Vol 11, No 4 (2021)

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Full Issue


Methodology for assessing herd immunity to the SARS-CoV-2 virus in the context of the COVID-19 pandemic

Popova A.Y., Totolian A.A.


Serological monitoring of the study of population immunity to the SARS-CoV-2 virus in the context of COVID-19 pandemic is a necessary component in epidemiological surveillance, since population epidemiological wellbeing in a context of COVID-19 is determined by state of population immunity to the SARS-CoV-2 virus. The population herd immunity is the limiting factor in spread of the SARS-CoV-2 virus. Information on the state of population immunity is necessary to make a forecast for development of epidemiological situation, as well as to plan measures for specific and non-specific prevention of COVID-19. In this regard, the study of population immunity during the pandemic is necessary to predict development of the epidemic and identify features of epidemic process in any certain region and in the country in general. In May 2020, the Rospotrebnadzor program “Assessment of population immunity to the SARS-CoV-2 virus in the population of the Russian Federation in the context of the COVID-19 pandemic” was developed taking into account WHO recommendations in the format of a longitudinal cohort study with age stratification: at the first stage, a cohort of volunteers is formed; at the second and subsequent stages, the cohort of volunteers formed at the first stage is subject to examination; the number of stages depends on the epidemiological situation. In addition to age-related randomization while forming a cohort, at the first stage, the principle of population coverage uniformity was observed, the participation of volunteers from one institution was excluded, and the use of donated blood or patient blood from medical organizations was excluded. The survey was carried out among 7 age groups of healthy children and adults, regardless present or absent previous COVID-19 disease. Due to the fact that the population study is carried out in the context of COVID-19 pandemic, the optimal timing for collecting biomaterial at each stage is no more than 5–7 days. Questioning, selection of volunteers, their registration for blood donation, as well as processing of the results at the first stage, as well as the implementation of the second and subsequent stages of the Program are carried out only by using cloud service technology. This Program and the technology for its implementation have been successfully tested in 26 regions of the Russian Federation during the implementation of four stages from June 2020 to March 2021. Thus, at present, Rospotrebnadzor has developed a methodology and created an effectively working system of serological monitoring to assess level of herd immunity in different regions of the Russian Federation to predict the epidemiological situation, develop recommendations, and plan vaccination.

Russian Journal of Infection and Immunity. 2021;11(4):609-616
pages 609-616 views


COVID-19 as a zoonotic infection

Kulichenko A.N., Maletskaya O.V., Sarkisyan N.S., Volynkina A.S.


Here we discuss the issues for attributing the new coronavirus infection COVID-19 to zoonoses based on the data on probable origin of the SARS-CoV-2 virus, the possible formation of its reservoir in animals (bats) as well as human susceptibility. Today, the dominant point of view is that the outbreak of COVID-19 arose as a result of the SARS-CoV-2 coronavirus overcoming the interspecies barrier, acquiring ability to infect and spread in human population. Comparative phylogenetic analysis at the molecular level showed that SARS-CoV-2 is genetically closest to bat coronaviruses, particularly to the RmYN02 and RaTG13 strains isolated from the horseshoe bat, a species considered to be the main host of SARSCoV and MERS-CoV coronaviruses. The ability of the SARS-CoV-2 coronavirus to infect various wild animal has been revealed. SARS-CoV-2 has been found in minks on farms in the Netherlands with mortality rates ranging from 1.2 to 2.4%. While infecting rhesus monkeys with the SARS-CoV-2, it resulted in productive infection and detected viremia. Cats have been found to be susceptible hosts for the human SARS-CoV-2 virus. A likely explanation for this lies in the high similarity between the human and feline counterpart of the ACE2 receptor. It has been shown that dogs can become infected but transmit no virus to other animals. To date, over the entire period of the pandemic the World Organization for Animal Health provides no information about cases of human infection transmitted from pets. Thus, there is no evidence that animals play a role in the spread of SARS-CoV-2 among people during the current period of the pandemic. Human outbreaks are caused by human-to-human virus transmission, and based on the currently available information, the risk of spreading COVID-19 from animals is considered low. More research is needed to understand how COVID-19 can affect animals of a wide variety of species and how big might be the risks of infection transmission from them to humans.

Russian Journal of Infection and Immunity. 2021;11(4):617-623
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FeLV-infection: problems and prospects of vaccine prevention and interferon-therapy of feline leukemia

Moskvina T.V., Shchelkanov M.Y., Tsybulski A.V.


Here, we review an overall effectiveness of interferon-based preparations and interferon biosynthesis inducers for treatment of feline leukemia, as well as development of methodological approaches to improve efficacy of interferon therapy. Feline leukemia is a systemic hematopoietic malignancy caused by a single-stranded RNA retrovirus called Feline Leukemia Virus (FeLV) that leads to lethal outcome within about 3 years after the onset. FelV is widely distributed in population of domestic cats worldwide, being often detected in the blood of wild cats, including those of rare and endangered species. In some regions, FeLV prevalence may be high not only among domestic cats, but among wild as well. Currently, there are several commercially available vaccines to protect cats from FeLV infection (e.g., inactivated whole-virion vaccines such as Nobivac adjuvanted Feline 2-FeLV, two-adjuvant subunit vaccine FeLV-derived protein antigens as well as non-adjuvanted vector DNA vaccine). However, none of such vaccines provides durable protection. In addition, vaccination of cats against FeLV is often associated with development of diverse inflammatory, allergic and shock complications, and highly serious side effects such as developing vaccine-associated sarcoma at the injection site that some researchers connect with use of adjuvants like aluminum salts etc. We briefly describe FeLV virus, pathogenetic parametersassociated with FeLV infection as well as current technologies for preventing and treating feline leukemia. A historic background and current state of interferon therapy for FeLV infection as well as associated neoplastic processes in domestic cats and some wild species are evaluated. Possible interventions aimed at improving efficiency of interferon therapy of feline leukemia based on using new recombinant interferon preparations of various types and subtypes, as well as interferon inducers are discussed. In conclusion, it is noted that another interesting and potentially highly promising option in defining strategy of biotherapy associated with modulating IFN system in FeLV-infected animals might be to use of synthetic inducers triggering endogenous IFN production.

Russian Journal of Infection and Immunity. 2021;11(4):624-634
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Molecular genetic and clinical aspects of socially relevant viruses underlying congenital diseases

Vasilev V.V., Rogozina N.V., Grineva A.A.


Congenital viral infectious diseases are characterized by polyetiologic pathology holding an important place in the structure of perinatal losses. Due to the wide distribution and lack of specific prophylaxis, the problem of herpesvirus infections is of greatest interest, namely of herpes infection caused by herpes simplex virus type 1 and 2, human herpes simplex virus type 6 and cytomegalovirus infection, as well as parvovirus infection B19. The opportunities to investigate a relation between manifestations of the infectious process and host molecular genetic characteristics have been expanded after developing full genome sequencing methods and creating genetic data international banks. It has been proven that herpes virus genetic variations can account for related neurovirulence, showing that diverse cytomegalovirus genotypes are associated with hepatosplenomegaly, hearing impairment and the symptoms of the central nervous system diseases. Nevertheless, the data on correlation between genotypes and clinical manifestations are still scarce and contradictory, whereas high level of variability becomes extremely evident while comparing genomic sequences of viral strains. The herpesvirus type 6 has been proven to integrate into germ cells with potential for subsequent vertical transmission of chromosomally integrated virus to the offspring and its further intergeneration inheritance. А direct relationship between B19V genospecies and disease manifestations including congenital infections has not yet been identified. Taking into account possible differences in the geographical distribution of such viruses on the territory of the Russian Federation, ethnic populational characteristics, and high frequency of related congenital infectious diseases with a wide range of clinical manifestations, it seems promising to expand scientific research on the genotyping of herpes simplex viruses, cytomegalovirus, herpes viruses type 6 and parvovirus B19V in Russia. The results of such studies will be demanded by practical healthcare in order to develop and use more effective etiotropic drugs and specific prophylaxis in the light of trends to develop personalized and preventive medicine.

Russian Journal of Infection and Immunity. 2021;11(4):635-648
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Sepsis-3: new edition — old problems. analysis from the perspective of general pathology

Gusev E.Y., Zotova N.V., Chereshnev V.A.


Sepsis-3 Guidelines defines sepsis as an organ dysfunction caused by dysregulated host response to infection. To record organ dysfunction, the SOFA/quick SOFA scales were recommended. In fact, in medical practice, sepsis is considered nothing more than a critical infection that requires intensive care. Therefore, sepsis is pathogenetically a nonhomogeneous condition manifested by diverse nosologies and syndromes. Unlike the previous two editions, Sepsis-1 and Sepsis-2 Guidelines, the formal criteria provided in the Sepsis-3 are closer to the de facto position, describe more specific, but less sensitive features to predict mortality. However, the initial, latent manifestations of critical conditions, which can be relatively effectively controlled by intensive therapy, remain outside the Sepsis-3 criteria. Not all signs of multiple organ dysfunctions (according to the Sepsis-3 criteria) will require intensive care. Hence, obviously the presence or absence of formal criteria of Sepsis-3 will not be always taken into account while verifying sepsis. The only relatively pathogenetically homogeneous definition in Sepsis-3 is “septic shock”. However, it also does not fully consider the staging (according to the degree of compensation of hemodynamic disturbances) and the phasing (according to the severity of the proinflammatory response) of the dynamics of the shock condition. From our point of view, a positive result of the Sepsis-3 consensus would be in transition of the systemic inflammatory response syndrome (SIRS) from the main to additional (optional) verifying sepsis criteria. We also believe that the weak side of the Sepsis-3 Guidelines is in underestimated mechanisms of systemic inflammation as a general pathological process in the genesis of developing critical conditions of various origins. From the perspective of general pathology, sepsis is a combination of the three common fundamental pathological processes: classical (canonical) and systemic inflammation (SI), as well as chronic systemic low-grade inflammation (parainflammation), the latter can be considered as an unfavorable background for development of the former two processes. All three processes are characterized by any SIR signs and require to be differentiated on the basis of integral criteria, which reflect specific blocks of the SI complex process. The pathogenesis of the SARS-CoV-2 infection (COVID-19) is a relevant example underlying inevitability of such approach. The systemic microvascular vasculitis, and its main clinical manifestations such as systemic microcirculatory disorders in the form of shockogenic conditions is the SI pathogenetic basis. Apparently, one of the modalities for further evolution of critical care medicine will be coupled to development of a more multilayered but effective methods for assessing pathogenesis of critical states and more differentiated methods of pathogenetic therapy. Therefore, it will require to modernize a number of fundamental premises in our knowledge about pathobiology, pathophysiology, and general pathology.

Russian Journal of Infection and Immunity. 2021;11(4):649-662
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An impact of 1H-indol-4-, -5-, -6-, -7-ylamines-substituted compounds on the microbial cell genetic apparatus

Maseykina A.A., Stepanenko I.S., Yamashkin S.A., Slastnikov E.D.


The study of new antimicrobial compounds includes determining the mechanism of their effect on the microbial cell. As a rule, an effect for the majority of current synthetic antimicrobials is associated either with suppressed DNA synthesis, or with inhibiting bacterial protein production at translational or transcriptional level. A number of sensitive and easy-todo methods are available for screening and monitoring potential genotoxic activity of a wide range of natural and synthetic compounds. To date, the Ames test has been widely used, which is based on the sensitivity of Salmonella strains to carcinogenic chemicals, although some compounds resulting in Ames negative reactions could actually be carcinogenic to animals. Likewise, the SOS chromotest represents a SOS transcriptional analysis able to assess DNA damage caused by chemical and physical mutagens by measuring the expression of a reporter gene (β-galactosidase) encoding the β-galactosidase enzyme that metabolizes ortho-nitrophenyl galactopyranoside resulting in emerging a yellow-colored compound detected at wavelength 420 nm. Next, the induction of β-galactosidase is normalized by the activity of alkaline phosphatase, an enzyme expressed constitutively by Escherichia coli. SOS chromotest is also widely used for genotoxicological studies providing a quick answer (several hours) and requiring no survival of the test strain. Dose-response curves for various chemicals consist of a linear region, which slope corresponds to the SOS induction. Therefore, the SOS chromotest was selected for the study allowing to identify DNA-mediated effects of the analyzed compounds. The aim of the study was to evaluate the SOSinducing activity for 1H-indol-4-, -5-, -6-, -7-ylamines-substituted antimicrobial compounds. The Escherichia coli PQ 37 with the genotype F-thr leu his-4 pyrD thi galE lacΔU169 srl300::Th10 rpoB rpsL uvrA rfa trp::Mis+ sfiA:: Mud (Ar, lac) cts was used as a test strain. Due to the link of the sfi A::lac Z genes, lacZ β-galactosidase gene expression in the strain PQ 37 is controlled by the sfiA gene promoter, one of the components in the E. coli SOS regulon. Activity of β-galactosidase assessed relative to constitutive microbial alkaline phosphatase reflects SOS-inducing activity triggered by examined compounds in the SOS chromotest that also allows to control their toxic effects on bacterial cells. The data showed that 4,4,4-trifluoroN-(6-methoxy-1,2,3-trimethyl-1H-indol-5-yl)-3-oxobutanamide (1), 4,4,4-trifluoro-N-(6-methyl-2-phenyl-1H-indol-5-yl)- 3-oxobutanamide (2) and N-(1,5-dimethyl-2-phenyl-1H-indol-6-yl)-4,4,4-trifluoro-3-oxobutanamide (3) exerted no SOSinducing activity at the examined concentrations. In contrast, 4-Hydroxy-8-phenyl-4-(trifluoromethyl)-1,3,4,7-tetrahydro- 2H-pyrrolo [2,3-h]-quinoliN-2-one (4), 9-hydroxy-5-methyl-2-phenyl-9-(trifluoromethyl)-1,6,8,9-tetrahydro-7Н-pyrrolo- [2,3-f]-quinoliN-7-one (5), 6-hydroxy-2,3-dimethyl-6-(trifluoromethyl)-1,6,7,9-tetrahydro-8H-pyrrolo[3,2-h]quinoliN-8- one (6) and 1,2,3,9-tetramethyl-6-(trifluoromethyl)-1,9-dihydro-8H-pyrrolo [3,2-h]-quinoliN-8-one (7) displayed a dosedependent SOS-inducing activity at bactericidal concentrations. The data obtained allowed us to identify compounds 4, 5, 6, 7, which mechanism of action relies on affecting microbial cell DNA.

Russian Journal of Infection and Immunity. 2021;11(4):663-670
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Adenosine-regulated mechanisms in the pathogenesis of ventilation disorders in patients with pulmonary tuberculosis

Dyakova M.E., Serebryanaya N.B., Kiryukhina L.D., Esmedlyaeva D.S., Yablonskiy P.K.


Uncovering involvement of the purinergic system in the pathogenesis of ventilation disorders (VD) may provide additional information about the pathophysiological mechanisms leading to the development of VD in pulmonary tuberculosis (PT). The aim was to identify a relationship between the parameters of adenosine metabolism, inflammatory response and altered ventilation metabolism in PT patients. Materials and methods. Obstructive and mixed PT patients were assigned to subgroups with/without VD for assessing adenosine deaminase activity (ADA-1, 2) in serum, mononuclear cells, neutrophils; ecto-5’-nucleotidase (ecto-5’-NT); CD26 (dipeptidyl peptidase-4, DPP-4), phagocyte oxidative burst measured by NO generation. Results. PT patients showed decreased ADA-1 and CD26 (DPP-4), but increased ADA-2. Elevated intracellular adenosine concentration was found in mononuclear cells in patients lacking VD, whereas patients with mixed and obstructive VD — had it in neutrophils. Mononuclear cells of patients with PT lacking VD as well as with obstructive VD type had decreased NO3– concentration. Neutrophil hyperactivity was recorded in all groups of PT patients. Patients with PT lacking VD as well as with mixed VD type showed that the parameters of external respiration were associated with activity of extra-/intracellular ADA, whereas obstructive VD was caused by excessive formation of serum adenosine. Changes in respiratory function in PT were associated with decreased level of serum NO radicals, impaired nitrogen-dependent bactericidal phagocyte activity, and overproduced neutrophil oxygen radicals. Conclusion. Purinergic regulation is involved in regulating inflammatory and compensatory processes in PT patients as well as impaired ventilation efficiency. The most severe respiratory disorders observed in PT patients with mixed VD type are associated with the most prominent changes in nucleotidase activity, particularly ecto-ADA-2 and DPP-4/CD26.

Russian Journal of Infection and Immunity. 2021;11(4):671-682
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Characterization of toxigenic Corynebacterium diphtheriae strains isolated in Russia

Borisova O.Y., Gadua N.T., Pimenova A.S., Chaplin A.V., Chagina I.A., Urban Y.N., Maksimova N.M., Korzhenkova M.P., Afanasiev S.S., Kafarskaya L.I., Afanasyev M.S., Krikun V.V., Yakunina O.Y.


The aim of the study was to characterize toxigenic strains of Corynebacterium diphtheriae by examining 12 toxigenic strains of C. diphtheriae isolated in Russia between January, 2017 to June, 2019. The morphological, toxigenic and biochemical properties of C. diphtheriae was studied. Genotyping of C. diphtheriae strains was performed using MLST and dtxR gene sequencing with subsequent phylogenetic analysis. Results. Toxigenic strains of C. diphtheriae were isolated in the Novosibirsk, Samara and Chelyabinsk Regions, the Khanty-Mansi Autonomous Okrug — Yugra as well as the Republic of Northern Ossetia — Alania. Among these strains, 5 were isolated from diphtheria patients (moderate disease found in one case, mild course — remaining patients) and 7 strains were isolated from bacterial carriers. In two cases C. diphtheriae from diphtheria patients were identified as ST25 sequence type, gravis variant; in one case — ST8 type, gravis variant; two cases — ST67 sequence type, mitis variant. In asymptomatic carriers of tox-positive C. diphtheriae strains they belonged to ST25 sequence type, gravis variant — in two cases, ST67 type, mitis variant — in four cases. A sequencing type was not identified in one case. All sequence types were widespread globally being presented by a large number of isolates in the PubMLST and characterized by a substantial amount of derivative sequence types. At the same time, they belonged to different clonal complexes and differed markedly from each other contributing to their reliable difference as assessed by MLST. Study of gene dtxR sequence diversity showed that all allelic variants were typical for the representatives of these sequence types. New alleles of gene dtxR were not revealed in strains examined. It was shown that non-synonymous substitution C440T leading to A147V amino acid substitution was found solely in one allele distributed in ST8, ST185, ST195 and ST451 types suggesting at late mutation. In contrast, the polymorphism C640A resulting in the amino acid substitution L214I was found not only in the same allele, but also in the basal tree branches indicating that isoleucine was in the ancestral sequence of the protein.

Russian Journal of Infection and Immunity. 2021;11(4):683-691
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Hepatitis E virus seroprevalence in indigenous residents of the Hà Giang northern province of Vietnam

Lichnaia E.V., Pham T.G., Petrova O.A., Tran T.N., Nguyen T.T., Bui T.N., Vo V.C., Dmitriev A.V., Kalinina O.V.


Vietnam is an endemic territory of the South-East Asia in terms of the prevalence of hepatitis E virus. However, the data on the prevalence of HEV infection among the indigenous population of Vietnam are limited, whereas the data on various minor ethnic groups are not available. Рopulation of the Northern province Hà Giang is characterized by ethnic diversity and consists of about 22 ethnic groups that have preserved their ethnic identity determining the features of their lifestyle and farming. The goal of the current study was to conduct a cross-sectional examination to assess prevalence of serological markers of HEV infection in the indigenous population of the Northern province of Vietnam, Hà Giang. Materials and methods. A total of 1127 healthy indigenous residents aged 18 to 83 years (average age 42.8±1.5) who lived in three regions (Yên Minh, Bắc Mê and Đông Văn) of Hà Giang province in 2019 were enrolled in the study. The presence of HEV-specific IgG antibodies (anti-HEV IgG) was determined by the ELISA using kits “DS-IFA-ANTI-HEV-G” (LLC NPO “Diagnostic Systems”, Russia). Results. The prevalence of anti-HEV IgG antibodies in the indigenous population in the Hà Giang province was 74.4% (838/1127; 95% CI 71.7–76.8), with the peak occurrence of anti-HEV IgG (87.6%) found in Đông Văn region, which was significantly higher compared to those in the Bắc Mê (χ2 = 16.37, p = 0.000052) and Yên Minh (χ2 = 214.64, p < 0.00001) regions. The Yên Minh Region was characterized by the lowest percentage of subjects involved in the epidemic process (χ2 = 77.55, p < 0.00001). No significant gender-related differences were detected in antiHEV IgG level both in general and in individual regions. The peak frequency of anti-HEV IgG (85.9%) was found in the H’mong ethnic group, which was significantly higher than in the Tay ethnic groups (χ2 = 77.32, p < 0.00001) and in the remaining minor ethnic groups (χ2 = 63.44, p < 0.00001). Conclusion. The results of this study indicate a high seroprevalence of hepatitis E virus in the minor ethnic groups, which preserve the national lifestyle in the Hà Giang province of the Northern Vietnam. As the Hà Giang province is located in remote mountain areas, a number of which are still difficult to access, its low economic status, poor sanitary and hygienic living conditions, lack of high-quality water supply, multinational population following different lifestyles, the contact of population with natural potential sources of HEV infection, including various wild and domestic animals, contribute to the successful spread of the hepatitis E virus in the region and the involvement of all populational age groups in the epidemic process. Taking into account the rapid development of the tourism industry in the Hà Giang Province particularly in the Đông Văn Region, where the Đông Văn Karst Plateau Geopark being recognized by UNESCO as national treasure is located, the results of this study emphasize a need to plan and perform the events aimed for preventing and monitoring HEV infection in endemic regions in Vietnam in order to reduce a risk of spread of hepatitis E virus not only inside, but also outside the country.

Russian Journal of Infection and Immunity. 2021;11(4):692-700
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Geographical diversity of Helicobacter pylori strains circulating in the European Part of the Russian Federation

Sorokin V.M., Svarval A.V., Vodop'janov A.S., Pisanov R.V.


The aim of the study was to identify INDEL markers and study geographical origin of regional H. pylori strains circulating in the European part of the Russian Federation. The study included 56 strains of H. pylori isolated in three regions of the Russian Federation: Saint Petersburg, Astrakhan and Rostov Regions. Genomic DNA was isolated using a set of Probe NA (DNA Technology, Russia), according to the manufacturer’s instructions. Detection of INDEL markers hp5605, hp6405, hp340, hp1390, hp3660 was performed using PCR. Clustering of the identified INDEL genotypes and building a phylogenetic tree were performed using the BioNumerics 7.6 and GrapeTree software packages. 21 strains from the GenBank database with known geographical origin were used as reference strains. In 20 strains from Saint Petersburg, 13 individual genotypes were identified, while 17 strains belong to the European cluster (hpEurope), 2 strains belong to the hspEAsia cluster and one strain belongs to the hspWAfrica cluster. The most common genotype identified in the European cluster includes six strains from Saint Petersburg and two strains from the GenBank database. For further differentiation of these strains, the VNTR typing method was used, which allowed identifying eight individual genotypes in eight strains. Fifty-six studied russian strains are represented by thirty individual genotypes, which reflects the high heterogeneity of strains circulating in the European part of the Russian Federation. The most frequent genotype is represented by two hpEurope strains, one strain from the Astrakhan region, as well as 5 and 6 strains from the Rostov Region and Saint Petersburg, respectively. The vast majority of Russian strains (52/56) belong to the hpEurope population, while two strains from Saint Petersburg are included in the hspEAsia population, and one strain from Saint Petersburg and the Astrakhan Region is included in the hspWAfrica population. Total, 77 H. pylori strains are represented by 37 individual genotypes with a high diversity index (DI = 0.95), which allows us to consider the proposed INDEL typing method as an independent method for genotyping H. pylori strains. Taking into consideration the complexity of the problem of accurately determining the geographical origin of H. pylori strains, the proposed simple and convenient method of INDEL typing of H. pylori strains, based on an available PCR method becomes very relevant and allows us to conduct an adequate primary analysis of the geographical origin of Russian H. pylori strains.

Russian Journal of Infection and Immunity. 2021;11(4):701-706
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Long-term monitoring of tick-borne viral encephalitis and tick-borne borreliosis in the Komi Republic

Gnativ B.R., Tokarevich N.K.


Our study was aimed at analyzing data combining objective epidemiological, zoological and entomological research intended to determine the environmental and epidemiological patterns of tick-borne encephalitis (TBE) and Lyme borreliosis (LB) foci, as well as the role of anthropogenic factors in epidemic manifestations to improve anti-epidemic activities. Long-term data on the abundance of ticks flagged from vegetation in various districts of the Komi Republic (RK) have been analyzed. The prevalence of tick-borne encephalitis virus (TBEV) and Borrelia burgdorferi (agent of LB) in ticks picked from vegetation, humans and domestic animals in various districts of the RK was measured by using enzyme-linked immunosorbent assay and polymerase chain reaction (PCR-ELISA). In addition, the data on 1994–2017 tick-bite incidence in RK, 1970–2017 TBE incidence, and 1997–2017 LB incidence were also examined and correlated with the impact of forest transformation on the TBE incidence. The rise of tick population in the southern districts of RK and its northward expansion were noted. It is also shown that the RK territory, where tick bites are registered, expanded significantly. Mean annual tick-bite incidence rate in 2006–2017 vs. 1994–2005 timeframe was increased by 4-fold. RK regions where deforestation took place, the tick-bite incidence was increased, and the local TBE incidence elevated distinctly. In recent years, there was a rise in TBEV prevalence in ticks, collected either from vegetation or from humans and animals. In 2006–2017 and 1970–1981, mean annual TBE incidence rate increased by a 11- and 36-fold as compared to that one registered in 1982–1993. In recent years, the most severe focal TBE forms began to be recorded. In 1996–2017, the TBE mortality rate was 2.3%. The main features of LB epidemiology mimic those found in TBEV. In particular, the prevalence of Borrelia burgdorferi in ticks flagged from vegetation increased from 9.5% to 34.7% in 2010 vs. 2017, respectively. A sharp rise in LB incidence rate and profound northward shift for bacterial range, where this infection started to be registered only in recent years, were noted. Both TBE and LB demonstrated marked occupation-related pattern. The need in conducting task-oriented prophylaxis of tick-borne infections is necessitated by taking into account geographic specifics. The RK northern regions should be considered as potentially endemic, where tick bites in human population has recently begun to be reported.

Russian Journal of Infection and Immunity. 2021;11(4):707-722
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Etiology of influenza-like illnesses in the population of Novosibirsk city in the 2018–2019 epidemic season

Kurskaya O.G., Anoshina A.V., Leonova N.V., Simkina O.A., Komissarova T.V., Esikova E.Y., Pozdnyakova L.L., Sobolev I.A., Prokopyeva E.A., Murashkina Т.A., Kazachkova E.A., Alekseev А.Y., Danilenko D.M., Komissarov A.B., Stolyarov K.A., Fadeev A.V., Sominina A.A., Shestopalov А.M., Sharshov K.A.


Influenza and other acute respiratory viral infections lead to a substantial incidence of severe cases and hospitalizations and so remain a global health problem. Within the frame of the Global Influenza Hospital Surveillance Network (GIHSN), we assessed the contribution of influenza and other respiratory viruses to severe cases of influenzalike diseases in patients hospitalized to the Novosibirsk infectious hospitals in the years 2018–2019. We analyzed 484 nasopharyngeal swabs collected from patients admitted to the hospitals with acute respiratory infections (ARI) using real-time polymerase chain reaction commercial kits. We confirmed viral etiology of ARI in 69.8% cases. Influenza viruses were detected in 47.1% cases, wherein concomitant circulation of influenza A(H1N1)pdm09 and A(H3N2) viruses was observed in 20.7% and 26% of patients, respectively, whereas influenza B virus was detected only in one sample. All analyzed influenza A viruses were antigenically similar to vaccine strains. Genetically, the Novosibirsk strains were closely related to influenza A viruses distributed in Russia and worldwide. Influenza A(H1N1)pdm09 virus was detected in all patients aged 0 to 14 years and required intensive care. Other respiratory viruses were detected in 36.4% of children and 5.8% of adults, and 8.3% of children had viral coinfection, whereas no cases of coinfection were detected in adults. The most common viruses in children were metapneumovirus — 12.8%, rhinovirus — 9.3% and respiratory syncytial virus — 8.0%. In adults, metapneumovirus, adenovirus, parainfluenza virus and rhinovirus were detected with a detection rate no exceeding 2%. In this study, we found no differences in the detection rate of the influenza virus due to concomitant chronic diseases, pregnancy, or smoking habits. At the same time, the detection rate of other respiratory viruses in non-smokers vs. smokers was significantly lower than in smokers and former smokers (26.15%, 66.67% and 62.50%, respectively). In addition, the level of detection of respiratory viruses in children with vs. without chronic pathology was significantly higher (55.3% and 38.7%, respectively). Thus, our and similar studies are important for monitoring and control of the infection.

Russian Journal of Infection and Immunity. 2021;11(4):723-736
pages 723-736 views

The structure of the oropharyngeal genus Candida fungi community in HIVinfected patients

Voropaev A.D., Yekaterinchev D.A., Nesvizhsky Y.V., Zverev V.V., Afanasiev S.S., Volchkova E.V., Afanasiev M.S., Budanova E.V., Boshjan R.E., Likhanskaya E.I., Urban Y.N., Filina Y.S., Suleymanova M.E., Voropaeva V.A.


At the present time virtually no data are available about the structure of the genus Candida fungus able to target HIV-infected patients and serve as an etiological factor of candidiasis. The aforementioned shaped the aim of the study: to examine structure of the Candida genus community colonizing the oropharynx in HIV-infected patients with clinical manifestations of oropharyngeal candidiasis. There was conducted a microbiological study of the oropharynx in 31 HIV-infected patients (51.6% males and 48.4% females) with clinical manifestations of oropharyngeal candidiasis treated at Moscow Infectious Clinic No. 2 inpatient department in the years 2015–2017. We confirmed the diversity of the oropharyngeal Candida spp. community found in HIV-infected patients. Total 52 isolates of the genus Candida were isolated. C. albicans dominated in 57.7% cases, whereas C. glabrata prevailed (21.1%) among non-albicans species. Minor components were represented by C. tropicalis (11.5%) and C. krusei (9.6%). C. albicans and C. glabrata were sensitive to polyenes, whereas minor community components — to itroconazole and clotrimazole. The vast majority of fungal strains were resistant to fluconazole. The genus Candida community reveals a unique architecture so that any member may exist in the oropharyngeal biotope of HIV-infected patients as a monoculture or in association: homogeneous, consisting of a single species strains, or heterogeneous, formed by several species. Candida fungi in 18 patients (58.1%) were isolated as a monoculture, whereas in 13 (41.9%) subjects — in association consisting of 34 isolates (65.4% of total number), of which 16 (30.8%) and 18 (34.6%) were isolated from homogeneous and heterogeneous associations, respectively. There were identified 9 two-component associations (69.2%), and 4 (30.8%) consisting of three or more components. It turned out that pattern of the examined community was mainly determined by species composition that agrees with previous data. Most common associations were presented by C. krusei (100%) and C. albicans (73.3%). Upon that, most often C. albicans (72.7%) formed a homogeneous type of associations. Sensitivity of Candida fungi to antimycotic drugs also depended on the architecture of related community. C. albicans isolates in heterogeneous associations revealed a wide range of resistance acquired by contact with non-albicans species.

Russian Journal of Infection and Immunity. 2021;11(4):737-745
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Prognosis of severe cytomegalovirus infection in newborns

Kravchenko L.V.


Objective is to study the features of impaired activation of T and B lymphocytes in order to predicting severe cytomegalovirus infection in newborns. Materials and methods. 133 newborns with cytomegalovirus infection were examined. Immediately after diagnosing cytomegalovirus infection, all patients observed were immunologically ex amined, including assessing count of peripheral blood T and B lymphocytes, as well as their intercellular interaction by using flow cytometry immunostaining for CD3, CD3+CD28, CD3+CD28+, CD3CD28+, CD4, CD8, CD20, CD20+CD40+, CD28, CD40. The test was performed by using a Beckman Coulter Epics XL laser flow cytofluorometer. Depending on the condition severity, all children were divided into two groups: 1 — cytomegalovirus infection, severe form — 60 subjects (45.1%); 2 — cytomegalovirus infection, moderate form — 73 subjects (54.9%). Results of the entire set of studied indicators for cellular and humoral arms of immune system revealed statistically significant differences for the prognosis of severe cytomegalovirus infection: CD3+CD28, CD20, CD20+CD40+, CD4. T lymphocytes with CD3+CD28+ activation markers, through which costimulating signals necessary for the activation of T helper cells are exerted cell-intrinsic features, serving as an important factor ensuring immune response. Using the “classification trees” method, we developed a differentiated approach to forecast severe cytomegalovirus infection in newborns. Systems of inequalities were obtained, four of which classify a subgroup of newborns with severe cytomegalovirus infection. The consistent application of the obtained inequalities makes it possible to isolate from the input stream of sick patients with a prognosis of the development of severe cytomegalovirus infection. The proposed diagnostic rules can be considered as screening markers for predicting a severe cytomegalovirus infection in newborns, which makes possible the timely onset of specific therapy.

Russian Journal of Infection and Immunity. 2021;11(4):745-751
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A relationship between causative agents of infectious diarrhea and fatal outcomes in pre-school children

Podkolzin A.T., Kozhakhmetova T.A., Kyasova D.K., Dalelova Z.K., Kuleshov K.V., Guseva A.N., Pavlova A.S., Veselova O.A., Parkina N.V., Konovalova T.A., Yatsyshina S.B.


Infectious diarrhea is one of the leading causes of fatal outcomes in young children. Differential diagnostics of such infections within the first hours of illness poses significant objective obstacles. Data from laboratory studies of autopsy material and pathological studies provide valuable information for understanding the spectrum of differential diagnostics and etiological structure of infectious diarrhea with fatal outcomes in young children. Materials and methods. There were analyzed 100 cases of fatal outcomes in children under the age of six years registered in Russia from November 2011 to December 2019, who was diagnosed with infectious diarrhea at different levels of the healthcare system. The data were assessed based on available medical case reports and the laboratory testing of autopsy samples performed by using nucleic acid amplification methods. Results. The diagnosis of infectious diarrhea was revised in 24 patients, based on the data of a set of intravital and post-mortem studies. In patients with unconfirmed diagnosis of acute intestinal infections, pneumonia was the most often detected — in 45.8% (11/24), sepsis — in 29.2% (7/24), meningitis/meningoencephalitis, acute surgical pathology and asphyxiation associated with vomit aspiration — in 16.7 % (4/24) cases. The causative agents of infectious diarrhea were identified in 71 of 76 patients with confirmed diagnosis of acute intestinal infections. Most prevalent were group A rotaviruses — 52.6% (40/76), group F adenoviruses — 17.1% (13/76), and noroviruses — 13.2% (10/76). Combination of pathogens was detected in 29 cases (38.2%). Prehospital lethal outcomes in patients with infectious diarrhea were observed in 17 cases (22.4%). In total, rate of neonatal deaths due to acute intestinal infections accounted for 62.2% and 2-year-old toddlers — 20.3%. 64 of 76 (84%) children had no unfavorable premorbid background. The most common pathologies associated with infectious diarrhea with developing fatal outcomes were pneumonia (including aspiration pneumonia) in 22.4% (17/76) and aspiration asphyxia in 6.6% (5/76). Hemolytic-uremic syndrome associated with diarrhea was diagnosed in 7.9% (6/76) of children. Conclusions. Within the first years of life children comprise a risk group for developing fatal outcomes during infectious diarrhea. Lack of unfavorable premorbid background should not be considered as a reliable positive prognostic criterion. Diagnostics of pneumonia should be included in the mandatory examination plan for children with severe infectious diar rhea. Based on study of clinical and autopsy material, group A rotaviruses were the lead causative agents among those resulting in infectious diarrhea with fatal outcomes in young children. Special attention should be paid to preventing vomit aspiration within the first days after disease onset.

Russian Journal of Infection and Immunity. 2021;11(4):752-762
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Generation and evaluation of specific activity and authenticity of recombinant vaccine designed preventing against Pseudomonas aeruginosa

Kaloshin A.A., Zimina E.M., Kalinichenko E.O., Mihailova N.A.


The aim of the study was to obtain and characterize a recombinant vaccine for the immunoprophylaxis of infections caused by Pseudomonas aeruginosa. A set of two highly immunogenic P. aeruginosa recombinant proteins was used to create related vaccine. The first vaccine component was presented by recombinant outer membrane protein F (OprF), whereas the second one — by recombinant atoxic exotoxin A (toxoid). These antigens allowed to develop vaccine inducing immune response against the surface bacterial cues and promote production of neutralizing antibodies against exotoxin A, one of the most dangerous P. aeruginosa pathogenicity factors. Recombinant proteins were synthesized in Escherichia coli cells and isolated by two-step purification. In case of recombinant OprF protein, it was initially (stage 1) isolated as a precipitate containing hydrophobic fraction of producer cell-derived proteins, whereas for recombinant toxoid we purified inclusion bodies. At stage 2, a Ni Sepharose column affinity chromatography was performed. Next, purified recombinant proteins were dialyzed against buffer solution containing 50 mМ Tris-HCl (pH 9.0) and 0.01% Tween 20 followed by filtration sterilization. Three lots of the Pseudomonas Recombinant Vaccine (PRV) were obtained for the study, wherein the recombinant antigens were absorbed with aluminum hydroxide. Recombinant OprF and toxoid protein in vaccine formula were used at a dose of 25 μg and 50 μg, respectively. Absorption completeness of the recombinant antigens within the vaccine was evaluated by polyacrylamide gel electrophoresis with PRV preparations concentrated by ultrafiltration in spin columns. Authenticity of recombinant vaccine was assessed by using customized method by desorbing antigens followed by ultrafiltration concentration in spin columns. Final concentrated desorbed vaccine preparations were analyzed by polyacrylamide gel electrophoresis and immunoblotting, which allowed to confirm presence of specific recombinant antigens in the vaccine. The experimental PRV series demonstrated specific activity (protective properties) after inoculation in animals (mice) by using a dual vaccination protocol, wherein mice were immunized intraperitonially twice with a two-week interval. Next, two weeks later mice were infected by toxigenic P. aeruginosa strain PA-103 culture cells. The index of protective efficiency (IE) for experimental vaccine series was at least a value of three (IE: 3.0–3.3) that was by 1.5-fold higher than that for using single vaccine components (IE: 2.0–2.3). Thus, we confirmed an additive effect of using a set preparation to protect against infection caused by toxigenic Pseudomonas aeruginosa strains.

Russian Journal of Infection and Immunity. 2021;11(4):763-770
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Metal nanoparticle antibacterial effect оn antibiotic-resistant strains of bacteria

Udegova E.S., Gildeeva K.A., Rukosueva T.V., Baker S.


The rapid formation of microbial resistance to modern antibacterial drugs requires to search for new, alternative therapies. It is known that some organisms, such as plants, algae, fungi, are able to convert inorganic metal ions into metal nanoparticles due to the recovery process carried out by proteins, sugars and metabolites contained in the tissues and cells of these organisms. At the same time, many plants (e.g., plantain, yarrow, wormwood, turmeric long, calendula, marsh bagulnik, etc.) and metals (copper, silver, gold, zinc, etc.) themselves have antibacterial properties, so that metal nanoparticles obtained by biological method, or via “Green” synthesis method, from extracts of such plants can become a current alternative to many modern antibacterial drugs. The antibacterial mechanism of action of nanoparticles depends on the type of microorganisms affected, as well as on the type of nanoparticles, their concentration, size, and how they are obtained. Based on this, the study of the antibacterial effect of nanoparticles is one of the promising directions of solving the problem of microbial antibiotic resistance. There was examined antibacterial effect of metal nanoparticles containing silver, copper and gold obtained by biological method from the salts of AgNO3, CuSO4, H[AuCl4] metals, respectively, and the extract of the plant — turmeric long (lat. Curcuma longa) — related to the following bacteria strain collection: E. coli (ATCC 25922), S. aureus (ATCC 25923), MRSA (ATCC 38591) and polyresistant clinical strains isolated from patients of the Regional clinical hospital (Krasnoyarsk) — К. рneumoniae, strain 104, P. аeruginosa, strain 40, P. аeruginosa, strain 215, А. baumannii, strain 210, А. baumannii, strain 211. Study allowed to identify the minimum suppressive concentration of nanoparticles by the method of serial dilutions (MUK 4.2.1890-04) with azurin dye. It was proved that metal nanoparticles exhibit different antibacterial efficacy depending on the type of nanometals used and bacterial cultures. Copper nanoparticles have the highest antibacterial activity, and gold nanoparticles have the lowest. The most marked antibacterial effect was observed against clinical polyresistant strains. Metal nanoparticles can become an alternative to the currently known antibacterial drugs, but despite the high efficiency of nanoparticles against polyresistant to antibacterial drugs microorganisms in vitro, it is necessary to take into account their possible toxic effect on live tissues, which requires further study in experiments in vivo.

Russian Journal of Infection and Immunity. 2021;11(4):771-776
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Enhancing the specific T cell immune response against micro- and nanoparticle immobilized antigen

Sakhabeev R.G., Polyakov D.S., Goshina A.D., Vishnya A.A., Kudryavtsev I.V., Sinitcina E.S., Korzhikov-Vlakh V.А., Tennikova T.B., Shavlovsky M.M.


The current study was a part of the project on generating viral particle traps occurring due to covalent immobilization on the interface of recombinant virus-specific polymer-based nano- and microparticles. It is assumed that protein-particle conjugates could be able to bind virions followed by engulfment by immune cells. The study was aimed to examine the effect of polylactic acid (PLA) and PLA block-copolymer with polyethylene glycol (PLA-PEG)-based micro- and nanoparticles on the cellular immune response against polymeric particle-bound antigen. Materials and methods. A recombinant chimeric protein beta-2-microglobulin — green fluorescent protein (β2M-sfGFP) was obtained by affine chromatography. The recombinant protein was immobilized onto the polymer particles, which were further used for mice immunization. Female F1 hybrid mice (CBA x C57BL) in experimental and control groups consisted of 4–6-month-old 15 animals (weighted 20–25 g). Intracellular cytokine staining was used to evaluate the cellular immune response. Results and discussion. It was shown that the nanoparticles of PLA block-copolymer with polyethylene glycol (PLA-PEG) were able to bind 10 microgram protein per 1 mg polymer. The polylactic acid nanoparticles were able to bind 2,3 microgram protein per 1 mg polymer. In experiment, mice in group 1 were immunized with 100 nm PLA-PEG particle-β2M-sfGFP conjugate, in group 2 — with same particles together with soluble β2M-sfGFP. In group 3, mice were immunized with 1400 nm PLA particles-β2M-sfGFP conjugate, and in group 4 — with same particles together with soluble protein. The spleens isolated 2 weeks after the four-time intraperitoneal immunization. Comparison of immune response between groups was assessed by nonparametric Kruskal–Wallis criterion with Tukey correction. It was shown that the number of antigen-specific CD4+ T cells produced to model protein was significantly higher after immunization with particle-β2M-sfGFP conjugate, as compared to control groups, wherein immunization was performed with a mixture of protein and unmodified particles (p < 0.001). It was found that the number of antigen-specific CD8+ T cells formed against β2m-sfGFP did not differ between all groups examined.

Russian Journal of Infection and Immunity. 2021;11(4):777-783
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Clinical and morphological case of developing liver cirrhosis associated with viral hepatitis in a young patient

Vorobeva O.V., Lastochkin A.V.


The significance of chronic hepatitis is determined not only by the disease per se, but also by the increased risk of the formation of long-term adverse effects such as liver cirrhosis. Viral cirrhosis of the liver (as the outcome of chronic hepatitis B, C, B + D) comprise from 10% to 24.5% of all liver cirrhosis cases. Cirrhosis of the liver is considered as an irreversible stage of chronic hepatitis, more often observed in men above 40 years, but recently more and more its cases are found in young, working ones leading to disability. Due to the high liver regenerative potential, a prognosis for liver lesions of different etiologies may be rather favorable. As a result, early diagnostics, dynamic monitoring and the use of promising methods for treating liver pathology to stimulate its regeneration that compensates for lost liver functions are necessary. In the clinical and morphological case, pathomorphological changes in organs with liver cirrhosis, which developed as a result of viral hepatitis are described. The aim of the study was to describe pathomorphological changes in organs during liver cirrhosis, which developed due to viral hepatitis, which led to multiple organ failure in a young patient. Materials and methods. The analysis of the obtained accompanying medical documentation (outpatient card, medical history) was performed. The standard methodology of autopsy was used. To process histological sections of autopsy material, hematoxylin-eosin staining was used. Results. Histological examination in the liver shows development of portal tract fibrosis with lymphohistio cytic infiltration, formation of monolobular regenerated nodes, signs of edema, areas of demyelination, dystrophic changes in neurocytes, signs of acute renal failure, a combined profound change in the kidneys detected in the lungs and brain, which resulted in multiple organ failure and subsequent lethal outcome in a young patient. The early formation of portal hypertension with liver cirrhosis, esophageal and gastric varicose veins dilatation lead to fatal bleeding in half of patients. Therefore, timely diagnosed cirrhosis and hepatitis as their predecessors is one of the most relevant issues in medicine.

Russian Journal of Infection and Immunity. 2021;11(4):784-788
pages 784-788 views


Features of antifungal therapy during long-lasting infectious process: a clinical case of fungal keratitis and profile of antifungal sensitivity based on assessing biofilm formation

Valieva R.I., Lisovskaya S.A., Mayanskaya K.A., Samigullin D.V., Isaeva G.S.


Among infectious diseases, opportunistic mycoses hold a special place. There has been accumulating a lot of evidence regarding the clinical and epidemiological aspects of infection caused by Fusarium spp., which global incidence rate among microbial keratitis ranges from 2 to 40% depending on the geographical location of the country. Colonizing mucous membranes, fungi can exist not only in the form of plankton, but form biofilms after surface attachment, which leads to elevated resistance to multiple antifungal agents. Here we describe a clinical case of fungal keratitis due to Fusarium solani by determining profile of the antifungal sensitivity for isolated fungal strains, by taking into account their potential for biofilm formation. We used an F. solani culture isolated from the patient as well as F. solani test culture obtained from the Russian National Collection of Microorganisms. While determining the sensitivity of fungal planktonic cultures to antifungal agents from the azole group (fluconazole, voriconazole), amphotericin B and terbinafine, it was revealed that antimycotics amphotericin B and voriconazole exerted a marked antifungal activity against clinical isolate, whereas the plankton F. solani test culture was more sensitive to all groups of antifungal agents. Due to a long-lasting progressive course of the infectious process and the high biofilm-forming ability of the clinical strain F. solani, the activity of antifungal agents on biofilm cells was modeled and examined in vitro. It was shown that regarding to the fungal biofilms, value of the minimally inhibitory concentration exceeded those for planktonic cultures by 100-fold. The mechanisms of action for antifungal agents on vital parameters of fungal cell structures were analyzed by using confocal laser scanning microscopy after staining samples with propidium iodide and acridine orange for 15 min to detect changes between intact and damaged cell surface. It was found that within the biofilm fungal cells preserved viability even after exposure to high concentrations of antifungals. In addition, despite the fungicidal drug activity at substantial concentrations acting on the biofilm cell membrane, the cell nuclei remained viable. Owing to the presence ot the mechanism of resistance in mycelial fungi shown in the study, it is necessary to take into account and investigate characteristics of biofilms in terms of drug sensitivity that will allow to optimize a choice of antimicrobial therapy.

Russian Journal of Infection and Immunity. 2021;11(4):789-797
pages 789-797 views

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