Vol 6, No 1 (2016)

REVIEW

COXIELLA BURNETII PATHOGENICITY MOLECULAR BASIS

Panferova Y.A.

Abstract

Coxiella burnetii is an obligate intracellular gram-negative bacterial pathogen, an ethiological agent of Q-fever, a zoonotic disease, elapsing as an acute (mostly atypical pneumonia) or a chronic (mostly endocarditis) form. The host range is represented by wide range of mammal, avian and arthropod species, but the main source of human infection are farm animals. The main route of infection is aerosolic. In case of contact with organism pathogen binds with phagocytal monocytic-macrophagal cell line. C. burnetii promotes maturation of specific phagolysosome-like compartment in host cell, called coxiella-containing vacuole, within this vacuole pathogen becames metabolically activated and actively replicates. Coxiella persists as metabolically inactive spore-like form in environment. Internalisation of C. burnetii occurs using actin-mediated phagocytosis and zipper mechanism. After internalization of bacteria maturation of phagolysosome-like compartment and large coxiella-containing vacuole formation occure, and vacuole can occupy nearly the whole cytoplasm of the host cell. Survivance of infected cells is important for chronic infection with C. burnetii. C. burnetii elongate the viability of host cell by two ways: it actively inhibits apoptotic signal cascades and induce pro-survival factors. Except
that C. burnetii involves autophagic pathway during coxiella-containing vacuole formation, and induction of autophagy promotes pathogen replication. During infection C. burnetii translocates effector substrates from bacterial cytosole to euca ryotic host cell cytosole using type IV secretion system, where effectors modulate host cell proteins. Overall approximately 130 secreted effectors of type IV transport system, but function of most of them remains unknown to date. Specific sec reted proteins for variety of strains and isolates were identified, confirmed that certain pathotypes of C. burnetii can exist. Identification and characterization of novel virulence factors it is now possible through axenic media for C. burnetii cultivation and development of site-specific mutagenesis and other genetic technics, which is important for research of C. burnetii molecular pathogenesis.

Russian Journal of Infection and Immunity. 2016;6(1):7-24
pages 7-24 views

ACTUAL TICK-BORNE INFECTIONS IN CRIMEA

Gorovenko M.V., Karimov I.Z.

Abstract

The Crimean Peninsula is located in the Northern part of the Black sea, from the East it is washed by the Sea of Azov, to the South and West by the Black Sea. The unique geographical and climatic conditions facilitate leptospirosis, tularemia, tick-borne encephalitis, Lyme disease, intestinal yersiniosis, pseudotuberculosis, hemorrhagic fever with renal syndrome, Crimean-Congo hemorrhagic fever, Mediterranean fever, Q-fever and other infectious diseases natural foci formation on the territory of Crimea Republic. Tick-borne natural focal infections have the most significance due to favorable epidemiologic conditions especially on the background of high raid ticks attacks on people. A leading role in the epizootology and epidemiology of tick-borne natural-focal infections of the Crimea are playing Ixodidae that occur in different landscape-climatic zones, with the greatest their species diversity is observed in mountain-foothill, forest and forest-steppe regions. There are about 30 species in Ixodidae fauna of the Crimean Peninsula. Ticks species composition identification shows that over 50% of people attacks episodes in the Crimea on recent years is caused by Ixodes ricinus ticks species, the remaining are associated with Haemophisalis punctata, Rhipicephalus sanguineus, Hyalomma marginatum, Dermacentor marginatus and other. Refusal of treatment in medical institutions of the people affected by tick bites, and the possibility of an attack on people subtle phases of mites are lubricates the real picture of the frequency of contacts of the population with ticks and complicates the forecasting of the epidemiological situation. This review summarizes the available information about spreading of tick-borne encephalitis, Lyme disease, Mediterranean and Crimean-Congo haemorrhagic fevers on the territory of Crimea Republic and demonstrates the modern trends and manifestations of epidemic process of these nosological forms. The results obtained in the analysis of our investigations and literature data, showed that the conditions of globalization lead to an increase in the frequency of contacts of the population with natural foci, and one of the most common tick-borne natural focal infections on the territory of the Peninsula are Lyme disease and the Mediterranean fever. Epidemiological analysis of the prevalence of tick-borne encephalitis and Crimean-Congo haemorrhagic fever in Crimea revealed a decrease in the activity of natural foci of these infections at the present stage. The problem of tick-borne natural focal infections in Crimea Republic requires further careful study.

Russian Journal of Infection and Immunity. 2016;6(1):25-32
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ORIGINAL ARTICLES

LYMPHOCYTE SUBSETS AND CYTOKINES IN BLOOD AND CEREBROSPINAL FLUID IN CHILDREN WITH VIRAL AND BACTERIAL MENINGITIS

Alekseeva L.A., Zheleznikova G.F., Zhirkov A.A., Skripchenko N.V., Vilnits A.A., Monakhova N.E., Bessonova T.V.

Abstract

Introduction of flow cytometry caused an increase in the investigation of liquor lymphocyte pool phenotype in the case of different brain disorders, including viral and bacterial meningitis, however this type of research in children has been relatively rare. Phenotype and lymphocyte functions are under cytokine control system, therefore detection of interconnections between lymphocyte pool subpopulation composition and cytokine level in blood and liquor of the patients concerns a great interest. The purpose of this research was to study lymphocyte subpopulation composition and the level of cytokines IL-1β, IL-6, IL-8, IL-10, IFNα, IFNγ and IL-4, and also IgG in liquor and blood of children with viral and bacterial meningitis. There was performed blood and liquor investigation in 46 children aged from 1 to 16 years old with viral (n = 35) and bacterial (n = 11) meningitis. Immunophenotyping of blood and liquor cells was performed by the method of flow cytometry with the use of monoclonal antibodies to CD3, CD4, CD8, CD19, CD16, CD56, CD25 and CD95. The content of cytokines was detected in ELISA, and that of IgG — by the method of quantitative immunoturbodimetry. During an acute period of viral meningitis there was detected a decrease in NK portion and activated CD25+ cells in the blood of patients accompanied by the increase in B-lymphocytes number, along with cytokine IFNγ, IL-8 and IL-10 serum level rise. There was determined T-lymphocytes accumulation in liquor with the prevalence of CD4+ Т-cells and, to a lesser degree, CD25+ and CD95+ cells, NK and B-lymphocytes. Intrathecally there was noted the predominance of IL-6 response accompanied by the growth of IL-8 and IL-10 concentration as well. During an acute period of bacterial meningitis there was noted a decrease in percentage of CD3+, CD4+, CD8+ Т-lymphocytes, NK, CD25+ and CD95+ cells, along with, on the contrary, sharp increase in B-cells pool, simultaneously with an expressed system response of IL-8 and IL-10. Liquor T-lymphocyte content was relatively correlated with blood indicators whereas the fraction of NK exceeded it, and B-lymphocyte content was 3–4 times higher than in patients with viral meningitis. There was IL-6, IL-10, IFNγ and IL-4 response intrathecally, and 10-multiply-growth of IgG level. Thus, the redistribution of lymphocyte subpopulations, and system and local cytokine response in children with meningitis have both common and special features depending on the aetiology and severity of disease. Phenotyping of lymphocytes and determination of both cytokines and immunoglobulins simultaneously in two biologic fluid allow to clear up the pathogenetic value of immunologic abnormalities in blood and cerebrospinal fluid of the patients in the aspect of interactions between cell and humoral factors of system and local immune response in neuroinfections of various aetiology.

Russian Journal of Infection and Immunity. 2016;6(1):33-44
pages 33-44 views

INTERLEUKIN 1 AND INTERLEUKIN 4 GENES POLYMORPHISM ASSOCIATED WITH EARLY AND PRESCHOOL AGE CHILDREN SENSITIZATION TO STREPTOCOCCUS PYOGENES

Shabaldin A.V., Shabaldina E.V., Ryazantsev S.V., Simbirtsev A.S.

Abstract

Background. Streptococcus pyogenes infection and sensitization to its antigens is considered to be an unfavorable factor for the induction of rheumatic pathology. The search for genetic predictors of rheumatic diseases in general, and sensitization to S. pyogenes, in particular, is of high relevance in modern medicine.

Objective. To study the associations between interleukin 1 and interleukin 4 gene polymorphisms and the development of sensitization to antigens of S. pyogenes in toddlers and preschool children.

Materials and methods. 771 children aged 2–6 years with recurrent acute respiratory tract infections treated by allergist-immunologist and otorhinolaryngologist were included in the study. Antibodies against S. pyogenes were determined by ELISA using commercial kits “Immunoteks” (Stavropol, Russia) in all children. Children with IgG immune response to S. pyogenes were assigned to the study group (n = 306), whereas children without this response were assigned to the control group (n = 465). Both groups underwent gene typing of IL1B (+3953, C→T, rs 114634), IL1Ra (VNTR, intron 2, 89 bp) and IL4 (VNTR intron 3, 70 bp) gene polymorphisms in the Laboratory for Pharmacogenomics, ICBFM SB RAS. The data were processed using routine statistical methods for genetic analysis and the statistical software package Statistica 6.0. There were no deviations from Hardy–Weinberg equilibrium across all loci, suggesting validity of association studies between individual and combined genotypes and sensitization to antigens of S. pyogenes.

Results. Positive association between sensitization to antigens of S. pyogenes and individual genotypes have been found: IL1B (+3953, C→T)*C,T (52.6% in the study group vs. 39.8% in the control group, p = 0.001; OR = 2.02; CI(99%) 0.47–5.93), IL1Ra (VNTR, intron 2, 89 bp)*2r,5r (7.19% in the study group vs. 1.29% in the control group, p = 0.001; OR = 5.59; CI(99%) 1.58–19.77), IL4 (VNTR intron 3, 70 bp)*2r,2r (6.86% in the study group vs 3.01% in the control group, p = 0.05; OR = 2.34; CI(99%) 0.66–8.29); as well as for combined genotypes: IL1B (+3953, C→T)*C,C / IL1Ra (VNTR, intron 2, 89 bp)*2r,4r / IL4 (VNTR intron 3, 70 bp)*2r,2r (OR = 46.15); IL1B (+3953, C→T)*T,T / I-1Ra (VNTR, intron 2, 89 bp)*4r,4r / IL4 (VNTR intron 3, 70 bp)*2r,3r (OR = 8.82) and IL1B (+3953, C→T)*C,T / IL1Ra (VNTR, intron 2, 89 bp)*2r,2r / IL4 (VNTR intron 3, 70 bp)*3r,3r (OR = 7.23). Conclusion. High odds ratio (OR = 46.15) for IL1B (+3953, C→T)*C,C / IL1Ra (VNTR, intron 2, 89 bp)*2r,4r / IL4 (VNTR intron 3, 70 bp)*2r,2r suggests that combined genotype is a main marker of sensitivity and impaired immune tolerance to S. pyogenes in toddlers and preschool children. Thus, this study has confirmed the association between gene polymorphisms, and pro-inflammatory and proallergic cytokines, and autoimmune and allergic diseases.

Russian Journal of Infection and Immunity. 2016;6(1):45-54
pages 45-54 views

VIRUS-SPECIFIC HUMORAL IMMUNE RESPONSE ISOTYPIC STRUCTURE IN ADULT PATIENTS HOSPITALIZED WITH INFLUENZA A

Krivitskaya V.Z., Vasilieva A.A., Voytsekhovskaya E.M., Petrova E.R., Pisareva M.M., Buzitskaya Z.V., Elpaeva E.A., Go A.A., Voloshchuk L.V., Lvov N.I., Smirnova T.D., Sominina A.A.

Abstract

The aim of this investigation was a comparative analysis of isotypic structure of specific antiviral systemic humoral immune response in hospitalized patients with influenza caused by virus A(H3N2) or A(H1N1), including the A(H1N1)pdm09. Paired acute and convalescent phase sera from 109 adult patients aged 18 to 67 years with laboratoryconfirmed influenza A were analyzed by ELISA. Purified surface glycoproteins of influenza A viruses of different subtypes containing the hemagglutinin and neuraminidase were used as antigen for sensitization of plates in ELISA.The absence of type-specific conserved internal proteins in antigenic material allowed to carry out a subtype-specific differentiation of antibodies against influenza viruses in ELISA. Regardless of the subtype of influenza A viruses caused the disease, the most pronounced response was observed by subtype-specific IgG1 (70–90% of seroconversions). It has been shown for the first time that low activity of virus-induced IgG2 (6–9% of seroconversions) is a peculiarity of the immune response both to primary or recurrent infections with A(H1N1)pdm09. In patients repeatedly suffered by «seasonal» influenza A(H1N1) in 2007/2008 or influenza A(H3N2) in 2012–2014 IgG2 seroconversion’s rates were 40–59% (р < 0,05). Reaction virusspecific IgG3 was also weaker in patients with influenza A(H1N1)pdm09 (29–44% of seroconversions) than in subjects with influenza A(H1N1) or A(H3N2) (65% and 56% of seroconversions, respectively). Geometric mean titers of virus neutralizing antibodies identified during recovery phase in patients with primary and secondary influenza A(H1N1)pdm09 (1/28 and 1/103, respectively) were significantly lower than in patients recovered from influenza A(H1N1) or A(H3N2) (GMT were 1/594 and 1/378, respectively). It was shown that the surface glycoproteins of influenza A viruses may be an allergens. Virus-specific IgE seroconversion rates were comparable in all groups reaching 25–45%. The high activity of virus-induced serum IgA was detected in patients with influenza A(H3N2) or A(H1N1)pdm09 (60–79% of seroconversions). Thus, study of virus-specific activity of various immunoglobulin isotypes provides important information about the formation of adaptive antiviral immune response to influenza A viruses, and also estimate the contribution of its protective and immunopathogenic components to pathogenesis of the disease.

Russian Journal of Infection and Immunity. 2016;6(1):55-66
pages 55-66 views

DIAGNOSTICS ISSUES OF CHLAMYDOPHILA PNEUMONIAE INFECTION IN PATIENTS WITH ACUTE CORONARY SYNDROME

Tarasov A.V., Kuliashova L.B., Zheltakova I.R., Khirmanov V.N., Drygina L.B.

Abstract

Chlamydophila pneumoniae is nadotrophic to endothelial, smooth muscle cells of blood vessels. Proven ability of the pathogen to initiate atherosclerosis and exacerbate it. The incidence of acute C. pneumoniae infection is higher in patients with acute coronary syndrome than in patients with chronic ischemic heart disease according to the published papers. The aim of the research was the diagnostics of C. pneumoniae infection in patients with acute coronary syndrome by two methods based on different principles. A total of 20 patients admitted to hospital with a preliminary acute coronary syndrome diagnosis. During the first hospital hours of stay based on complaints, medical history, physical examination, results of laboratory and instrumental examination those patients were diagnosed as unstable angina (n = 10) or nontransmural myocardial infarction (n = 10). According to treatment standart all patients underwent coronary angiography and angioplasty. Furthermore, these patients fulfilled fence of the clinical material as mucosal scrapings nasal passages and posterior wall of the oropharynx applied on glass slides. Also, there were samples of arterial blood smears, obtained from the conductors installed in the locations pointed to implement the coronary arteries and angioplasty. These samples were examined by indirect immunofluorescence with the form of specific monoclonal antibodies against the cell wall major outer membrane protein of C. pneumoniae. Serum was used for immunoassay to quantify classes A and G immunoglobulins against C. pneumoniae. When comparing the results of two diagnostics methods of C. pneumoniae chronic infection, it was diagnosed in 5 of the 20 patients studied. One patient was with unstable angina and 4 were with nontransmural myocardial infarction. The presence of acute infection C. pneumoniae has been proven in 9 of 20 patients, including 4 patients with unstable angina and 5 with nontransmural myocardial infarction. Also found that patients with acute coronary syndrome, the infection can occur both by seropositive and seronegative types. Thus, acute coronary syndrome may be associated with chronic or acute infection of C. pneumoniae. The relevance of further study of the infection in patients with atherosclerosis was confirmed once again.

Russian Journal of Infection and Immunity. 2016;6(1):67-72
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CLINICAL AND EPIDEMIOLOGICAL FACTORS DETERMINING PROPAGATION AND CLINIC OF UROGENITAL TRICHOMONIASIS IN WOMEN

Akyshbayeva K.S., Nurusheva S.M., Almenova L.T.

Abstract

The problem of urogenital trichomoniasis (UGT) is relevant not only due to its high prevalence and multiple organ lesions, but also to the ability to have a negative impact on reproductive health. In Kazakhstan, UGT is one of the leading infections in the structure of sexually transmitted infections: in 2011 51.5%; 2012 — 43.5%; 2013 — 42.0% with the prevalence of co-infection with other STIs, in which the rate of complications is increased by 2 times and are more profound with the involvement of inflammation in the upper urogenital tract. The recorded incidence of trichomoniasis in the RK is characterized by annual rate decrease (since 2011 a 1.5 times decrease) due to small fluctuations of syphilis, gonorrhea, chlamydia morbidity which indicates a large reservoir of latent infection, and low level of diagnostics. Most clearly demonstrates this situation an incidence of UGT in 2 cities: so in Astana in 2013, the recorded incidence decreased by 2.8 times compared to 2011; in Almaty — 6 times in 2012 and 4.3 times in 2013. Conducted clinical and epidemiological analysis of UGT morbidity in women allowed to identify the following: in recent years the tendency of UGT to growth with a significant proportion of latent asymptomatic forms (for more than one quarter of patients with UGT, UGT is most common in young adults, average age 30.5±2.5 years); in half of the cases recorded, mixed trichomonas infection, mostly in combination with Chlamydia, which causes a high incidence of complications of the upper urogenital tract; there is a high frequency of trichomonas infection combination with infections caused by Candida, mycoplasma, which determines the prospects of the combination therapy UGT in combination with drugs, correcting immunodeficiency. There is quite a high incidence of gynecological pathology, the severity of which depends on the frequency of the spectrum of pathogens that are associated with T. vaginalis. The data obtained allows to select women with trichomonas infection of the urogenital tract with the complication risk that affect the reproductive function; UGT develops together with urogenital tract disbacteriosis with a predominance of Staphylococcus species, having adhesive, lizotsimogenic, hemolytic activity that must be considered when conducting a combined therapy with drugs, correcting microflora. The frequency of various complications was significantly higher in patients with mixed infection. Particular attention is drawn to the attention of the high frequency of adnexitis, uterine fibroids, their rate was equivalent to and higher than the corresponding figures of 1.9 times and 5 times, respectively (38.0% versus 20.0% and 7.8%, p < 0,05) at monoinfection. In this group of ovarian cyst recorded in 10.1% of cases. Basically, the above-mentioned diseases were observed in patients with trichomonas, chlamydial infection. Adnexitis and uterine fibroids in all 30 cases were recorded in patients co-infected with this that has made 75,0±6,8%. Our findings are consistent with studies of high risk of pelvic inflammatory disease in women with trichomoniasis. Other studies have reported increases of 1.9 times the risk of tubal infertility in women with trichomoniasis. Trichomoniasis can also play a role in cervical neoplasia and postoperative infections.

Russian Journal of Infection and Immunity. 2016;6(1):73-80
pages 73-80 views

SHORT COMMUNICATIONS

HIV INFECTION STAGE, ANTIRETROVIRAL THERAPY SCHEME AND PATIENT IMMUNE STATUS INFLUENCE ON HIV/TB CO-INFECTION OUTCOME

Mordyk A.V., Sitnikova S.V., Puzyreva L.V.

Abstract

Retrospective research of 381 clinical records is conducted to study HIV infection influence on stationary stage of tuberculosis treatment outcome in HIV-TB co-infected patients. All cases were divided depending on a hospitalization outcome on favorable and adverse. At most of patients tuberculosis of respiratory organs met. Immunological researches were conducted, the stage of HIV infection was registered and the issue of purpose of anti-retroviral therapy was resolved. Besides, as indirect signs of an immunodeficiency at the patients with a combination of tuberculosis and HIV infection who were on hospitalization the indicators received when carrying out clinical laboratory trials were analyzed: absolute and relative quantity of lymphocytes according to the general blood test, the contents the globulin fractions and circulating immune complexes concentration according to the clinical chemistry blood test. At an assessment of results in both groups of research more than at a half of patients existence of HIV infection at late stages that speaks about late identification and neglect of an immunodeficiency was revealed. At patients with tuberculosis of lungs in combination with HIV infection at a failure statistically significant decrease in an immunoregulatory index is revealed. It is interesting that the level of CD4 lymphocytes and a stage of HIV infection had no impact on the co-infection’s outcome. However, existence of virus loa ding more than 100 000 copies/ml reduced probability favorable an outcome of treatment of tuberculosis at the patient with HIV infection. Timely purpose of anti-retroviral therapy at patients with co-infection increased chances of treatment of tuberculosis at patients with an immunodeficiency. Frequency of adverse side effect of antiviral therapy met equally often at patients in both groups. Thus, patients at any stages of HIV infection with any forms of tuberculosis, including generalized, had a chance to have a favorable outcome of a disease. We consider the reasonable recommendation about carrying out anti-retroviral therapy of patients by all with a combination of tuberculosis and HIV infection, irrespective of the HIV infection stage.

Russian Journal of Infection and Immunity. 2016;6(1):81-86
pages 81-86 views

LIVING MICROORGANISM’S STABILYZATION IN BIOMASS BIOTECHNOLOGY AND PLAGUE VACCINE PREPARATION

Budika D.A., Abzaeva N.V., Gostischeva S.E., Rakitina E.L., Ivanova G.F., Fisun A.A.

Abstract

Over the years, the production release of the plague vaccine is well developed its technology. The technological cycle of production of the preparation consists of regulated steps, however, despite their effectiveness it is necessary to modernize the manufactoring process, for example, solutions for some of the pressing needs of the customers, in particular, small groups of immunization. Our research has focused on obtaining experimental samples plague vaccine smaller compared to the commercial vaccine, the number of doses per vial prepared in a biomass production unit (ACM-Sh) surface by cultivation using all regulated processing steps, except step of combining content two swabs, and then an additional 
dilution of the cell suspension stabilizer. However, the time information and the subsequent preparation of such a vaccine is excluded us, since biomass is the second flush in quantitative terms is a ready raw material for the preparation of reduced dosage. The benefits of receiving the vaccine reduced the number of doses directly from the biomass of the second flush with the concentration of microbial cells Yersinia pestis EV 20–40 × 109 biotechnology greatly simplify the manufacture of such a preparation. The experimental vaccine series were tested by major regulated parameters: optical concentration, vitality, thermal stability, the loss on drying. In addition, the vaccine was prefabricated with high baseline viability to extreme temperatures (37±1)°C for 24 hours to exclude enough viable microbial cells for subsequent stabilization indicator of viability during storage. It should be noted that all the experimental samples preserved viability index not lower regulated (25%) during the experiment, in contrast to the commercial preparation. To determine the stability of the formulation during storage (over 3 years) was a comparative analysis of the viability of the experimental and commercial lots. To assess post vaccination immune analyzed the immune response to the introduction of a plague vaccine using FACSCalibur flow cytometer, considering that this technology has a high specificity, sensitivity and informativity. With regard to the immunogenic properties, the active component is recorded at a very high level as the white mice, and guinea pigs. Thus, the main biological indicators derived preparations (viability, thermal stability, storage stability) exceed those of commercial analog and provide effective immunological alterations and highly immunogenic in experimental animals.

Russian Journal of Infection and Immunity. 2016;6(1):87-92
pages 87-92 views

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