Hwa-Jung Kim

Chungnam National University, Daiden, Daejeon, South Korea

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Publications (61)175.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Reciprocal induction of the Th1 and Th17 immune responses is essential for optimal protection against Mycobacterium tuberculosis (Mtb); however, only a few Mtb antigens are known to fulfill this task. A functional role for resuscitation-promoting factor (Rpf) E, a latency-associated member of the Rpf family, in promoting naïve CD4(+) T-cell differentiation toward both Th1- and Th17-cell fates through interaction with dendritic cells (DCs) was identified in this study. RpfE induces DC maturation by increasing expression of surface molecules and the production of IL-6, IL-1β, IL-23p19, IL-12p70 and TNF-α but not IL-10. This induction is mediated through TLR4 binding and subsequent activation of ERK, p38 MAPKs and NF-κB signaling. RpfE-treated DCs effectively caused naïve CD4(+) T cells to secrete IFN-γ, IL-2 and IL-17A, which resulted in reciprocal expansions of the Th1- and Th17-cell response along with activation of T-bet and RORγt but not GATA-3. Furthermore, lung and spleen cells from Mtb-infected WT mice but not from TLR4(-/-) mice exhibited Th1 and Th17 polarization upon RpfE-stimulation. Taken together, our data suggest that RpfE has the potential to be an effective Mtb vaccine because of its ability to activate DCs that simultaneously induce both Th1- and Th17-polarized T-cell expansion. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 04/2015; DOI:10.1002/eji.201445329 · 4.52 Impact Factor
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    ABSTRACT: Antibody responses are useful indicators of Mycobacterium bovis infection in cattle. Many studies have evaluated the ability of immunoglobulin G (IgG) to serodiagnose bovine tuberculosis (TB). In the current study, immunoglobulin A (IgA) and IgG responses against the MPB70 and MPB83 antigens of M. bovis, the 38 kDa phosphate-binding lipoprotein (PstS1) that is a well-known serodiagnostic M. tuberculosis antigen, and a newly identified protein, termed Rv1483c, were compared in M. bovis-infected and noninfected cattle as well as in field samples. The diagnostic utility of the IgA antibody to MPB70 and MPB83 for bovine TB was superior or comparable to that of the IgG antibody, and the sensitivity of serodiagnosis increased when the results of antigen binding by IgA and IgG were combined. The sensitivities of the IgG and IgA antibodies to the Rv1483c and PstS1 proteins were significantly lower than those to MPB70 and MPB83, and no diagnostic utility for Rv1483c was observed in field samples. Importantly, the IgA antibody reacted strongly to the MPB70 and MPB83 antigens and differentiated cattle with TB from healthy cattle in a multiantigen printed immunoassay. The results of this study support the feasibility of using IgA antibody against the MPB70 and MPB83 antigens to detect bovine TB. In addition, approaches using assays for both IgA and IgG antibodies may increase detection accuracy. © 2015 The Author(s).
    Journal of veterinary diagnostic investigation: official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 04/2015; 27(3). DOI:10.1177/1040638715578879 · 1.23 Impact Factor
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    ABSTRACT: The CFP-10 antigen (Ag), found in the tissue fluids of tuberculosis (TB) patients, is an excellent candidate marker for early and simplified diagnosis of TB when combined with an effective sensing method. In this study, clinical level immunosensing of CFP-10 in urine samples from TB patients was performed using a self-assembled interferometric optical fiber array system. To generate the immunosensing interface, two directions of assay designs were introduced: (I) the direct immobilization of anti-CFP-10 monoclonal antibody (mAb) on a fiber tip surface, (II) the indirect conjugation of anti-CFP-10 mAb with the assistance of primary capture layer. Then, the orientation and accessibility of the antibody were assessed by the selective binding of CFP-10 to this interface. The results revealed a linear relationship between the optical phase shift of the interferometric sensing system and the acid-fast bacilli (AFB) staining stage (0-3) of the TB patients. Significant differences were observed between urine samples from infected and non-infected patients. This method, which uses urine samples and an interferometric sensing system, allows fast and ultrasensitive clinical monitoring and can be rapidly developed into a reliable diagnostic method to monitor TB infection.
    Sensors and Actuators B Chemical 04/2015; 216. DOI:10.1016/j.snb.2015.04.046 · 4.29 Impact Factor
  • Journal of Bacteriology and Virology 01/2015; 45(2):112. DOI:10.4167/jbv.2015.45.2.112
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    ABSTRACT: Endoplasmic reticulum (ER) stress responses play critical roles in the pathogenesis of tuberculosis. To investigate the regulatory role of the ER stress response in 38-kDa antigen-induced apoptosis, we examined the relationship between the ER stress response and apoptosis in bone marrow-derived macrophages (BMDMs) stimulated with Mycobacterium tuberculosis antigen (38-kDa Ag). The expression of ER molecular chaperones, including C/EBP homologous protein (CHOP), glucose-regulated protein (Bip) and phosphorylated alpha subunit of eukaryotic initiation factor 2, was induced in BMDMs stimulated with the 38-kDa Ag. Interestingly, 38-kDa Ag-stimulation induced apoptosis via activation of caspase-12, -9 and -3. However, 38-kDa Ag-induced apoptosis was significantly reduced in TLR2- and TLR4-deficient macrophages. Because toll-like receptors (TLRs) initiate the activation of mitogen-activated protein kinase (MAPK) signaling cascades, we evaluated the effect of MAPK activation on ER stress. The 38-kDa Ag activated Jun N-terminal kinase, extracellular signal-regulated kinase and p38 phosphorylation. MAPK signaling induced the secretion of proinflammatory cytokines such as MCP-1, TNF-α and IL-6. The 38-kDa Ag-induced MCP-1 was especially associated with the induction of MCP-1-induced protein (MCPIP), which increased the generation of reactive oxygen species (ROS) and ER stress. To investigate the role of MCPIP in ROS-induced ER stress by 38-kDa Ag stimulation, we transfected MCPIP siRNA into RAW264.7 cells before 38-kDa Ag stimulation, and measured the generation of ROS and expression of ER molecular chaperones. ROS production and CHOP expression were decreased by the silencing of MCPIP induction. Our results demonstrate that the expression of MCPIP by 38-kDa Ag stimulation is increased through a TLR-MAPK-dependent signaling pathway, and leads to ER stress-induced apoptosis. In conclusion, MCPIP is important for host defense mechanisms in mycobacterial pathogenesis.
    APOPTOSIS 12/2014; 20(3). DOI:10.1007/s10495-014-1080-2 · 3.61 Impact Factor
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    ABSTRACT: Mycobacterium kansasii (Mk) is an emerging pathogen that causes a pulmonary disease similar to tuberculosis. Macrophage apoptosis contributes to innate host defense against mycobacterial infection. Recent studies have suggested that lithium significantly enhances the cytotoxic activity of death stimuli in many cell types. We examined the effect of lithium on the viability of host cells and intracellular Mk in infected macrophages. Lithium treatment resulted in a substantial reduction in the viability of intracellular Mk in macrophages. Macrophage cell death was significantly enhanced after adding lithium to Mk-infected cells but not after adding to uninfected macrophages. Lithium-enhanced cell death was due to an apoptotic response, as evidenced by augmented DNA fragmentation and caspase activation. Reactive oxygen species were essential for lithium-induced apoptosis. Intracellular scavenging by N-acetylcysteine abrogated the lithium-mediated decrease in intracellular Mk growth as well as apoptosis. These data suggest that lithium is associated with control of intracellular Mk growth through modulation of the apoptotic response in infected macrophages.
    The Journal of Microbiology 02/2014; 52(4). DOI:10.1007/s12275-014-3469-6 · 1.53 Impact Factor
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    ABSTRACT: The failure of Mycobacterium bovis BCG as a TB vaccine against TB reactivation suggests that latency-associated proteins should be included in alternative TB vaccine development. Further, antigens known to generate protective immunity against the strong Th1 stimulatory response to reactivated TB should be included in novel vaccine design. Recent studies have emphasized the importance of Rpfs from Mycobacterium tuberculosis in the reactivation process and cellular immunity. However, little is known about how RpfB mediates protective immunity against M. tuberculosis. Here, we investigated the functional roles and signaling mechanisms of RpfB in DCs and its implications in the development of T cell immunity. DCs treated with RpfB displayed features of mature and functional status, with elevated expression of cell surface molecules (CD80, CD86, and MHC class I and II) and proinflammatory cytokine production (TNF-α, IL-1β, IL-6, and IL-12p70). Activation of DCs was mediated by direct binding of RpfB to TLR4, followed by MyD88/TRIF-dependent signaling to MAPKs and NF-κB signaling pathways. Specifically, we found that the RpfB G5 domain is the most important part in RpfB binding to TLR4. RpfB-treated DCs effectively polarized naïve CD4(+) and CD8(+) T cells to secrete IFN-γ and IL-2. Importantly, RpfB induced the expansion of memory CD4(+)/CD8(+)CD44(high)CD62L(low) T cells in the spleen of M. tuberculosis-infected mice. Our data suggest that RpfB regulates innate immunity and activates adaptive immunity through TLR4, a finding that may help in the design of more effective vaccines.
    Journal of leukocyte biology 07/2013; 94(4). DOI:10.1189/jlb.0912435 · 4.99 Impact Factor
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    Yun-Ji Lim · Yea-Hyeon Jo · Hwa-Jung Kim · Jeong-Kyu Park
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    ABSTRACT: Some Bacillus species present in fermented foods are regarded as probiotics because of their ability to modulate the prevention of some intestinal infections and the modulation of the inflammatory immune response. We isolated bacteriocin-like substances producing Bacillus subtilis and B. lentus from Cheonggukjang, a traditional Korean fermented soybean paste having an inhibitory effect against Salmonella Typhimurium using a well diffusion inhibition assay and a broth co-culturing method. B. subtilis or B. letus was fed to Drosophila melanogaster alone as well as in combination with Salmonella Typhimurium and survival was monitored daily. The survival rates by oral feeding B. subtilis, B. lentus and Salmonella Typhimurium separately resulted in 85, 90 and 75%, respectively. In contrast, survival rates of co-feeding of B. lentus with Salmonella Typhimurium were increased from 75 to 90% during 7 days post-feeding as compared to Salmonella Typhimurium alone. However, B. subtilis in co-feeding with Salmonella Typhimurium significantly reduced D. melanogaster survival rate (85 to 70%). We found that the immune response to B. lentus and Salmonella Typhimurium is characterized synergistic activation of antimicrobial peptide gene expression by Imd pathway. In conclusion, the in vitro and natural-route infection of the D. melanogaster digestive system can result in the use of the probiotic B. lentus for effective treatment of Salmonella Typhimurium infection. We therefore propose the strain B. lentus as a suitable candidate probiotics for use in the prevention and treatment of the intestinal infections caused by Salmonella Typhimurium.
    Journal of Bacteriology and Virology 01/2013; 43(2):120. DOI:10.4167/jbv.2013.43.2.120
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    ABSTRACT: The Mycobacterium avium-intracellulare complex (MAC) causes a pulmonary disease (PD) similar to tuberculosis (TB). Diagnosis of MAC-PD is complicated and time-consuming. In this study, the serodiagnostic potential of the newly identified MAV2054 and MAV5183 proteins was evaluated in subjects with MAC-PD, pulmonary TB, latent TB, and non-infected healthy controls (HC), together with HspX and the 38-kDa antigen, well-known serodiagnostic M. tuberculosis antigens. All four antigens evoked significantly higher IgG responses in MAC-PD and active TB than in latent TB and HC subjects. Among the antigens, MAV2054 elicited the highest antibody responses in pulmonary TB and MAC-PD patients. IgG titers against MAV2054 and MAV5183 were significantly higher in MAC-PD than in pulmonary TB subjects. In addition, the levels of IgG to all antigens in the M. intracellulare and fibrocavitary forms were higher than those in the M. avium and nodular bronchiectatic forms, respectively. Based on sensitivity and receiver operator characteristic curve analysis, the best candidates for detection of MAC-PD and pulmonary TB were MAV2054 and the 38-kDa antigen, respectively. In total, 76.0% of MAC-PD and 65.0% of active TB patients were reactive to at least more than one antigen. In contrast, only 2.8% of HC subjects were reactive with two or more antigens. Our findings suggest that an ELISA-based assay using the four antigens would be valuable for screening for mycobacterial lung disease including MAC-PD and pulmonary TB, although it does not provide good discrimination of the causing pathogens.
    Clinical and vaccine Immunology: CVI 12/2012; 20(2). DOI:10.1128/CVI.00649-12 · 2.37 Impact Factor
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    ABSTRACT: Although pathogenic mechanisms of tuberculosis have been extensively studied, little is known about the pathogenic mechanisms of Mycobacterium kansasii. In this work the influence of virulence and ER-stress mediated apoptosis of macrophages during two different strains of M. kansasii infection was investigated. We show that M. kansasii infection is associated with ER stress-mediated apoptosis in the murine macrophage cell line RAW 264.7. Infection of RAW 264.7 cells in vitro with apoptosis-inducing a clinical isolate of M. kansasii SM-1 (SM-1) resulted in strong induction of ER stress responses compared with M. kansasii type strain (ATCC 12478)-infected RAW 264.7 cells. Interestingly, inhibition of calpain prevented the induction of CHOP and Bip in ATCC 12478-infected RAW 264.7 cells but not in RAW 264.7 cells infected with SM-1. In contrast, reactive oxygen species (ROS) were significantly increased only in RAW 264.7 cells infected with SM-1. We propose that ROS generation is important for triggering ER stress-mediated apoptosis during SM-1 infection, whereas ATCC 12478-induced, ER stress-mediated apoptosis is associated with calpain activation. Our results demonstrate that the ER stress pathway plays important roles in the pathogenesis of M. kansasii infections, and that different strains of M. kansasii induce different patterns of ER stress-mediated apoptosis.
    Apoptosis 12/2012; 18(2). DOI:10.1007/s10495-012-0792-4 · 3.61 Impact Factor
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    ABSTRACT: We have developed a simple electrochemical biosensing strategy for the label-free diagnosis of hepatitis B virus (HBV) on a gold electrode surface. Gold-binding polypeptide (GBP) fused with single-chain antibody (ScFv) against HBV surface antigen (HBsAg), in forms of genetically engineered protein, was utilized. This GBP-ScFv fusion protein can directly bind onto the gold substrate with the strong binding affinity between the GBP and the gold surface, while the recognition site orients toward the sample for target binding at the same time. Furthermore, this one-step immobilization strategy greatly simplifies a fabrication process without any chemical modification as well as maintaining activity of biological recognition elements. This system allows specific immobilization of proteins and sensitive detection of targets, which were verified by surface plasmon resonance analysis and successfully applied to electrochemical cyclic voltammetry and impedance spectroscopy upto 0.14 ng/mL HBsAg.
    Sensors 12/2012; 12(8):10097-108. DOI:10.3390/s120810097 · 2.05 Impact Factor
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    ABSTRACT: Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne disease in animals and MAP involvement in human Crohn disease has been recently emphasized. Evidence from M. tuberculosis studies suggests mycobacterial proteins activate dendritic cells (DCs) via Toll-like receptor (TLR) 4, eventually determining the fate of immune responses. Here, we investigated whether MAP CobT contributes to the development of T cell immunity through the activation of DCs. MAP CobT recognizes TLR4, and induces DC maturation and activation via the MyD88 and TRIF signaling cascades, which are followed by MAP kinases and NF-κB. We further found that MAP CobT-treated DCs activated naive T cells, effectively polarized CD4+ and CD8+ T cells to secrete IFN-γ and IL-2, but not IL-4 and IL-10, and induced T cell proliferation. These data indicate that MAP CobT contributes to T helper (Th) 1 polarization of the immune response. MAP CobT-treated DCs specifically induced the expansion of CD4+/CD8+CD44highCD62Llow memory T cells in the mesenteric lymph node of MAP-infected mice in a TLR4-dependent manner. Our results indicate that MAP CobT is a novel DC maturation-inducing antigen that drives Th1 polarized-naive/memory T cell expansion in a TLR4-dependent cascade, suggesting that MAP CobT potentially links innate and adaptive immunity against MAP.
    Journal of Biological Chemistry 09/2012; 287(46). DOI:10.1074/jbc.M112.391060 · 4.57 Impact Factor
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    Eui-Ryoung Han · Inseon S Choi · Han-Gyu Choi · Hwa-Jung Kim
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    ABSTRACT: Live/killed mycobacteria and culture supernatants can suppress asthmatic reactions. This study investigated whether mycobacterial secretory proteins have therapeutic effects on asthma. Mycobacterium bovis bacille Calmette-Guérin (BCG; 2×10(5) CFUs) and mycobacterial secretory proteins (Ag85 complex, 38-kDa protein or MPB70; 4 or 20 µg) were administered intraperitoneally to female BALB/c mice with established airway hyperresponsiveness. One week after treatment, the mice underwent a methacholine challenge test, and then inflammatory cell numbers in bronchoalveolar lavage fluid (BAL) and around bronchi (<500 µm), and cytokine levels in splenocyte supernatants, were assessed. BCG and all of the tested secretory proteins significantly improved airway sensitivity compared to baseline values (P<0.05). The secretory protein Ag85 complex significantly suppressed airway reactivity also (P<0.05), while 38-kDa protein significantly suppressed reactivity and maximal narrowing (P<0.05). The number of eosinophils in BAL and around bronchi, and the goblet cell proportion, were also significantly reduced in mice in both the BCG and secretory protein groups compared to the asthma control group. IFN-γ/IL-5 ratios were significantly higher in mice treated with BCG, 4 µg MPB70 or 4 µg 38-kDa protein than in asthma control mice (P<0.05), and were negatively associated with airway hyperresponsiveness, peribronchial eosinophil numbers and goblet cell proportion (all P<0.05). IL-17A was positively correlated with IL-5 (r=0.379, P<0.001), maximal airway narrowing, peribronchial eosinophil numbers and goblet cell proportion (all P<0.05). Secretory proteins from BCG and M. tuberculosis and live BCG were effective against established asthma, their effects being accompanied by increased IFN-γ/IL-5 ratios. Thus, allergic asthma could be effectively treated with mycobacterial secretory proteins.
    Allergy, asthma & immunology research 07/2012; 4(4):214-21. DOI:10.4168/aair.2012.4.4.214 · 3.08 Impact Factor
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    ABSTRACT: Tuberculosis (TB) caused by Mycobacterium tuberculosis constitutes an ongoing threat to global health. An antigen that can induce dendritic cell (DC) maturation and lead to enhanced cellular immunity is crucial to the development of an effective TB vaccine. Here, we investigated the functional roles and the related signaling mechanism of the Rv0577 protein, a M. tuberculosis complex-restricted secreted protein involved in the methylglyoxal detoxification pathway. Rv0577 recognizes Toll-like receptor 2 (TLR2) and functionally induces DC maturation by augmenting the expression of cell surface molecules (CD80, CD86, and MHC class I and II) and proinflammatory cytokine production (TNF-α, IL-1β, IL-6, and IL-12p70) in DCs on MyD88-dependent signaling, mitogen-activated protein kinases, and nuclear factor κB signaling pathways. In addition, Rv0577-treated DCs activated naive T cells, effectively polarized CD4(+) and CD8(+) T cells to secrete IFN-γ and IL-2, and induced T-cell proliferation, indicating that this protein possibly contributes to Th1-polarization of the immune response. More important, unlike LPS, Rv0577-treated DCs specifically induced the proliferation of memory CD4(+)/CD8(+)CD44(high)CD62L(low) T cells in the spleen of M. tuberculosis-infected mice in a TLR2-dependent manner. Taken together, these findings suggest that Rv0577 may regulate innate and adaptive immunity by interacting with TLR2, a finding that could be helpful in the design of new TB vaccines.
    The FASEB Journal 03/2012; 26(6):2695-711. DOI:10.1096/fj.11-199588 · 5.48 Impact Factor
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    ABSTRACT: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the most deadly infectious diseases, with approximately two million people dying of TB annually. An effective therapeutic method for activating dendritic cells (DCs) and driving Th1 immune responses would improve host defenses and further the development of a TB vaccine. Given the importance of DC maturation in eliciting protective immunity against TB, we investigated whether Rv0315, a newly identified Mtb antigen, can prompt DC maturation. We found that Rv0315 functionally activated DCs by augmenting the expression of the co-stimulatory molecules CD80 and CD86 as well as MHC class I/II molecules. Moreover, it increased DC secretion of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Unlike LPS, however, Rv0315 induced the secretion of IL-12p70, but not IL-10. In addition, Rv0315-treated DCs accelerated the proliferation of CD4(+) and CD8(+) splenic T cells from Mtb-infected mice, with increased levels of IFN-γ, in syngeneic and allogeneic mixed lymphocyte reactions, indicating that Rv0315 contributes to Th1 polarization of the immune response. Importantly, both mitogen-activated protein kinases and nuclear factor κB signaling mediated the expression of DC surface markers and cytokines. Taken together, our results indicate that Rv0315 is a novel DC maturation-inducing antigen that drives T cell immune responses toward Th1 polarization, suggesting that Rv0315 plays a key role in determining the nature of the immune response to TB.
    Journal of Molecular Medicine 03/2012; 90(3):285-98. DOI:10.1007/s00109-011-0819-2 · 4.74 Impact Factor
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    ABSTRACT: Mycobacterial proteins interact with host macrophages and modulate their functions and cytokine gene expression profile. The protein Rv0652 is abundant in culture filtrates of Mycobacterium tuberculosis K-strain, which belongs to the Beijing family, compared with levels in the H37Rv and CDC1551 strains. Rv0652 induces strong antibody responses in patients with active tuberculosis. We investigated pro-inflammatory cytokine production induced by Rv0652 in murine macrophages and the roles of signalling pathways. In RAW264.7 cells and bone marrow-derived macrophages, recombinant Rv0652 induced predominantly tumour necrosis factor (TNF) and monocyte chemoattractant protein (MCP)-1 production, which was dependent on mitogen-activated protein kinases and nuclear factor-κB. Specific signalling pathway inhibitors revealed that the extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and phosphatidylinositol 3-kinase (PI3K) pathways were essential for Rv0652-induced TNF production, whereas the ERK1/2 and PI3K pathways, but not the p38 pathway, were critical for MCP-1 production in macrophages. Rv0652-stimulated TNF and MCP-1 secretion by macrophages occurred in a Toll-like receptor 4-dependent and MyD88-dependent manner. In addition, Rv0652 significantly up-regulated the expression of the mannose receptor, CD80, CD86 and MHC class II molecules. These results suggest that Rv0652 can induce a protective immunity against M. tuberculosis through the macrophage activation.
    Immunology 02/2012; 136(2):231-40. DOI:10.1111/j.1365-2567.2012.03575.x · 3.74 Impact Factor
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    ABSTRACT: Apoptosis is thought to play a role in host defenses against intracellular pathogens, including Mycobacterium tuberculosis (Mtb), by preventing the release of intracellular components and the spread of mycobacterial infection. This study aims to investigate the role of endoplasmic reticulum (ER) stress mediated apoptosis in mycobacteria infected macrophages. Here, we demonstrate that ER stress-induced apoptosis is associated with Mtb H37Rv-induced cell death of Raw264.7 murine macrophages. We have shown that Mtb H37Rv induced apoptosis are involved in activation of caspase-12, which resides on the cytoplasmic district of the ER. Mtb infection increase levels of other ER stress indicators in a time-dependent manner. Phosphorylation of eIF2α was decreased gradually after Mtb H37Rv infection signifying that Mtb H37Rv infection may affect eIF2α phosphorylation in an attempt to survive within macrophages. Interestingly, the survival of mycobacteria in macrophages was enhanced by silencing CHOP expression. In contrast, survival rate of mycobacteria was reduced by phosphorylation of the eIF2α. Futhermore, the levels of ROS, NO or CHOP expression were significantly increased by live Mtb H37Rv compared to heat-killed Mtb H37Rv indicating that live Mtb H37Rv could induce ER stress response. These findings indicate that eIF2α/CHOP pathway may influence intracellular survival of Mtb H37Rv in macrophages and only live Mtb H37Rv can induce ER stress response. The data support the ER stress pathway plays an important role in the pathogenesis and persistence of mycobacteria.
    PLoS ONE 12/2011; 6(12):e28531. DOI:10.1371/journal.pone.0028531 · 3.23 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis heparin-binding hemagglutinin (HBHA), a virulence factor involved in extrapulmonary dissemination and a strong diagnostic antigen against tuberculosis, is both surface-associated and secreted. The role of HBHA in macrophages during M. tuberculosis infection, however, is less well known. Here, we show that recombinant HBHA produced by Mycobacterium smegmatis effectively induces apoptosis in murine macrophages. DNA fragmentation, nuclear condensation, caspase activation, and poly (ADP-ribose) polymerase cleavage were observed in apoptotic macrophages treated with HBHA. Enhanced reactive oxygen species (ROS) production and Bax activation were essential for HBHA-induced apoptosis, as evidenced by a restoration of the viability of macrophages pretreated with N-acetylcysteine, a potent ROS scavenger, or transfected with Bax siRNA. HBHA is targeted to the mitochondrial compartment of HBHA-treated and M. tuberculosis-infected macrophages. Dissipation of the mitochondrial transmembrane potential (ΔΨ(m)) and depletion of cytochrome c also occurred in both macrophages and isolated mitochondria treated with HBHA. Disruption of HBHA gene led to the restoration of ΔΨ(m) impairment in infected macrophages, resulting in reduced apoptosis. Taken together, our data suggest that HBHA may act as a strong pathogenic factor to cause apoptosis of professional phagocytes infected with M. tuberculosis.
    PLoS Pathogens 12/2011; 7(12):e1002435. DOI:10.1371/journal.ppat.1002435 · 8.06 Impact Factor
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    ABSTRACT: The antigen (Ag) CFP-10, found in tissue fluids of tuberculosis (TB) patients, is an excellent candidate for use as a sensitive TB marker for early and simplified diagnosis of TB when combined with an effective sensing method. In this study, chemical and optical optimizations were carried out using novel immunomaterials to establish a self-assembled surface plasmon resonance (SPR) optical immunosensing system for the detection of CFP-10 Ag in clinical urine samples from TB patients, which is the first clinical trial as far as we know to monitor Ag in urine. To create a simple sensing interface, a monoclonal antibody (anti-CFP-10) was immobilized directly on a gold surface, followed by blocking with cystamine. The orientation and accessibility of anti-CFP-10 were assessed by the selective binding of CFP-10. The results reveal a linear relationship between the SPR angle shift and the acid-fast bacilli stain stage (0-4) of TB patients. Significant differences were seen between urine samples from TB patients and controls. This method, using urine samples and SPR spectroscopy, is promising and can be rapidly developed into a reliable diagnostic method to monitor TB.
    Sensors and Actuators B Chemical 12/2011; 160(1):1434-1438. DOI:10.1016/j.snb.2011.10.006 · 4.29 Impact Factor
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    ABSTRACT: Bacterial infection can affect hematopoietic precursor cells in bone marrow, because the infected tissues produce various cytokines and chemokines. Little is known about hematopoietic precursor cells, including hematopoietic stem cells and their progenitors, during mycobacterial infection. Here, we showed that mycobacterial infections result in the expansion of not only the lin-c-kit+sca-1+ (LKS+) cell population, but also granulocyte-monocyte progenitor cells in a chronic murine tuberculosis model. Interestingly, stimulation of LKS+ cells with attenuated Mycobacterium tuberculosis H37Ra culture filtrate (RaCF) was significantly stronger than that by virulent H37Rv culture filtrate (RvCF). Lower TNF-α and IL-6 levels were observed in RvCF-stimulated bone marrow cells. Neutralization of TNF-α or IL-6 in RaCF-stimulated bone marrow cells markedly suppressed LKS+ cell clonal expansion. Additionally, numbers of LKS+ cells were lower in TLR2(-/-) and MyD88(-/-) mice after mycobacterial infection. Taken together, LKS+ cell proliferation related to mycobacterial virulence may be related to the secretion of TNF-α and IL-6 associated with TLR signaling. Expansion of hematopoietic progenitor cells may, therefore, play an important role during mycobacterial infection.
    Microbes and Infection 08/2011; 13(14-15):1252-60. DOI:10.1016/j.micinf.2011.08.001 · 2.73 Impact Factor

Publication Stats

658 Citations
175.11 Total Impact Points

Institutions

  • 2003–2015
    • Chungnam National University
      • • Department of Microbiology
      • • College of Medicine
      Daiden, Daejeon, South Korea
  • 2008
    • Yonsei University Hospital
      Sŏul, Seoul, South Korea
  • 2006
    • Konyang University
      • College of Medicine
      Ronsan, South Chungcheong, South Korea
    • University of Central Florida
      • Burnett School of Biomedical Sciences
      Orlando, Florida, United States