Vol 8, No 2 (2018)

REVIEW ARTICLES

GENOMOSYSTEMATICS OF RICKETTSIAE

Shpynov S.N., Pozdnichenko N.N., Gumenyuk A.S., Skiba A.A.

Abstract

The definition of the term genome was given by the German botanist G. Winkler almost one hundred years ago in 1920. A genome  definition for bacterial (rickettsia) with a single chromosome was  recently presented from the perspective of information theory,  biology and bioinformatics as the information chain of nucleotides.  The systematics of rickettsiae (obligate intracellular microorganisms) is based on a limited number of phenotypic characters.  Classifications built on the analysis of genes, fragments of genomes  and their concatenations cause discussion. Application of the Formal  Order Analysis (FOA, http://foarlab.org) in the study of complete  genomes allowed to submit the systematics of representatives of the family Rickettsiaceae. This approach confirmed the existence of  typhus group (TG), spotted fever group (SFG), and an «ancestral»  group within the genus Rickettsia, and allowed the isolation of the  Rickettsia felis group within this genus, located between the  «ancestral» group and the SFG and the R. akari group on the border  between the SFG group and the genus Orientia. The development of  the tools of FOA — «Map of Genes» and «Matrix of Similarity» —  helped to conduct an in-depth study of the complete genomes of  rickettsia, taking into account the characteristics of their genes and  noncoding sequences. Application of these instruments, with the  help of the obtained classification, confirmed the notion of ecological  features of rickettsia, the structure of nosological forms and the  epidemiological patterns of rickettsiosis, and made it possible to  assess the virulence of the strains of the two most pathogenic  species of rickettsia, R. prowazekii and R. rickettsia. In this work, for the first time, a holistic, consistent and multidimensional observation of a set of closely related bacteria (a family of bacteria) and the  manifestations associated with them was carried out. The basis of  the developed and herein described systematic approach to the  study of bacteria is a new mathematical model — the arrangement of nucleotides in a complete genome and its sensitive  unambiguous numerical characteristics. A new methodological  approach named genomosystematics and based on mathematical  modeling of complete genomes of rickettsiae (bacteria) using FOA.  Classification of rickettsiae and rickettsioses obtained with the help  of this approach corresponds to ecological, epidemiological and  etiological principles. Application of the genomosystematics can  serve the goals and objectives of preventive medicine. The  publication completes a series of scientific works presenting the  methodology of an integrated approach based on the application of  mathematical analysis tools in the study of objects and laws of  natural science disciplines of biological and medical profile.

Russian Journal of Infection and Immunity. 2018;8(2):107-118
pages 107-118 views

DISTURBANCE OF AN APOPTOSIS OF NEUTROPHILS AT A SEPSIS

Shen X., Guan W., Du J., Puzyryova L.V.

Abstract

The sepsis represents life-endangering disturbances of functions of the internals caused by a dizregulyation of a macroorganism to the  infectious agent and is difficult interaction of pro-inflammatory and  antiinflammatory processes that not seldom defines the fate of  patients. The predetermining factor of a sepsis is the originator. The  immunosupression caused by the originator promotes generalization  of an infection, and the intensive bacteriemia caused by generalization leads to the accruing endotoxinemia that aggravates  immunosupression even more and leads finally to systemic inflammatory reaction — the main and most dangerous implication  of a sepsis. The syndrome of systemic inflammation with  uncontrollable emission of cytokines is the cornerstone of a sepsis.  The pathophysiology of a sepsis begins with impassioned inflammatory reaction which can last several days, and then passes  into more lingering immunosupressivny period where the outcome  depends on the immune system of the patient. Cellular apoptosis is  one of leaders in sepsis immunosupression development. In article  mechanisms of disturbance of an apoptosis of neutrophils are  described that, undoubtedly, affects weighting of a current of a  sepsis and as a result, a failure. Migration of neutrophils under  natural conditions includes four various phases which during a sepsis  are broken. The mechanisms worsening migration of  neutrophils, contributing to the development of a sepsis were  investigated in numerous scientific works. Authors of Peking  University offered schemes of a way of disturbance of an apoptosis  of neutrophils and migration of neutrophils at a sepsis. Despite the  extensive accumulated experience on studying of a pathogenesis of  septic states, there are no effective and specific remedies of fight  from a sepsis now. Perhaps, by prevention of disturbance of the  programmed death of a cell the cytokines developed anti-apoptotic,  caspase inhibitors will be. 

Russian Journal of Infection and Immunity. 2018;8(2):119-126
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THE PREVALENCE OF HIV RECOMBINANT FORMS IN RUSSIA AND COUNTRIES OF THE CIS: SYSTEMATIC REVIEW AND METAANALYSIS

Pasechnik O.A., Blokh A.I.

Abstract

This review was to aimed to access the prevalence of HIV recombinant forms in Russia and countries of the CIS, which have  close social and economic ties. We conducted a search in Russian  Science Citation Index and PubMed for a depth of 8 years. We  included 22 articles, which contained the results of 35 independent  cross-sectional studies, in our review. Meta-analysis of HIV  recombinant forms prevalence was conducted in Open Meta-analyst  with the use of Der Simonian & Laird method, arcsin transformation  and correction factor for zero values. Subgroup analysis was used  along with meta-regression (by date of collection). Pooled prevalence of HIV recombinant forms was 21.3% (95% CI 16.2–26.5) and was  highly heterogeneous. Blood samples from 3,494 HIV patients living  in various regions of the Russian Federation and CIS countries —  Belarus, Kazakhstan, Kyrgyzstan, Uzbekistan, Tajikistan, Armenia,  Georgia — were examined. Among subtypes of HIV-1, the main  share was occupied by subtype A — 75.6% (n = 2643), subtype B —  5.5% (n = 193), C — 0.8% (n = 31), G — 0.2% (n = 7), F —  0.14% (n = 5). Among the recombinant forms (n = 616), the  fraction of CRF02_ AG was 39.6% (n = 244), CRF02_AG/A was  32.9% (n = 203), CRF63_02A1 was 15.9% (n = 98), CRF03_AB —  5.2% (n = 32), CRF06_cpx — 2.1% (n = 13). Unique recombinant  forms were 2.7% (n = 17), including URF63_A1 (2.5%). In Russia, the highest prevalence of recombinant forms of HIV-1 was  registered in the Siberian Federal District (33.2% (95% CI 12.2– 54.1), the lowest in the Northwest Federal District — 1.6% (95% CI  0.9–2.3). In the CIS countries, the highest prevalence of  recombinant forms of HIV-1 is found in a subgroup of the Central  Asian republics — Uzbekistan, Tajikistan, Kyrgyzstan, Kazakhstan —  51.7% (95% CI 38.5–64.9). The significant upward trend was shown with a meta-regression. Our review is the first such research in  Russia and thus is of significant interest, but the result should be  applied with caution due to high risk of publication bias as well as significant heterogeneity of our results.

Russian Journal of Infection and Immunity. 2018;8(2):127-138
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IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN HIV INFECTION

Boeva E.V., Belyakov N.A.

Abstract

Antiretroviral therapy (ART) leads to suppression of HIV replication, contributes to increase in the number of CD4-lymphocytes count and  partial restoration or activation of the immune system. The  consequence is a reduction of incidence of opportunistic diseases,  increase in the duration and quality of life of people living with HIV  (PLHIV). However, in some patients with severe immunosuppression, this may be accompanied by a worsening of the condition and risks  of formation of the immune reconstitution inflammatory syndrome  (IRIS), which manifests itself in the development of new or  previously treated opportunistic, secondary and exacerbating non- infectious diseases against a virologically effective ART. The  frequency of the development of IRIS varies widely, in cases of  tuberculosis-associated manifestation it can reach 50%. Risk factors  for the development of IRIS are low initial CD4-lymphocyte count  and a high load of HIV RNA in the blood, the presence of  opportunistic infections during the initiation of ART. Discussed terminology issues, other possible risk factors for the  development of the syndrome, regularities of the pathological process are considered. Epidemiological statistics of  IRIS, pathogenetic bases, variants of clinical and laboratory  manifestations of complications are given. The criteria for diagnosis  of the syndrome, as well as the necessary conditions for its  occurrence, are considered. Particular attention is paid to the most  common opportunistic infections that cause the manifestation of  IRIS, the peculiarities and polymorphism of clinical manifestations  and the prevention of their occurrence. Currently, there is an  increasing incidence of HIV infection in the late stages. Laboratory  and clinical differences in the manifestations of acquired  immunodeficiency syndrome (AIDS) and IRIS have been sanctified. In view of the blurring of the diagnostic criteria, in the  Russian Federation specialists rarely expose IRIS to clinical or pathological diagnoses, therefore it is rather difficult to trace the  frequency of occurrence of this condition. Clinical and laboratory  manifestations are systematized, which allows to formulate this  diagnosis on the basis of their totality. Prevention of IRIS is the  prudent prescription of antiretroviral drugs. It is neces sary to  conduct a qualitative and timely diagnosis of concomitant diseases of infectious and non-infectious nature before the initiation of ART and  during treatment, the appointment of effective etiotropic therapy for  opportunistic and secon dary infections. In order to improve the  prognosis of HIV infection, preferably early onset of ART with stable  CD4-lym phocyte counts and low HIV RNA levels in the blood.

Russian Journal of Infection and Immunity. 2018;8(2):139-149
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ORIGINAL ARTICLES

CHANGES MONOCYTE CHEMOATTRACTANTS PROTEIN-1 IN HELICOBACTER PYLORIASSOCIATED GASTRODUODENAL DISEASES

Matveeva L.V., Kapkaeva R.C., Chudajkin A.N., Mishanina L.S.

Abstract

Chemoattractants monocyte protein-1 (MCP-1) is a low molecular weight cytokine, secreted by many cells of the body. The synthesis  of MCP-1 can induce the lipopolysaccharides of bacteria, a range of  cytokines. It is believed that MCP-1 regulates the migration and  infiltration of tissue by monocytes, T-lymphocytes memory, natural  killer cells, is involved in differentiation of naive T-helper cells. There  is evidence oncogenic and antitumor activity of MCP-1 at different stages of tumor progression. The aim of this work was the  determination and comparison of serum level of MCP-1 by infection  with Helicobacter (H.) pylori in precancerous conditions and gastric cancer.

Material and methods. Surveyed with the informed consent 204  patients with precancerous diseases of the stomach, 40 patients with gastric cancer and 40 healthy volunteers. Patients at  esophagogastroduodenoscopy conducted the fence of material for  target biopsy for histological and microbiological studies. Blood on  the immunoassay climbed in the morning on an empty stomach from the cubital vein in a volume of 5 ml in a vial without preserving  agent, the serum was separated by centrifugation for 10 minutes. By ELISA in the serum of patients determined the level of MCP-1, titer of total antibodies to the cytotoxin-associated protein of H. pylori. The obtained data statistically processed.

Results. The amount of MCP-1 in serum of the patients significantly  exceeded the data of healthy individuals in all groups of comparison. Values of MCP-1 during exacerbation of gastric ulcer  was higher than patients with exacerbation of chronic not atrophic  and focal atrophic gastritis. The concentration of MCP-1 > 280 pg/ml was detected in 17.6% of patients with pre-cancerous conditions of the stomach. When ulceration process there was a strong direct correlation of the severity of its course and the number of MCP-1 in  serum. Serum level of MCP-1 in 5.0% of patients with gastric cancer was at the upper limit of normal values, and 77.5% of  patients exceeded it. Indicator in gastric cancer significantly prevailed over the values in precancerous conditions, was correlated with the tumor stage. The level of MCP-1 in serum of  the examined healthy volunteers, patients with exacerbation of  chronic gastritis, gastric ulcer disease, polyposis, gastric cancer was  correlated with the titers of total antibodies to the cytotoxin-associated protein of H. pylori.

Conclusion. Determination of serum level of MCP-1 in precancerous conditions and gastric cancer is diagnostically valuable. Comparison  of indicator values with the titers of total antibodies to the cytotoxin- associated protein of H. pylori prognostically significant, as it allows  to assess the intensity of the induction signal to production of a  cytokine.

Russian Journal of Infection and Immunity. 2018;8(2):150-156
pages 150-156 views

OXYGEN-DEPENDENT PHAGOCYTOSIS OF BLOOD MONOCYTES IN CHILDREN WITH HELICOBACTER PYLORI-ASSOCIATED GASTRIC AND DUODENAL EROSIONS AND ULCER

Kolenchukova O.A., Gvozdev I.N., Gorbachova N.N., Litvinova I.S.

Abstract

The aim of the research is to study oxygen-dependent phagocytosis of blood monocytes in children with gastric and duodenal erosions  and ulcers by chemiluminescence analysis. The subjects of the  research were blood monocytes, extracted from blood in 44 children  with gastric and duodenal erosions and ulcers in the ages from 11 to  18 years. Microscopic tests for the bioptats of gastric mucosa of  both standard regions and edges of ulcer defects had resulted in the  determination of 2 groups of the patients with gastric and duodenal  erosions and ulcers. The 1st group was represented by Helicobacter  pylori high dissemination. As for the 2nd group, the patients showed  low bacterization. The tests for luminol-dependent hemiluminescence of blood monocytes in patients with H. pylorihigh  dissemination of gastric and duodenal mucosa demonstrated the  significant increase of the intensity and the growth of areas both  under the curve of spontaneous response and under the curve in the  zimozan-induced process as compared to the monocyte activity  in the group with low dissemination. Following the lucigenin- dependent chemiluminescence reactions in the group with H. pylori  high dissemination we had found significant increase of the time of  approaching the peak in both spontaneous response and zimozan- induced processes while the activation index was higher in  comparison with phagocyte activities of monocytes in the group with  low dissemination. Further stage of the research was to identify CagA-positive strains of H. pylori in the children with gastric and  duodenal erosions and ulcers. Studying chemiluminescence activity  of blood lymphocytes in the patients with anti-CagA antibodies we found the true increase of the time of reaching the peak, the  intensity and the area under the curve in spontaneous process in  luminol-dependent response and the time of reaching intensity peak  and the intensity of spontaneous chemiluminescence reaction,  lucigenin being an activator. So we marked the increase of the  activity of oxygen-dependent phagocytosis of blood monocytes in  children with H. pylori associated with gastric and duodenal erosions  and ulcers related to H. pylori increased bacterization. The growth of  H. pylori dissemination results in the higher stage of stomach  mucosa inflammation. Therefore active phagocytes generate more  intensively the formation of active forms of oxygen, free radicals and the products of peroxide oxidation. CagA-positive strains of H. pylori, as a rule, are associated with the higher level of inflammatory  activity than  CagA-negative ones. As a result of such influence the  functional activity of monocytes increases, because they are  «professional » phagocytes. The ability to perform phagocytosis is better expressed in them as compared to other leukocytes.

Russian Journal of Infection and Immunity. 2018;8(2):157-163
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DIFFICULTIES IN IDENTIFICATION OF СOMAMONAS KERSTERSII STRAINS ISOLATED FROM INTESTINAL MICROBIOTA OF RESIDENTS OF REPUBLIC OF GUINEA AND RUSSIAN FEDERATION

Voitenkova E.V., Matveeva Z.N., Makarova M.A., Egorova S.A., Zabrovskaia A.V., Suzhaeva L.V., Zueva E.V., Kaftyreva L.A.

Abstract

The Сomamonas genus, described in 1985, included one species — Сomamonas terrigena. At present, the Сomamonas genus includes  21 species. The ability of Comamonas to survive in environmental  objects (samples of water, soil and plants), including hospital  environment and medical equipment, allows them to be considered  as opportunistic microorganisms. The purpose of the research was to study the biological properties and antimicrobial susceptibility of  Сomamonas kerstersii strains isolated from fecal samples of healthy  people living in Saint Petersburg (Russian Federation) and the  Republic of Guinea. The study was carried out in the laboratory of  enteric infections of the St. Petersburg Pasteur Institute. 1532 fecal  samples were obtained from residents of St. Petersburg and 46  samples from residents of the Republic of Guinea. The generic and  species identification of the isolated microorganisms was carried out  using routine biochemical tests, the NEFERM test24 commercial test  system (MIKROLATEST, Erba Rus, Russia) and Vitek 2 Compact  (BioMerieux). The difficult for identification microorganisms were  studied by MALDI-TOF mass spectrometry, on a “Microflex LRF”  mass-spectrometer. Antimicrobial susceptibility was determined by  the gradient method with MICEvaluator™ (OXOID, UK) on Müller– Hinton agar (Russia). In the intestine microbiota of 1532 St.  Petersburg residents among the opportunistic microorganisms two  strains of С. kerstersii were isolated (0.13%). In a survey of 46  residents of the Republic of Guinea in 8 cases (17.4%) С. kerstersii  were isolated. The identification of C. kerstersii strains using various  methods and biochemical tests has shown different results: routine  biochemical tests allowed the strains to be assigned to the group of  non-fermenting gram-negative bacteria; NEFERM test24 kit identified all strains as С. testosteroni; VITEC 2 referred all strains to С.  testosteroni; using mass spectrometry with a coincidence ratio of  2.19–2.33, all strains were identified as С. kerstersii. It should be  taken into account that the С. kerstersii bacteria cannot be identified by the tests of NEFERM test24 kit and the GN VITEC 2 card, since  only the С. testosteroni is represented in the databases of both  methods. The taxonomic base of mass spectrometry includes  reference spectra of five species of Сomamonas from 21 known  ones, including С. kerstersii. Strains isolated from the inhabitants of  the Republic of Guinea were unsusceptible to at least one tested  antibiotic: ciprofloxacin (4 strains), tetracycline (5 strains) and  trimethoprim/sulfamethoxazole (5 strains), almost all strains being simultaneously unsusceptible to several antibio tics: ciprofloxacin  and trimethoprim/sulfamethoxazole (2 strains), tetracycline and  trimethoprim/sulfamethoxazole (2 strains), ciprofloxacin and  tetracycline (1 strain). One strain was unsusceptible to ciprofloxacin, tetracycline, and trimethoprim/sulfamethoxazole.

Russian Journal of Infection and Immunity. 2018;8(2):164-168
pages 164-168 views

REGULATION OF IMMUNE RESPONSE AGAINST MYCOBACTERIUM TUBERCULOSIS BY THE POPULATION OF REGULATORY DENDRITIC CELLS

Rubakova E.I., Kapina M.A., Logunova N.N., Majorov K.B., Apt A.S.

Abstract

On the background of a high level of genetic susceptibility to tuberculosis infection (TB), granulomatous reactions in the lung  tissue fail to effectively isolate infection foci and rather result in  diffuse pathology, confluence of granulomata and  formation of  necrotic zones. Uncontrolled inflammation severely affect breathing  function of the lung. Thus, effective disease control requires a good  balance between protective and pathogenic immune responses.  Immature regulatory dendritic cells (DCreg) and regulatory T  lymphocytes (Treg) represent a pool of important cellular regulators  of inflammation. Earlier we have demonstrated that stromal lung  cells support development of CD11b+CD11clowCD103– DCreg from  their bone marrowderived precursors in in vitro cultures. In addition,  significantly larger population size and more rapid  development of the lung CD4+Foxp3+ Treg cells characterize TB- resistant B6 mice compare to their TB-susceptible I/St counterparts.  Here, we report that adoptive transfer of DCreg cells into TB-infected I/St mice is capable to enlarge the population of Treg cells in the  lungs. This, in turn, attenuates lung pathology, decreases  mycobacterial multiplication and diminishes lung infiltration with  neutrophils, i.e., selectively restricts the population of cell largely  responsible for TB pathogenesis. The key difference in lung  pathology between DCreg recipients and control animals was the  lack of tissue-destructive foci and necrotic zones in the former  group. Meanwhile, the groups of mice did not differ in production of  regulatory (IL-10 and TGF-β) and key inflammatory (IFNγ and IL-6)  cytokines by lung cells. The latter result suggests that contact rather  than secretory mechanisms underlie moderate attenuation of  the TB process in the lungs of mice with an elevated lung Treg level,  given that plethora of such mechanisms were described for Treg  functioning. Although therapeutic effects were relatively weak, our  results indicate that cell therapy approaches are applicable to  regulation of lung tissue inflammation during TB course. 

Russian Journal of Infection and Immunity. 2018;8(2):169-174
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THE GROWTH RATE PHENOTYPIC PROPERTY OF MYCOBACTERIUM TUBERCULOSIS CLINICAL STRAINS: DEPENDENCE ON TUBERCULOSIS LOCALIZATION, TREATMENT, DRUG SUSCEPTIBILITY

Manicheva O.A., Dogonadze M.Z., Melnikova N.N., Vishnevskiy B.I., Manichev S.A.

Abstract

The phenotypic properties of the M. tuberculosis strains obtained from patients with pulmonary or extra-pulmonary tuberculosis are  determined by a complex set of factors: the genetic characteristics  of the pathogen, its ability to adapt in vivo and in vitro, the influence of the host’s immune system and chemotherapy. The growth rate as  the phenotypic property is the most accessible for the study of the  host-pathogen relationships at the level of host/strain population  interactions. The aim of the study is to assess in vitro of the growth  rate of M. tuberculosis strains isolated from patients with pulmonary  and extra-pulmonary tuberculosis: untreated and treated (with  surgical and non-surgical treatment) and also sensitive and resistant isolates in comparison with the reference strain H37Rv. To estimate  the growth rate of 116 clinical isolates we have used the modified  method originally developed by von Groll and co-authors: to get the  bacteria growth curve the fluorescence intensity of growing strains  (with indicator resazurin) has been measured daily for 8 days in 96- well plate. The growth rate is determined as the slope of the growth  curve. The mean values of the growth rate have been calculated in  the following groups of patients: 1 — untreated patients with  pulmonary tuberculosis (PT), respiratory material; 2 — non-surgical  treated PT patients, respiratory material; 3 — surgical treated PT  patients (mainly with chronic and hyperchronic process), respiratory  material; 4 — patients like in 3rd group, surgical material; 5 — bone  and joint tuberculosis (BJT), surgical material. In addition, groups of  sensitive and resistant strains have been examined, but there are no  significant differences in growth rates. It has been obtained that  the growth rate of strains isolated from the PT patients is higher than in BJT patients: it can be explained less favorable  conditions for the pathogen vegetation in the BJT. In the case of a  closed tuberculous lesion where the pathogen transmission to  another host is impossible, then the selection of strains with the  property to survive in the tissues of the osteoarticular system is  impossible too, therefor it should be observed only an adaptation of  the pathogen strain population to the individual host. The growth  rate of isolates from untreated PT patients is higher than that of the  treated ones. Comparison of the growth parameters of only MDR  strains 1–5 groups to eliminate the influence of the  sensitivity/resistance has resulted in the same conclusions. We  suggest that the decrease in the growth rate of strains from the  treated PT patients is in not only result of the treatment, but also is  conditioned by adaptation of the pathogen to its external  environment, which is the internal environment of the  macroorganism. To confirm this assumption, the bacterial load of  1,083 diagnostic specimens grouped in a similar manner has been  estimated, taking into account only MDR/XDR strains. In the group  of treated patients the frequency of high bacterial load (CFU ≥ 100)  reached 52.5–63.8% that shows the conserved fitness of bacteria in  such patients. The mean values of the growth rate of the strain  H37Rv non-adapted to the macroorganism (due to numerous  passages on artificial media) are higher than in all groups of clinical  strains. Thus, heterogeneity of phenotypic properties of M.  tuberculosis clinical strains on the basis of growth rate has been  obtained. The growth rate of M. tuberculosis clinical strains is  depended on the tuberculosis localization (PT, BJT) and on the joint  effect of patient treatment and pathogen adaptation to the host. 

Russian Journal of Infection and Immunity. 2018;8(2):175-186
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DYNAMICS OF IL-2 PLASMA LEVELS IN HIV PATIENTS WITH CONSIDERING DRUGS RESISTANCE

Eliseeva E.S., Kruglak S.P., Sklar L.F., Markelova E.V., Borovskaya N.A.

Abstract

Interleukin-2 (IL-2) is one of the most important cytokines involved in the regulation of innate and adaptive immunity. Its main  immunological function is to regulate a specific (antigen-dependent)  immune response by stimulating proliferation and differentiation of  immune cells involved in its realization, including Т-lymphocytes.  Dysfunction of cellular immunity is the main pathogenetic  mechanism for the development of HIV infection.

Objective: to  identify patterns of IL-2 levels change in HIV-infected patients on the background of drug resistance at the later stages of infection. The study included 83 patients with HIV infection receiving  highly active antiretroviral therapy; the control group  consisted of 20 healthy blood donors. All patients underwent a study  of the effectiveness of antiretroviral therapy, including an  assessment of HIV viral load and CD4+ Т lymphocyte levels. In  patients with ineffective antiretroviral therapy, a study of drug  resistance to HIV by Senger sequencing was additionally conducted.  According to the results of genome sequencing, HIV-infected  patients with ineffective antiretroviral therapy were divided into two  subgroups — with revealed drug resistance (58.5%) and absence of  detectable resistance mutations in the genome (41.5%). Levels of  IL-2 were measured in all persons included in the study by the  method of enzyme immunoassay. When comparing the levels of IL-2 between groups of patients with continuing viral load on the background of antiretroviral therapy (viral load is detected) with  drug resistance and without it, significant differences were obtained  (1.75±0.26 pg/ml versus 1.95±0.29 pg/ml, p ≤ 0.05, U-criterion,  respectively). The content of IL-2 is statistically significantly lower in  the group of patients who did not succeed with antiretroviral therapy than in the group of patients with treatment efficacy (1.83±0.29 pg/ml versus 4.89±0.55 pg/ml, respectively, p < 0.001, U-criterion). Thus, it is shown that in patients with revealed drug resistance  against the background of progression of HIV infection there is a  decrease in levels of IL-2. The increase in its levels in patients with  HIV infection who have reached virological and immunological  success of therapy is due to the reduction in the number of the cytokine-producing immune cells (T-lymphocytes). We assume that a significant decrease in the levels of IL-2 makes an additional  contribution to the disruption of the processes of proliferation and  differentiation of immunocompetent cells in HIV infection, which is of great importance in the formation of drug resistance of HIV in conditions of constant viral replication.

Russian Journal of Infection and Immunity. 2018;8(2):187-194
pages 187-194 views

PROTECTIVE ACTIVITY OF NOVEL BENZIMIDAZOLE DERIVATIVES AT EXPERIMENTAL INFLUENZA INFECTION

Zarubaev V.V., Vasilieva S.V., Esaulkova Y.L., Garshinina A.V., Veprintseva V.M., Galochkina A.V., Protsak Y.S., Teselkin I.V., Morkovnik A.S., Divaeva L.N., Lavrentieva I.N.

Abstract

Influenza is an acute respiratory viral infection, which represents an important health problem. Every year, influenza causes epidemics  and pandemics, leading to increase in morbidity and mortality in all  regions of the globe. Due to the segmental organization of the  genome and low accuracy of its replication, the influenza virus is  capable of escaping the host’s immune response (antigenic drift), as  well as the selection of drug-resistant variants. This calls for  constant monitoring of the sensitivity of viral isolates to antiviral  drugs and the development of new etiotropic antiviral agents that  have alternative targets and mechanisms of activity. The purpose of  this study was to characterize the new aminobenzimidazole  derivatives as protective agents in lethal influenza infection in white  mice. The efficacy of the compounds was assessed by their ability to  reduce specific mortality of animals in the course of lethal influenza  pneumonia caused by the influenza A/Puerto Rico/8/34 (H1N1)  irus, increase the life duration of animals, and normalize the  morphological structure of lung tissue comparing to the placebo  group. For all the compounds studied, a decrease in the specific  mortality of animals (from 20 to 60%) has been shown. The  reference drug (oseltamivir phosphate) reduced the mortality of  mice by 80%. The benzimidazole derivative 2519 demonstrated the  highest indices of protective activity, its use reduced the mortality of  animals by 60% and increased their mean day of death by 1.6 days in comparison with the control group. Morphological analysis showed that the activity of derivative 2519 was manifested in the  normalization of the morphological structure of lung tissue in the  course of influenza pneumonia. On day 5 after infection, the cells of  the bronchial epithelium looked intact, in contrast to destroyed cells  with numerous viral inclusions in control animals. The foci of  inflammation themselves occupied a smaller area compared to the  control. At the same time, there was no correlation between the  previously obtained data on the virus-inhibiting effect of these  compounds in vitro and the data obtained in animals. This suggests  that despite the presence of direct antiviral activity detected  previously in in vitro experiments, the protective properties of the  studied aminobenzimidazoles on animals are caused, in addition to  the etiotropic effect, by other pathogenetic factors. In conclusion,  amino derivatives of benzimidazole should be considered as  compounds that are promising for further development and  introduction as an anti-influenza agents. 

Russian Journal of Infection and Immunity. 2018;8(2):195-200
pages 195-200 views

REGULATORY INFLUENCE OF BLOOD MONOCYTES ON THE POPULATION COMPOSITION OF GRANULOCYTES AND THE STATE OF THEIR RESPIRATORY BURST IN THE WIDESPREAD PURULENT PERITONITIS

Savchenko A.A., Borisov A.G., Cherdancev D.V., Pervova O.V., Kudryavcev I.V., Belenyuk V.D.

Abstract

The aim of the study was to investigate the regulatory effect of monocytes and their subpopulations on the population composition  of granulocyte leukocytes and the state of their respiratory burst in  widespread purulent peritonitis (WPP). The study involved 24  patients aged 30-65 with acute surgical diseases and injuries of  abdominal organs complicated by WPP. As a control 25 relatively  healthy people of the same age range were examined. A study of the population composition of monocytes and granulocyte leukocytes in  blood was performed using a two-platform technology on the  hematological analyzer Sysmex XE-5000 (Sysmex Inc., USA) and  FC-500 flow cytometer (Beckman Coulter, USA) using the Cytodiff antibody kit (Beckman Coulter, USA). A study of the  monocytes number expressing HLA-DR- and CD64-receptor was performed by flow cytometry using direct immunofluorescence  of whole peripheral blood. The respiratory burst state of neutrophilic granulocytes was studied by chemiluminescence analysis on a 36-channel chemiluminescence analyzer BLM-3607 (MedBioTech, Russia). As indicators of chemiluminescence  were used luminol and lucigenin. The enhancement of  chemiluminescence induced by zymosan was evaluated by the ratio  of the area of the induced chemiluminescence to the spontaneous area and was defined as the activation index. It has  been established that the immune-inflammatory process in WPP is  characterized by a decrease in the number of classical monocytes in  the peripheral blood and an increase in the content of non-classical  monocytes. In WPP in peripheral blood the level of monocytes  expressing HLA-DR receptors decreases. The change in the ratio of  monocytes subpopulations characterizes the increase in the role of  the proinflammatory fraction in the WPP pathogenesis. Changes in  the population composition of granulocytes in the blood in patients  with WPP also characterize the development of an acute  inflammatory process. In this case, there is a decrease in the  number of basophils in the peripheral blood, which, apparently, is  determined by the presence of an allergic component in WPP and,  accordingly, their migration to the inflammation area. In patients  with WPP activation of a respiratory burst of granulocytes of blood  was detected, the intensity of which is determined by the synthesis  of primary and secondary active oxygen species. The results of the  correlation analysis made it possible to establish that in WPP the  regulatory role of non-classical monocytes increases aimed at  stimulating the inflammatory processes (an increase in the number  of mature and immature forms of neutrophils and stimulation of the activity of a respiratory explosion of granulocytes). The revealed features of the regulatory effect of monocytes on the population  composition and the intensity of the respiratory burst of granulocytes can be used in the development of immunotherapeutic methods aimed at reducing the activity of the inflammatory process in WPP.

Russian Journal of Infection and Immunity. 2018;8(2):201-210
pages 201-210 views

THE ROLE OF ARGININE DEIMINASE FROM STREPTOCOCCUS PYOGENES IN INHIBITION MACROPHAGES NITROGEN MONOXIDE (NO) SYNTHESIS

Starikova E.A., Sokolov A.V., Burova L.A., Golovin A.S., Lebedeva A.M., Vasilyev V.B., Freidlin I.S.

Abstract

The protective role of macrophages closely related to the production of bactericidal molecules, in which nitrogen monoxide (NO) play an  important role. Arginine serves as a substrate for inducible NO  synthase (iNOS) in course of NO production. Expression and activity  of iNOS are regulated by the availability of the substrate (arginine)  in the intercellular space. The bacterial enzyme arginine deiminase  also uses arginine as a substrate, causing its deficiency for host  cells. The aim of this study was to confirm the possible role of  arginine deiminase from S. pyogenes in inhibiting NO synthesis by  macrophages. For this purpose, a comparative study was made of  the effect on the synthesis of NO by macrophages of the products of  destruction of two strains: the initial S. pyogenes M49-16 and the  isogenic mutant S. pyogenes M49-16 delArcA with the inactivated  arginine deiminase gene (arcA). It has been shown that the ability of S. pyogenes M49-16 to inhibit production of NO by macrophages  depends on its arginine deiminase activity because the isogenous mutant of S. pyogenes M49-16 delArcA with the  inactivated gene arcA has lost its ability to inhibit NO synthesis. This allows us to consider the effects of S. pyogenes M49-16 as  effects of arginine deiminase. An analysis of the inhibitory mechanisms of the enzyme showed that suppression of NO synthesis was not associated with the effect of destruction products  of S. pyogenes M49-16 on the viability of macrophages. According to data of flow cytometry, incubation of cells in the presence of S.  pyogenes destruction products of the original and mutant strains did  not affect the level of iNOS expression, i.e. did not alter synthesis or  stability of this enzyme. At the same time, the decrease in NO  production under the influence of the original S. pyogenes strain  M49-16 correlated with a decrease in the content of arginine in the  culture medium. When exogenous arginine to the culture medium  was added, the effect of the original strain of the suppression of NO  production was declined. This confirms that the depletion of arginine  is the main mechanism of the inhibitory effect of arginine deiminase  on the production of NO by macrophages. The deficiency of NO  production in the course of streptococcal infection can lead to a  weakening of bactericidal activity of macrophages and to a decrease  in the effectiveness of antimicrobial protection.

Russian Journal of Infection and Immunity. 2018;8(2):211-218
pages 211-218 views

SHORT COMMUNICATIONS

BACTERIAL AND VIRAL PATHOGENS IN IXODES SP. TICKS IN ST. PETERSBURG AND LENINGRAD DISTRICT

Panferova Y.A., Suvorova M.A., Shapar A.O., Tokarevich N.K.

Abstract

Tick-borne infections are the most common group of zooanthroponotic diseases in the Northern Hemisphere. For the  Baltic Sea region and Fennoscandia, the dominant infectious pathologies transmitted by ticks are tick-borne borreliosis and tick- borne encephalitis. The presence of vast forested areas, actively  visited by people in St. Petersburg and the Leningrad region,  contributes to a rather high level of encroachment on the flares and  intelligence of the borreliosis and tick-borne encephalitis among the  population of these regions. The relatively dangerous pathogens that can be transmitted with the tick bite are also of particular danger:  Anaplasma sp., Ehrlichia sp., Coxiella burnetii, Rickettsia sp. In this  work, detection was performed using molecular genetic methods of  TBE virus, B. burgdorferi sensu lato and Rickettsia sp. in engorged  ticksple, as well as questing ticks collected from vegetation. The established levels of infection of TBE on infected ticks, levels of infection by pathogenic Borrelia of questing and engorgeded ticks  were approximately equal. Rickettsia was not found in the ticks. The  conducted analysis of the pathogens prevalence in comparison with  the data of russian and foreign authors. Monitoring the prevalence of tick-borne pathogens is an important issue in the prevention of tick- borne infections in the North-Western Russia. 

Russian Journal of Infection and Immunity. 2018;8(2):219-222
pages 219-222 views

DETERMINATION OF SOME IMMUNOLOGICAL FEATURES OF HHV-6-MEDIATED INFECTIOUS MONONUCLEOSIS IN CHILDREN BY THE METHOD OF DISCRIMINATORY ANALYSIS

Filatova E.N., Solntsev L.A., Presnyakova N.B., Kulova E.A., Utkin O.V.

Abstract

Human herpesvirus type 6 (HHV-6) is a lymphotropic virus that is an etiological agent of infectious mononucleosis (IM) in children. HHV-6- mediated infectious mononucleosis (HHV-6M) does not have clearly  defined clinical features. Nowadays immunopathogenetic aspects of  this disease have not been fully understood. The purpose of this  work was to study the characteristics of the quantitative composition  of populations of immunocompetent cells of peripheral  blood in children with HHV-6M. The material for the study was  samples of peripheral blood from children with “infectious  mononucleosis” diagnosis and from virtually healthy children.  Depending on the etiologic cause of the disease, children with IM  were divided into three groups: HHV-6M, IM of other etiology and  mixed infection (combination of HHV-6 and Epstein–Barr virus  and/or Cytomegalovirus). Virtually healthy children formed the  fourth group. In blood samples, the absolute content of the following populations of immunocompetent cells was determined by the  method of flow cytometry: the total population of T-lymphocytes, T- helpers, cytotoxic T-lymphocytes, double positive T-lymphocytes  (CD4+CD8+), NK cells and B-lymphocytes. Discriminant analysis  was carried out: based on the obtained data on the population  composition of blood cells we constructed a model of a child’s  attribution to one of the four groups analyzed in pairs. We used the  method of machine learning — the algorithm of gradient boosting  over decision trees. It was determined whether it is possible to  classify patients on the basis of the studied indicators and which  combination of indicators is optimal for classification. As a result of  the study it was possible to classify the following pairs of groups:  healthy children — children with HHV- 6M, healthy children —  children with IM of other etiology, children with HHV-6M — children  with IM of other etiology. When solving the problem of classifying  children from group with mixed infection and from any other group,  it was not possible to find a model of satisfactory quality. In  comparison with virtually healthy children, children with HHV-6M were characterized by an increased content of the total  population of T-lymphocytes and cytotoxic T-cells, as well as by a  reduced content of doub le-positive T-lymphocytes. Compared with  children with IM of other etiology, children with HHV-6M were  characterized by an increased content of cytotoxic T-lymphocytes, T- helpers, B-lymphocytes and a reduced number of double-positive T  cells. Our results indicate that HHV-6-mediated infectious  mononucleosis causes changes in the quantitative composition of  certain populations of immunocompetent cells of peripheral blood,  different from those of other etiology, in children.

Russian Journal of Infection and Immunity. 2018;8(2):223-229
pages 223-229 views

STUDY OF ELISA TEST-SYSTEMS OF DIFFERENT FORMATS FOR DETECTION OF MEASLES VIRUS SPECIFIC IgM IN DIFFERENT GEOGRAPHIC ZONES

Bichurina M.A., Zheleznova N.V., Lavrentieva I.N., Antipova A.Y., Kulyashova L.B., Totolian A.A.

Abstract

Detection of the measles virus (MV) specific IgM antibodies in blood serum of patients is considered to be the main standard for the  laboratory confirmation of measles diagnosis, the test being  acknowledged by WHO. As it was demonstrated earlier the specific  IgM antibodies as the marker of the acute MV infection were  detected in 97.2–100% of blood serum samples from patients using  the ELISA test-systems of the “capture” format (Microimmun Ltd.  and Vector Best). In case when the ELISA test-system of the  “indirect” format (Siemens, Germany) was used only 63.9% of these sera turned to be IgM positive. And on the contrary using the  “indirect” format ELISA test-system Euroimmun, Germany, for  detection of the MV specific IgM the false positive results were  obtained.

The aim of the study was the comparative evaluation of  the different format ELISA test-systems used for the detection of the  MV specific IgM antibodies in blood sera of patients and healthy  adults collected in different geographic zones.

Materials and  methods. In total 108 serum specimens collected in 2015–2017 were studied: from healthy adult Guineans, residents of the Republic of Guinea (RG); patients aged 1–70 with the initial  “infectious mononucleosis”, “infectious cytomegalovirus” and  “rubella” diagnosis and taken from the bank of sera in the  Subnational Measles/Rubella laboratory, StP Measles/Rubella RC in  NWFR. The MV specific IgM antibodies were detected using the commercial ELISA test-systems “VectoMeasles-IgM” (Vector-Best,  Russia) (“capture” format) and “Anti-Measles Virus ELISA IgM (NP)”  (Euroimmun Medizinische Labordiagnostik AG, Germany) («indirect»  format). The specific Epshtein-Barr Virus (EBV) IgM and IgG  antibodies were detected with the commercial ELISA test-systems «DS-ELISA-anti-EBV-VCA-M», «DS-ELISA-anti-EBV-EA-G» and «DS-ELISA-anti-EBV-NA-G» (“Diagnostic Systems”, Russia).

Results and discussion. The MV specific IgM antibodies were not revealed in the total of 108 blood serum samples from the healthy adults and patients, residents of the Russia and of the RG, with the “capture”  format “VectoMeasles-IgM” ELISA test-system. The absence of the  acute MV infection was also confirmed by the high measles immunity  level (i.e. IgG MV antibodies titers) as well as by detection of the IgG antibodies of high avidity. At the same time in 6  of 108 total sera (5.5%) IgM MV antibodies were detected with the «indirect» format ELISA test system Euroimmun, Germany. In these 6 sera the EBV specific antibodies were also evidenced. The results  obtained demonstrate the nonspecific reaction due to the possible  reactivity with anti-EBV antibodies. Besides this the different  percentage of the false positive reactions in sera from healthy  adults, residents of the RG and residents of Russia was determined  — 8.5±4.0% and 3.2±2.2% correspondently. Thus the preliminary  results, and to get the final results for general conclusions increase  of the total amount of the clinical specimens under studying is of extremely importance.

Russian Journal of Infection and Immunity. 2018;8(2):230-234
pages 230-234 views

GENETIC AND INFECTIOUS MARKERS OF INFERTILITY

Levkova E.A., Savin S.Z., Emelyanova E.B., Smirenina I.V.

Abstract

The report presents the results of own research of the most important factors in the genesis of various forms of sterility. A  married couples (n = 50) was examined with regard to possible  etiological structure of these forms of pathology — infections of the  family herpes (Herpes simplex types 1, 2, Cytomegalovirus hominis  (CMV), Epstein–Barr virus (EBV) and genetic distribution for the  second class of histocompatibilit (HLA II class): HLA-DRB1, HLA- DQA1 и HLA-DQB1. The authors present own data on genetic typing  of the couples for the second class of histocompatibility, which allow  to correlate these data with clinical and laboratory associations with  infectious agents (infections of the herpes family). The genetic  characteristics that determine the reproductive ability of the couple  are associated with susceptibility to certain infectious markers. It is  shown that the dominant majority of couples determined the HLA- DRB1 gene, which is more frequently associated with infections of  the herpes family. Despite the fact that the level of positive PCR results in the group of couples with primary infertility was  higher than in couples with secondary sterility (100 and 92%, respectively), maximum titers of specific antibodies to  infections of the herpes family, including the frequency of markers of exacerbation, definition of IgM was higher than in the group of  couples with primary infertility, and significantly higher than in  couples with normal fertility. So, this antigen histocompatibility  (HLA-DRB1) is associated with significant frequency of sterility,  especially the secondary one, and infectious contamination infections  of the family of herpes — HSV 1, 2 types, CMV, EBV in the study group — couples with secondary infertility. Marker HLA-DRB1,  the most frequent in coup les with infertility, including idiopathic,  associated in this group not only with significant contamination of  infectious of the herpes family, but the presence of a chronic  infectious process at the stage of reactivation. Conducted clinical and  immunological studies clearly demonstrate the need for  a comprehensive survey of women with disabilities in the system of  immunogenesis with the mandatory assessment of the level of  infectious (viral) contamination. Analysis of the results of their  clinical and immunological studies allows us to propose an algorithm  of complex examination in functional disorders in the system of  immunogenesis, including the study of viral load as a necessary  component.

Russian Journal of Infection and Immunity. 2018;8(2):235-240
pages 235-240 views

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