M.A., Saifullin M.A., Samkov A.A., Vlasov E.V.


23 children diagnosed with acute infectious mononucleosis were hospitalized and examined after a short prednisolone treatment course. Related interferon status during infection was compared with that in 38 patients with acute infectious mononucleosis receiving no hormone therapy. Interferon status was investigated by Ershov method, allowing to estimate amount of interferon in the blood serum samples or patient blood cell culture by assessing interferon biological activity. Along with measuring IFNα or IFNγ biological activity, their level was quantified by using enzyme immunoassay. Immunological examination conducted on the next day after the end of hormone therapy revealed sharply decreased potential of patient blood cells to produce both IFNα and IFNγ. The multiplicity of IFNα and IFNγ titer reduction in various patients varied by 4–5 and 3–4-fold, respectively. The concentration of IFNα, determined by ELISA, decreased by 4–6-fold, whereas for IFNγ — by 1.5–2-fold. A follow-up examination 1 month after discharge from the clinic showed that mean IFNα titer in children aged 3–6 years and treated with prednisolone was significantly reduced compared to the baseline, whereas most patients receiving no hormone therapy had normal IFNα production. The change in the level of IFNα 1 month after hormone therapy in 7–14-year age group was similar. IFNγ production quickly recovered, and 1 month after discharge from the clinic, its concentration in culture supernatants from patients reached 10–15 ng/ml, exceeding normal values more than twice. The biological activity of IFNγ in these culture supernatants was significantly higher than those immediately after hormone therapy, whereas in 3–6-year-old group of patients it was also higher than baseline level. These results can serve as a laboratory justification for including recombinant IFNα-2b drugs in the therapy of such patients, presumably immediately after the end of hormone course. Overall, laboratory justified administration of interferon preparations seems to be necessary to determine optimal timepoint for applying such drugs to increase effectiveness for achieving a durable patient recovery.

Russian Journal of Infection and Immunity. 2021;11(5):943-950
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Features of the course of hemorrhagic fever with renal syndrome in HIV-infected patients

Manakhov K.M., Povysheva E.V., Gilyazova A.R., Sarksyan D.S.


Human immunodeficiency virus (HIV) is a significant medical and social problem for many developed countries. HIV infection is featured with developing chronic kidney pathology as well as acute renal damage. In some regions, hemorrhagic fever with renal syndrome (HFRS) can contribute somehow to developing renal pathology in HIVinfected subjects. The aim of the study was to identify clinical and laboratory features of HFRS course during HIV infection. A retrospective study was conducted by forming two groups: group 1 consisted of 9 patients suffered from HFRS together with verified HIV infection, group 2 — 53 patients with HFRS but lacking any clinical and epidemiological indications supporting HIV infection. Subjects in both groups were age- and sex-matched. The average age of the patients in group 1 and group 2 was 34 and 31 years, respectively. For statistical analysis, the licensed SPSS 22.0 software was used. A significance level p for statistical criteria was set equal to 0.05. In general, HFRS course in all patients was accompanied by characteristic signs: intoxication syndrome, impaired vision, hemorrhagic rash, pain in the lumbar region, decreased diuresis, thrombocytopenia, proteinuria, polymorphic urinary syndrome and azotemia. HFRS patients with concomitant HIV infection often complain of dry mouth, bloating, visible shortness of breath. Laboratory changes describe more severe kidney damage. A direct strong correlation was shown between leukocyte count and level of blood urea in patients with concomitant HIV infection (r = 0.798; p = 0.01). The combination of HFRS and HIV was accompanied by a milder HFRS course — rate of mild disease was almost 6-fold higher among patients of this group. In this case, no cases of severe hemorrhagic fever with renal syndrome combined with HIV were noted. Our study allowed to obtain unambiguous data. Predisposition of HIV-infected patients to renal pathology may be a determining factor in kidney damage upon emerging HFRS: more prominent rise in creatinine and urea level. Moreover, according to rating scale for assessing HFRS severity, it formally turned out that during concomitant HIV infection patients more often fit to a mild disease severity, even in the presence of more pronounced renal manifestations. The occurrence of acute renal pathology in HIV-infected patients is a life-threatening condition, a factor of deterioration of chronic renal pathology and a predictor of death. Consequently, this patient population requires thorough monitoring both at inpatient and outpatient stages.

Russian Journal of Infection and Immunity. 2021;11(5):951-957
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Multi-drug resistance and biofilm production among diarrheagenic Escherichia coli pathotypes isolated from stools of children with acute diarrheal disease

David E.E., Yameen M.A., Igwenyi I., Okafor A.C., Obeten U.N., Obasi D.O., Ezeilo U.R., Emeribole M.N., David C.N.


Background. Diarrheagenic E. coli (DEC) is an etiological agent of childhood diarrhea. Resistance against commonly used drugs in the empirical treatment of enteric infections has increased among DEC. Relationship between antibiotic resistance and biofilm formation in microorganisms have been widely reported. This study was aimed to determine the antibiotic resistance and biofilm production pattern among DEC pathotypes isolated from stools of children aged 0–5 years with acute diarrheal disease in Abakaliki, Nigeria. Materials and methods. Diarrheal stool samples were obtained from 60 children and E. coli were isolated and identified using standard guidelines provided for laboratory diagnosis of enteric pathogens. Molecular identification was done by amplification of E. coli universal stress protein A (uspA) using polymerase chain reaction (PCR) method. Detection of virulent genes of DEC pathotypes was performed in a group of multiplex PCR using their specific primers. Kirby–Bauer disk diffusion method was used to determine the antibiotic susceptibility patterns of the isolates while biofilms production was detected by thiazolyl blue tetrazolium bromide dye in a 96-well plate. Results. DEC was isolated in 40 stools among which EIEC [40% (n = 16)] was commonly detected followed by ETEC [30% (n = 12)], EAEC [20% (n = 8)] and typical EPEC [10% (n = 4)]. Half of EAEC showed the highest multidrug resistance against ampicillin, cefoxitin, ciprofloxacin, levofloxacin, and tetracycline with the strongest biofilm production followed by all the EPEC which were resistant to ampicillin, ciprofloxacin, levofloxacin, and tetracycline with moderate biofilm production. All the LT-ETEC exhibited the least resistance to ampicillin and tetracycline with the weakest biofilm production. Conclusion. High frequency of the EIEC pathotype suggests its role as the primary etiological agent of diarrhea in children. Correlation between high drug resistance and biofilm production among the pathotype may indicate that biofilms may provide compatible uptake of resistance genes.

Russian Journal of Infection and Immunity. 2021;11(5):958-964
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Аcinetobacter baumannii bv Tryptophandestruens bv nov. isolated from clinical samples

Sivolodskii E.P., Kraeva L.A., Starkova D.A., Mikhailov N.V., Gorelova G.V.


The aim of the study was to determine the taxonomic status of a group consisting of atypical strains of Acinetobacter baumannii, outline relevant characteristics and methods necessary for their identification. There were examined 10 strains of A. baumannii (6 of them primary comprised) bearing similar profile of atypical features isolated from clinical samples (urine, sputum) in 2017–2019 at the Military Medical Academy. Сlinical strains of typical A. baumannii (n = 36), Acinetobacter nosocomialis (n = 14), Acinetobacter pittii (n = 9) and 1 strain of Acinetobacter calcoaceticus isolated from the external environment were used in comparative studies. Atypical strains had the characteristics of A. calcoaceticus — A. baumannii (ACB) complex bacteria and were identified as A. baumannii. The utilization of substrates as the only carbon source was studied on a dense synthetic medium added with 0.2 % substrate during incubation for 72 hours at 37°C. Carbohydrate oxidation coupled to acid formation was detected on the Hugh–Leifson medium by using a micromethod. Aromatic amino acid biotransformation was carried out in liquid and dense nutrient media assessed in chromogenic reaction. The rpoB gene was used for strain genetic characterization. Amplification of two 940 and 1210 base pair (bp)-long fragments from the rpoB gene was performed by the routine polymerase chain reaction using primers with previously described sequences. Amplification products were sequenced by Sanger using Big Dye Terminator v3.1 (Applied Biosystems, USA) and capillary electrophoresis on an automatic sequencer ABI PRISM 3130 (Applied Biosystems, USA), followed by using methods for determining the similarity levels of sequenced fragments with the rpoB gene sequences of the reference strain A. baumannii ATCC 17978 (GenBank accession no. CP053098.1). It was found that all strains belonging to atypical A. baumannii spp. had a specific set of features that distinguish them from typical strains of A. baumannii as well as other types of the ACB complex: detected biotransformation of L-tryptophan (via anthranilate pathway) and anthranilic acid under unambiguous lack of such signs in other bacteria; lack of utilized sodium hippurate and L-arabinose being unambiguously evident in other bacteria; lack of utilized L-tryptophan, putrescine, L-ornithine being utilized in the majority of strains of belonging to other bacterial species. Genetic analysis showed that the control strains of typical A. baumannii displayed 99.20–99.21% similarity within the sequenced fragments of the rpoB gene with those from the rpoB gene of the reference strain. All 10 strains of atypical A. baumannii had similar features (99.20–99.21%). At the same time, parameters of control strains from other bacterial species significantly differed: A. nosocomialis (95.10–95.97%), A. pittii (94.63–94.92%), A. calcoaceticus (93.00%). Hence, the strains of atypical and typical A. baumannii are genetically homogeneous and belong to the same species. The data presented allow us to consider this group of atypical A. baumannii strains as a new biovar. We propose the name for this new biovar — tryptophandestruens (tryptophan-destroying) stemming from the Latin word destruens — destroying. Identification of A. baumannii bv. tryptophandestruens bacteria can be carried out in laboratory of any level by using tests for L-tryptophan biotransformation as well as sodium hippurate utilization.

Russian Journal of Infection and Immunity. 2021;11(5):965-972
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Parameters of blood short-chain peptides and digestive hydrolases in patients with chronic hepatitis B virus infection

Zhuraeva M.A., Aleinik V.A., Ashuralieva N.D., Halikova D.S., Ravzatov J.B., Abdulazizhozhyv B.K.


The aim of the study was to examine specifics of changes in the level of stomach- and pancreas-released blood hydrolases in chronic viral hepatitis B and analyze the mechanisms underlying such changes. We assessed serum markers of HBV infection, liver enzymes tests as well as gastric and pancreatic hydrolase level. The patients examined were divided into three groups: control (healthy) and two study groups — HBV post-infection and chronic HBV infection. Patients with HBV post-infection had no significant deviations from normal range for blood level of gastric and pancreatic hydrolases. Patients with chronic HBV infection were found to contain increased blood level of amylase and lipase, which may evidence about increasing pancreatic functional activity and development of covert pancreatitis. At the same time, decline in the concentration of serum pepsinogen-1 below 40 μg/l could indicate about prominently decreased secretion of hydrochloric acid and development of atrophic gastritis, and it was found that the major factor contributing to development of such disorders was the short-chain peptide CCK-8, which utilization declines in patients with chronic HBV infection. CCK-8 can play a pivotal role in inhibiting stimulation of gastric acid secretion and controls gastric acid, plasma gastrin and somatostatin secretion. Cholecystokinin has been found to inhibit acid secretion by activating CCK type A receptors as well as via somatostatin-involving mechanism. The secretion of gastric somatostatin-14 increased by fivefold due to CCK-8 alone, but was blocked by the CCK-A receptor blocker loxiglumide. These data show that CCK-8 directly inhibits acid reactions by stimulating the release of gastric somatostatin indirectly through the CCK-A receptor. Thus, it can be assumed that normally CCK-8 is mainly utilized by the liver, which is altered during chronic hepatitis B resulting in elevated blood CCK-8 concentration. As a consequence, it enhances pancreatic secretion resulting in developing pancreatitis that is paralleled with inhibited gastric secretion and emerged atrophic gastritis.

Russian Journal of Infection and Immunity. 2021;11(5):973-978
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Profile of several autoantibodies, complement and vitamin D levels in Brazilian patients with Chikungunya infection

Carvalho J.F., Cordeiro L.R., Silva F.F., Mota L., Rodrigues C., Andrade C.F., Caldas C.


Introduction. Chikungunya virus infection (CKV) may lead to chronic arthritis in up to 40% of the patients. There are previous data regarding positive auto antibodies in CKV. Objective is to systematically evaluate the prevalence of auto antibodies in CKV patients. Methods. All study participants had clinical manifestations being CKV positive at least serologally or by RT-PCR data. The following autoantibodies were assessed: antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-Ro/SS-A, anti-La/SS-B, anti-U1RNP, IgG and IgM anticardiolipin, anticyclic citrullinated peptide (antiCCP), rheumatoid factor (RF), antiribosomal P protein, lupus anticoagulant, anti-Jo-1 and anti-Scl-70. CH100, C3 and C4 complement components, serum levels of immunoglobulins, C-reactive protein, erythrocyte sedimentation rate, alpha1-acid glycoprotein, antithyroglobulin, antithyroperoxidase, TRAb, 25 hydroxyvitamin D (25OHD), dengue and zika IgG and IgM antibodies were also measured. Results. 30 CKV patients were included. Mean age was 59.1±15.7 years, 85% females and 77% Caucasian subjects. Disease duration comprised 4.9±4.0 months. Oligoarthritis was observed in 93% cases. Mean C-reactive protein levels were 10.1±6.8 ng/dL, erythrocyte sedimentation rate — 34.2±19.9 mm/1st hour and alpha1-acid glycoprotein 115.5±52.6 mg/dL. Intramuscular betamethasone depot single dose injection was administered in 54%, prednisone — in 15% and methotrexate — in 23% cases. Importantly, 1/30 (3.3%) cases was positive for ANA, 4/30 (13.3%) — for RF and none was positive for anti-CCP or any other autoantibodies. Complement and immunoglobulin levels were all within the normal range. Low levels of 25OHD were observed in 88% cases.

Russian Journal of Infection and Immunity. 2021;11(5):979-983
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Pseudomonas aeruginosa significantly increases expression of receptor for advanced glycation endproducts (RAGE) in the septicemia suffering patients

Kariminik A., Hosseini F., Nasiri E.


Receptor for Advanced Glycation Endproducts (RAGE) is a cell surface receptor, which recognizes several endogenous and exogenous molecules and subsequently induces expression of several molecules including chemokines. Chemokines are members of the cytokine superfamily and participate in several immune system functions, including cell migration, inflammation, angiogenesis/angiostasis etc. CXC ligand 11 (CXCL11) is an important chemokine which participates in the induction of appropriate immune responses against microbes, including bacteria. The main mechanisms responsible to overcome septicemia are yet to be clarified. Thus, it has been hypothesized that RAGE may participate in induction of CXCL11 in response to the microbial agents. Due to the fact that immune responses play key roles in limitation of infection, it has been proposed that RAGE may inhibit spread of septicemia. Therefore, in this project mRNA levels of RAGE and CXCL11 were explored in the patients suffering from septicemia versus healthy controls. RAGE and CXCL11 expression levels in the 80 subjects, including 40 septicemia patients and 40 healthy controls were explored using Real-Time PCR technique. Accordingly, by using the specific primer against RAGE and CXCL11 in a Rotorgene vehicle the mRNA levels have been determined. The septicemia and the sources of the bacteria in the blood were diagnosed using microbial cultures. The results demonstrated that although mRNA levels for RAGE and CXCL11 did not change in the septicemia patients vs. healthy controls, mRNA levels of RAGE were significantly higher in the patients infected by Pseudomonas aeruginosa compared to those infected by other bacteria, Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii. RAGE and CXCL11 mRNA levels did not differ among male and female patients. Based on the results it seems that RAGE is a critical receptor against P. aeruginosa during septicemia and more investigations, especially on the RAGE down-stream molecules can clarify its main roles against P. aeruginosa.

Russian Journal of Infection and Immunity. 2021;11(5):984-988
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Epidemiological analysis of factors influencing the course of multidrug-resistant tuberculosis in HIV-infected patients with concomitant viral hepatitis

Kukurika A.V., Yourovskaya E.I., Lyakhimets V.A.


The epidemiological significance of combined forms of especially dangerous infections has not been studied enough, unlike mono-infections. Currently, there is a tendency towards an increase in the incidence of multidrug-resistant tuberculosis. The formation of severe forms of the disease is caused by other widespread infections, such as chronic viral hepatitis and HIV. Polymorbid conditions distort the clinical manifestations of tuberculosis, reduce the effectiveness of anti-tuberculosis therapy and worsen the prognosis of the disease. Risk factors among patients in this category need analysis to carefully monitor patients and ensure infection control. Objective is to analyze the factors affecting the course of multidrug-resistant tuberculosis in HIV-infected patients with concomitant viral hepatitis. Materials and methods. Cases of the combined pathology of multiresistant tuberculosis, HIV infection and viral hepatitis with a dominant diagnosis of tuberculosis are analyzed. Results and discussion. The influence of the immunological status on the course of combined pathology was revealed. Since all the patients under study had clinical stage 4 of HIV infection, tuberculosis developed as an opportunistic infection. Severe immunosuppression (CD4 < 200 cells/ml) contributed to the progression of the generalized tuberculosis process. Long-term immunodeficiency was an unfavorable factor; in the overwhelming majority of cases, antiretroviral therapy was prescribed only after tuberculosis was detected. The dependence of the clinical form of tuberculosis on the level of CD4-lymphocytes was noted: isolated lesion of the chest organs prevailed in patients with a level of CD4-lymphocytes more than 200 cells/ml, generalization of TB process — with CD4 less than 200 cells/ml. Patients with miliary tuberculosis had a higher mortality rate compared to patients with other clinical forms, regardless of antiretroviral therapy. It was revealed that socially disoriented young people with viral hepatitis C prevailed in the structure of patients, the prevalence of which was due to the influence of aggravating factors, such as alcohol and drug abuse, and stay in prisons. Against the background of combined treatment, there was no significant effect of viral hepatitis on the course of polymorbid conditions and the effectiveness of the therapy.

Russian Journal of Infection and Immunity. 2021;11(5):989-993
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Автор: Рахим Мусаевич Хаитов — доктор медицинских наук, профессор, академик РАН. 

Russian Journal of Infection and Immunity. 2021;11(5):994-996
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