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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. Source


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. Source


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. Source


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. Source


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. Source

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