Central Institute for Tuberculosis

Skolkovo, Russia

Central Institute for Tuberculosis

Skolkovo, Russia

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Ignatov D.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry | Malakho S.,Moscow State University | Majorov K.,Central Institute for Tuberculosis | Skvortsov T.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry | And 2 more authors.
PLoS ONE | Year: 2013

Deep sequencing was implemented to study the transcriptional landscape of Mycobacterium avium. High-resolution transcriptome analysis identified the transcription start points for 652 genes. One third of these genes represented leaderless transcripts, whereas the rest of the transcripts had 5′ UTRs with the mean length of 83 nt. In addition, the 5′ UTRs of 6 genes contained SAM-IV and Ykok types of riboswitches. 87 antisense RNAs and 10 intergenic small RNAs were mapped. 6 intergenic small RNAs, including 4.5S RNA and rnpB, were transcribed at extremely high levels. Although several intergenic sRNAs are conserved in M. avium and M. tuberculosis, both of these species have unique intergenic sRNAs. Moreover, we demonstrated that even conserved small RNAs are regulated differently in these species. Different sets of intergenic sRNAs may underlie differences in physiology between conditionally pathogenic M. avium and highly specialized pathogen M. tuberculosis. © 2013 Ignatov et al.


Kondratieva T.,Central Institute for Tuberculosis | Azhikina T.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry | Nikonenko B.,Central Institute for Tuberculosis | Kaprelyants A.,Institute of Biochemistry | Apt A.,Central Institute for Tuberculosis
Tuberculosis | Year: 2014

About 90% of all cases of tuberculosis (TB) infection are comprised of latent mycobacterial persistence in the absence of clinical manifestations. In a proportion of latently infected individuals infection eventually reactivates and becomes contagious, seriously influencing epidemiological situation. Mechanisms of Mycobacterium tuberculosis transition to dormancy and TB reactivation are poorly understood, and biological markers of latency remain largely unknown. Data are accumulating that the dynamical equilibrium between the parasite and the host (expressed as a long term asymptomatic infection) and its abrogation (expressed as a reactivation disease) are genetically controlled by both parties. In this short review, the authors summarize the results of experimental studies on genetic regulation of the latent TB infection. © 2014 Elsevier Ltd. All rights reserved.


Kapina M.A.,Central Institute for Tuberculosis | Rubakova E.I.,Central Institute for Tuberculosis | Majorov K.B.,Central Institute for Tuberculosis | Logunova N.N.,Central Institute for Tuberculosis | Apt A.S.,Central Institute for Tuberculosis
PLoS ONE | Year: 2013

The balance between activation and inhibition of local immune responses in affected tissues during prolonged chronic infections is important for host protection. There is ample evidence that regulatory, tolerogenic dendritic cells (DC) are developed and present in tissues and inhibit overwhelming inflammatory reactions. Also, it was firmly established that stromal microenvironment of many organs is able to induce development of immature regulatory DC (DCreg), an essential element of a general immune regulatory network. However, direct experimental data demonstrating inhibition of immune responses by stroma-instructed immature DCreg in infectious models are scarce, and virtually nothing is known about functioning of this axis of immunity during tuberculosis (TB) infection. In this study, we demonstrate that lung stromal cells are capable of supporting the development in culture of immature CD11b+CD11clowCD103- DCreg from lineage-negative (lin-) bone marrow precursors. DCreg developed on lung stroma isolated from mice of genetically TB-hyper-susceptible I/St and relatively resistant B6 inbred strains inhibited proliferative response of mycobacteria-specific CD4+ T-cell lines a dose-dependent manner. Importantly, the inhibitory activity of B6 DCreg was substantially higher than that of I/St Dcreg. Moreover, when the donors of stromal cells were chronically infected with virulent mycobacteria, the capacity to instruct inhibitory DCreg was retained in B6, but further diminished in I/St stromal cells. DCreg-provided suppression was mediated by a few soluble mediators, including PGE2, NO and IL-10. The content of CD4+Foxp3+ Treg cells in the mediastinal, lung-draining lymph nodes at the advanced stages of chronic infection did not change in I/St, but increased 2-fold in B6 mice, and lung pathology was much more pronounced in the former mice. Taken together, these data provide genetic evidence that the capacity to maintain populations of regulatory cells during M. tuberculosis infection is a part of the host protective strategy. © 2013 Kapina et al.


Yeremeev V.,Central Institute for Tuberculosis | Linge I.,Central Institute for Tuberculosis | Kondratieva T.,Central Institute for Tuberculosis | Apt A.,Central Institute for Tuberculosis
Tuberculosis | Year: 2015

Abstract Summary Mice of the I/St inbred strain genetically hyper-susceptible to TB infection and prone to form neutrophil-abundant necrotic lung lesions and relatively resistant mice of the C57BL/6 (B6) strain were infected with 100 CFU of M. tuberculosis H37Rv. To verify the role of neutrophils in TB immunity, we selectively depleted neutrophils from infected mice with highly specific 1A8 anti-Ly6G antibodies at day 2 and 6 post-challenge. Depletion of neutrophils resulted in reduced lung tissue pathology, mycobacterial CFU counts and an increase of the survival time in genetically susceptible I/St, but not in B6 mice. Furthermore, we demonstrated that in vivo neutrophil depletion at the onset of TB infection results in a significant increase in numbers of mycobacteria-specific IFN-γ-producing T-cells at the time point when the acquired immunity to mycobacteria is fully developed. These results suggest antagonistic activity of neutrophils and immune T-cells in the course of TB infection and provide further evidence of deleterious rather than protective role of the former. © 2015 Elsevier Ltd.


Shleeva M.,RAS A.N. Bach Institute of Biochemistry | Kondratieva T.,Central Institute for Tuberculosis | Rubakova E.,Central Institute for Tuberculosis | Vostroknutova G.,RAS A.N. Bach Institute of Biochemistry | And 2 more authors.
Microbial Pathogenesis | Year: 2015

Three stocks of Mycobacterium tuberculosis H37Rv were cultured invitro under prolonged hypoxic or acidified conditions until partial or complete loss of the capacity to form colonies on agar medium was achieved. Such dormant "non-culturable" mycobacteria were assessed for the growth resuscitation after intra-tracheal injection into mice of the two inbred strains with different genetic susceptibility to M.tuberculosis-triggered disease: hyper-susceptible I/St and relatively resistant B6. The results indicate that bacteria which are able to resuscitate spontaneously in liquid medium invitro started to multiply in organs of infected mice, and that the outcome of such infection strongly depended upon the level of genetic TB susceptibility. However, dormant bacteria required inducers for resuscitation invitro lost the capacity to multiply even in genetically susceptible mice. The established model of dormancy/reactivation is suitable for the studying host-pathogen interactions and testing vaccine and drug candidates specifically targeting latent TB. © 2014 Elsevier Ltd.


Logunova N.,Central Institute for Tuberculosis | Korotetskaya M.,Central Institute for Tuberculosis | Polshakov V.,Moscow State University | Apt A.,Moscow State University
PLoS Genetics | Year: 2015

The level of susceptibility to tuberculosis (TB) infection depends upon allelic variations in numerous interacting genes. In our mouse model system, the whole-genome quantitative trait loci (QTLs) scan revealed three QTLs involved in TB control on chromosomes 3, 9, and in the vicinity of the H2 complex on chromosome 17. For the present study, we have established a panel of new congenic, MHC-recombinant mouse strains bearing differential small segments of chromosome 17 transferred from the TB-susceptible I/St (H2j) strain onto the genetic background of TB-resistant C57BL/6 (B6) mice (H2b). This allowed narrowing the QTL interval to 17Ch: 33, 77–34, 34 Mb, containing 36 protein-encoding genes. Cloning and sequencing of the H2jallelic variants of these genes demonstrated profound polymorphic variations compare to the H2bhaplotype. In two recombinant strains, B6.I-249.1.15.100 and B6.I-249.1.15.139, recombination breakpoints occurred in different sites of the H2-Aβ 1 gene (beta-chain of the Class II heterodimer H2-A), providing polymorphic variations in the domain β1 of the Aβ-chain. These variations were sufficient to produce different TB-relevant phenotypes: the more susceptible B6.I-249.1.15.100 strain demonstrated shorter survival time, more rapid body weight loss, higher mycobacterial loads in the lungs and more severe lung histopathology compared to the more resistant B6.I-249.1.15.139 strain. CD4+T cells recognized mycobacterial antigens exclusively in the context of the H2-A Class II molecule, and the level of IFN-γ-producing CD4+T cells in the lungs was significantly higher in the resistant strain. Thus, we directly demonstrated for the first time that the classical H2- Ab1 Class II gene is involved in TB control. Molecular modeling of the H2-Ajproduct predicts that amino acid (AA) substitutions in the Aβ-chain modify the motif of the peptide–MHC binding groove. Moreover, unique AA substitutions in both α- and β-chains of the H2-Ajmolecule might affect its interactions with the T-cell receptor (TCR). © 2015 Logunova et al.


Knaul J.K.,Max Planck Institute for Infection Biology | Jorg S.,Max Planck Institute for Infection Biology | Oberbeck-Mueller D.,Max Planck Institute for Infection Biology | Heinemann E.,Max Planck Institute for Infection Biology | And 6 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: Myeloid cells encompass distinct populations with unique functions during homeostasis and disease. Recently, a novel subset of innate cells, myeloid-derived suppressor cells (MDSCs), has been described in cancer, which suppresses T-cell responses and fosters disease progression. The role of MDSCs in infection is insufficiently addressed. Objectives: To examine the presence and function of MDSCs during experimental pulmonary tuberculosis (TB) and further understand the immunologic consequences of direct interactions between MDSCs and lung bacterial pathogens. Methods: Using cell-based approaches and experimental mouse models for pulmonary TB we characterized MDSCs as novel myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). Measurements and Main Results: MDSCs readily phagocytosed Mtb, and released proinflammatory (IL-6, IL-1α) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in the lung in disease-resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4Rα and heightened TB lethality, whereas targeted depletion of MDSCs ameliorated disease. Conclusions: Our data reveal that MDSCs provide a niche for pathogen survival and tailor immunity in TB. These findings suggest MDSCs as amenable targets for host-directed therapies and emphasize them as cellular-immune regulators during chronic inflammatory conditions, including chronic infections and microbial complications of neoplastic disorders. Copyright © 2014 by the American Thoracic Society.


Kondratieva E.,Central Institute for Tuberculosis | Logunova N.,Central Institute for Tuberculosis | Majorov K.,Central Institute for Tuberculosis | Averbakh Jr. M.,Central Institute for Tuberculosis | Apt A.,Central Institute for Tuberculosis
PLoS ONE | Year: 2010

Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas B6 mice show a reversed pattern of susceptibility. Here, by directly comparing: (i) characteristics of susceptibility to two infections in vivo; (ii) architecture of lung granulomata assessed by immune staining; and (iii) expression of genes encoding regulatory factors of neutrophil influx in the lung tissue, we demonstrate that genetic susceptibility of the host largely determines the pattern of lung pathology. Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts. The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis. © 2010 Kondratieva et al.


Kondratieva T.K.,Central Institute for Tuberculosis | Rubakova E.I.,Central Institute for Tuberculosis | Linge I.A.,Central Institute for Tuberculosis | Evstifeev V.V.,Central Institute for Tuberculosis | And 2 more authors.
Journal of Immunology | Year: 2010

Mutations in the btk gene encoding Bruton's tyrosine kinase cause X-linked immune deficiency, with impaired B lymphocyte function as the major phenotype. Earlier, we demonstrated that CBA/N-xid mice, unlike the wild-type CBA mice, were not protected by bacillus Calmette-Guérin (BCG) vaccination against tuberculosis infection. Because IFN-γ - producing T cells and activated macrophages are key elements of antituberculosis protection, it remained unclear how the mutation predominantly affecting B cell functions interferes with responses along the T cell - macrophage axis. In this study, we show that B cell deficiency leads to an abnormally rapid neutrophil migration toward the site of external stimulus. Using adoptive cell transfers and B cell genetic knockout, we demonstrate a previously unappreciated capacity of B cells to downregulate neutrophil motility. In our system, an advanced capture of BCG by neutrophils instead of macrophages leads to a significant decrease in numbers of IFN-γ - producing T cells and impairs BCG performance in X-linked immune-deficient mice. The defect is readily compensated for by the in vivo neutrophil depletion. Copyright © 2010 by The American Association of Immunologists, Inc.


Dorhoi A.,Max Planck Institute for Infection Biology | Desel C.,Max Planck Institute for Infection Biology | Yeremeev V.,Max Planck Institute for Infection Biology | Yeremeev V.,Central Institute for Tuberculosis | And 8 more authors.
Journal of Experimental Medicine | Year: 2010

The cross talk between host and pathogen starts with recognition of bacterial signatures through pattern recognition receptors (PRRs), which mobilize downstream signaling cascades. We investigated the role of the cytosolic adaptor caspase recruitment domain family, member 9 (CARD9) in tuberculosis. This adaptor was critical for full activation of innate immunity by converging signals downstream of multiple PRRs. Card9-/- mice succumbed early after aerosol infection, with higher mycobacterial burden, pyogranulomatous pneumonia, accelerated granulocyte recruitment, and higher abundance of proinflammatory cytokines and granulocyte colony-stimulating factor (G-CSF) in serum and lung. Neutralization of G-CSF and neutrophil depletion significantly prolonged survival, indicating that an exacerbated systemic inflammatory disease triggered lethality of Card9-/- mice. CARD9 deficiency had no apparent effect on T cell responses, but a marked impact on the hematopoietic compartment. Card9-/- granulocytes failed to produce IL-10 after Mycobaterium tuberculosis infection, suggesting that an absent antiinflammatory feedback loop accounted for granulocyte-dominated pathology, uncontrolled bacterial replication, and, ultimately, death of infected Card9-/- mice. Our data provide evidence that deregulated innate responses trigger excessive lung inflammation and demonstrate a pivotal role of CARD9 signaling in autonomous innate host defense against tuberculosis. © 2010 Dorhoi et al.

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