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Takeshi Fukuda,
Takayuki Matsumura,
Manabu Ato,
Maho Hamasaki,
Yukiko Nishiuchi,
Yoshiko Murakami,
Yusuke Maeda,
Tamotsu Yoshimori, Sohkichi Matsumoto,
Kazuo Kobayashi,
Taroh Kinoshita,
Yasu S Morita
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ABSTRACT: ABSTRACT Lipomannan (LM) and lipoarabinomannan (LAM) are mycobacterial glycolipids containing a long mannose polymer. While they are implicated in immune modulations, the significance of LM and LAM as structural components of the mycobacterial cell wall remains unknown. We have previously reported that a branch-forming mannosyltransferase plays a critical role in controlling the sizes of LM and LAM and that deletion or overexpression of this enzyme results in gross changes in LM/LAM structures. Here, we show that such changes in LM/LAM structures have a significant impact on the cell wall integrity of mycobacteria. In Mycobacterium smegmatis, structural defects in LM and LAM resulted in loss of acid-fast staining, increased sensitivity to β-lactam antibiotics, and faster killing by THP-1 macrophages. Furthermore, equivalent Mycobacterium tuberculosis mutants became more sensitive to β-lactams, and one mutant showed attenuated virulence in mice. Our results revealed previously unknown structural roles for LM and LAM and further demonstrated that they are important for the pathogenesis of tuberculosis. IMPORTANCE Tuberculosis (TB) is a global burden, affecting millions of people worldwide. Mycobacterium tuberculosis is a causative agent of TB, and understanding the biology of M. tuberculosis is essential for tackling this devastating disease. The cell wall of M. tuberculosis is highly impermeable and plays a protective role in establishing infection. Among the cell wall components, LM and LAM are major glycolipids found in all Mycobacterium species, show various immunomodulatory activities, and have been thought to play roles in TB pathogenesis. However, the roles of LM and LAM as integral parts of the cell wall structure have not been elucidated. Here we show that LM and LAM play critical roles in the integrity of mycobacterial cell wall and the pathogenesis of TB. These findings will now allow us to seek the possibility that the LM/LAM biosynthetic pathway is a chemotherapeutic target.
mBio 01/2013; 4(1). · 5.31 Impact Factor
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Mayuko Osada-Oka,
Yoshitaka Tateishi,
Yukio Hirayama,
Yuriko Ozeki,
Mamiko Niki,
Seigo Kitada,
Ryoji Maekura,
Kunio Tsujimura,
Yukio Koide,
Naoya Ohara,
Taro Yamamoto,
Kazuo Kobayashi, Sohkichi Matsumoto
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ABSTRACT: Development of accurate methods for predicting progression of tuberculosis (TB) from the latent state has been recognized as being vitally important in controlling TB, because a majority of cases develop from latent infections. Past TB without medication has a higher risk of progressing than latent Mycobacterium tuberculosis infection alone. We evaluated antibody responses against 23 kinds of M. tuberculosis proteins in individuals with past TB who had not been medicated. The group showed significantly higher levels of antibodies against Antigen 85A, and mycobacterial DNA-binding protein 1 (MDP1) compared to those with active TB and uninfected controls. Besides, immunohistochemistry revealed colocalization of tubercle bacilli, Antigen 85 and MDP1 inside tuberculous granuloma lesions in an asymptomatic subject, showing that M. tuberculosis in the lesion expresses both Antigen 85 and MDP1. Our study suggests the potential usefulness of measuring antibody responses to Antigen 85A and MDP1 for assessing the risk of TB progression.
Microbiology and Immunology 11/2012; · 1.30 Impact Factor
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Yoshitaka Tateishi,
Seigo Kitada,
Keisuke Miki,
Ryoji Maekura,
Yoshitoshi Ogura,
Yuriko Ozeki,
Yukiko Nishiuchi,
Mamiko Niki,
Tetsuya Hayashi,
Kazuto Hirata,
Kazuo Kobayashi, Sohkichi Matsumoto
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ABSTRACT: We report herein the draft genome sequence of Mycobacterium intracellulare clinical strain M.i.198, which consistently exhibits hypervirulence in human patients, human macrophages in vitro, and immunocompetent mice.
Journal of bacteriology 11/2012; 194(22):6336. · 3.94 Impact Factor
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ABSTRACT: We have developed a novel vaccine against Shiga toxin (Stx) producing E. coli (STEC) infection using a recombinant BCG (rBCG) system. Two intraperitoneal vaccinations with rBCG expressing Stx2 B subunit resulted in an increase of protective serum IgG and mucosal IgA response to Stx2B in BALB/c mice. When orally challenged with 10(3) CFU of STEC B2F1 strain (O91: H21), the immunized mice survived statistically longer than the non-vaccinated mice. We suggest that intraperitoneal immunization with rBCG expressing Stx2B would be a potential vaccine strategy for STEC.
Clinical and vaccine immunology: CVI 10/2012; · 2.37 Impact Factor
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Makoto Niki,
Mamiko Niki,
Yoshitaka Tateishi,
Yuriko Ozeki,
Teruo Kirikae,
Astrid Lewin,
Yusuke Inoue,
Makoto Matsumoto,
John L Dahl,
Hisashi Ogura,
Kazuo Kobayashi, Sohkichi Matsumoto
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ABSTRACT: Tuberculosis remains one of the most deadly infectious diseases worldwide and is a leading public health problem. Although isoniazid (INH) is a key drug for the treatment of tuberculosis, tolerance to INH necessitates prolonged treatment, which is a concern for effective tuberculosis chemotherapy. INH is a prodrug that is activated by the mycobacterial enzyme, KatG. Here, we show that mycobacterial DNA-binding protein 1 (MDP1), which is a histone-like protein conserved in mycobacteria, negatively regulates katG transcription and leads to phenotypic tolerance to INH in mycobacteria. Mycobacterium smegmatis deficient for MDP1 exhibited increased expression of KatG and showed enhanced INH activation compared with the wild-type strain. Expression of MDP1 was increased in the stationary phase and conferred growth phase-dependent tolerance to INH in M. smegmatis. Regulation of KatG expression is conserved between M. smegmatis and Mycobacterium tuberculosis complex. Artificial reduction of MDP1 in Mycobacterium bovis BCG was shown to lead to increased KatG expression and susceptibility to INH. These data suggest a mechanism by which phenotypic tolerance to INH is acquired in mycobacteria.
Journal of Biological Chemistry 05/2012; 287(33):27743-52. · 4.77 Impact Factor
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Aki Tamaru,
Chie Nakajima,
Takayuki Wada,
Yajun Wang,
Manabu Inoue,
Ryuji Kawahara,
Ryoji Maekura,
Yuriko Ozeki,
Hisashi Ogura,
Kazuo Kobayashi,
Yasuhiko Suzuki, Sohkichi Matsumoto
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ABSTRACT: Infection and transmission of multidrug-resistant Mycobacterium tuberculosis (MDR-Mtb) and extensively drug-resistant M. tuberculosis (XDR-Mtb) is a serious health problem. We analyzed a total of 1,110 Mtb isolates in Osaka Prefecture and neighboring areas from April 2000 to March 2009. A total of 89 MDR-Mtb were identified, 36 (48.5%) of which were determined to be XDR-Mtb. Among the 89 MDR-Mtb isolates, 24 (27.0%) phylogenetically distributed into six clusters based on mycobacterial interspersed repetitive units-various number of tandem repeats (MIRU-VNTR) typing. Among these six clusters, the MIRU-VNTR patterns of four (OM-V02, OM-V03, OM-V04, and OM-V06) were only found for MDR-Mtb. Further analysis revealed that all isolates belonging to OM-V02 and OM-V03, and two isolates from OM-V04 were clonal. Importantly such genotypes were not observed for drug-sensitive isolates. These suggest that few but transmissible clones can transmit after acquiring multidrug resistance and colonize even in a country with a developed, well-organized healthcare system.
PLoS ONE 01/2012; 7(8):e42505. · 4.09 Impact Factor
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Sohkichi Matsumoto
Nippon Saikingaku Zasshi 12/2011; 66(4):531-7.
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ABSTRACT: Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most often used vaccine worldwide and sole vaccine against tuberculosis. BCG is protective against severe form of childhood tuberculosis but less or not protective to adult pulmonary tuberculosis. Therefore, improved vaccination strategies and development of new tuberculosis vaccines are urgent demands. For those purposes, appropriate animal models that reflect human are critically useful. However, in animal models, BCG vaccination protects well against subsequent challenge of Mycobacterium tuberculosis. In this study we evaluated the duration of protective efficacy of the BCG vaccination in mice over time and found that efficacy was diminished 40 weeks after vaccination. The aged mice older than 45 weeks are protected sufficiently after the vaccination with BCG, suggesting that loss of its efficacy is not dependent on the age of mice but rather depends on the period from vaccination. The loss of protection occurred in TH1 polarized STAT6 deficient mice despite the maintenance of interferon (IFN)-gamma production activity of lymph node cells and splenic CD4(+) T cells against M. tuberculosis antigens. Our data suggest that the duration from vaccination may explain the variation in BCG efficacy against adult pulmonary tuberculosis.
Vaccine 07/2011; 29(40):6881-7. · 3.77 Impact Factor
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ABSTRACT: We investigated the role of mitochondrial reactive oxygen species (ROS) in the response of macrophages to lipopolysaccharide (LPS) using RAW 264.7 cells and their ρ(o) cells lacking mitochondria. Mitochondrial density, respiratory activity and related proteins in ρ(o) cells were significantly lower than those in RAW cells. LPS rapidly stimulated mitochondrial ROS prior to cytokine secretion, such as TNF-α and IL-6, from RAW 264.7 cells by activating the MAPK pathway, while the response was attenuated in ρ(o) cells. Exposure of ρ(o) cells to H(2)O(2) partially restored the secretion of cytokines induced by LPS. These results suggest that mitochondrial density and/or the respiratory state contribute to intracellular oxidative stress, which is responsible for the stimulation of LPS-induced MAPK signaling to enhance cytokine release from macrophages.
FEBS letters 05/2011; 585(14):2263-8. · 3.54 Impact Factor
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Masaki Takatsuka,
Mayuko Osada-Oka,
Eisuke F Satoh,
Kengo Kitadokoro,
Yukiko Nishiuchi,
Mamiko Niki,
Masayasu Inoue,
Kazuhiro Iwai,
Tetsuo Arakawa,
Yoshihiro Shimoji,
Hisashi Ogura,
Kazuo Kobayashi,
Anura Rambukkana, Sohkichi Matsumoto
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ABSTRACT: Iron is an essential metal for living organisms but its level must be strictly controlled in cells, because ferrous ion induces toxicity by generating highly active reactive oxygen, hydroxyl radicals, through the Fenton reaction. In addition, ferric ion shows low solubility under physiological conditions. To overcome these obstacles living organisms possess Ferritin superfamily proteins that are distributed in all three domains of life: bacteria, archaea, and eukaryotes. These proteins minimize hydroxyl radical formation by ferroxidase activity that converts Fe(2+) into Fe(3+) and sequesters iron by storing it as a mineral inside a protein cage. In this study, we discovered that mycobacterial DNA-binding protein 1 (MDP1), a histone-like protein, has similar activity to ferritin superfamily proteins. MDP1 prevented the Fenton reaction and protects DNA by the ferroxidase activity. The K(m) values of the ferroxidase activity by MDP1 of Mycobacterium bovis bacillus Calmette-Guérin (BCG-3007c), Mycobacterium tuberculosis (Rv2986c), and Mycobacterium leprae (ML1683; ML-LBP) were 0.292, 0.252, and 0.129 mM, respectively. Furthermore, one MDP1 molecule directly captured 81.4±19.1 iron atoms, suggesting the role of this protein in iron storage. This study describes for the first time a ferroxidase-iron storage protein outside of the ferritin superfamily proteins and the protective role of this bacterial protein from DNA damage.
PLoS ONE 01/2011; 6(6):e20985. · 4.09 Impact Factor
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ABSTRACT: Lipomannan (LM) and lipoarabinomannan (LAM) are phosphatidylinositol-anchored glycans present in the mycobacterial cell wall. In Mycobacterium smegmatis, the mannan core of LM/LAM constitutes a linear chain of 20-25 alpha1,6-mannoses elaborated by 8-9 alpha1,2-monomannose side branches. At least two alpha1,6-mannosyltransferases mediate the linear mannose chain elongation, and one branching alpha1,2-mannosyltransferase (encoded by MSMEG_4247) transfers monomannose branches. An MSMEG_4247 deletion mutant accumulates branchless LAM and interestingly fails to accumulate LM, suggesting an unexpected role of mannose branching for LM synthesis or maintenance. To understand the roles of MSMEG_4247-mediated branching more clearly, we analyzed the MSMEG_4247 deletion mutant in detail. Our study showed that the deletion mutant restored the synthesis of wild-type LM and LAM upon the expression of MSMEG_4247 at wild-type levels. In striking contrast, overexpression of MSMEG_4247 resulted in the accumulation of dwarfed LM/LAM, although monomannose branching was restored. The dwarfed LAM carried a mannan chain less than half the length of wild-type LAM and was elaborated by an arabinan that was about 4 times smaller. Induced overexpression of an elongating alpha1,6-mannosyltransferase competed with the overexpressed branching enzyme, alleviating the dwarfing effect of the branching enzyme. In wild-type cells, LM and LAM decreased in quantity in the stationary phase, and the expression levels of branching and elongating mannosyltransferases were reduced in concert, presumably to avoid producing abnormal LM/LAM. These data suggest that the coordinated expressions of branching and elongating mannosyltransferases are critical for mannan backbone elongation.
Journal of Biological Chemistry 03/2010; 285(18):13326-36. · 4.77 Impact Factor
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ABSTRACT: M.tb is an intracellular pathogen which survives within the phagosomes of host macrophages by inhibiting their fusion with lysosomes. Here, it has been demonstrated that a lysosomal glycoprotein, CD63, is recruited to the majority of M.tb phagosomes, while RILP shows limited localization. This is consistent with the author's findings that CD63, but not RILP, is recruited to the phagosomes in macrophages expressing the dominant negative form of Rab7. These results suggest that M.tb phagosomes selectively fuse with endosomes and lysosomes to escape killing activity while acquiring nutrients.
Microbiology and Immunology 03/2010; 54(3):170-4. · 1.30 Impact Factor
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Yuriko Ozeki,
Isamu Sugawara,
Tadashi Udagawa,
Toshiaki Aoki,
Mayuko Osada-Oka,
Yoshitaka Tateishi,
Hajime Hisaeda,
Yuji Nishiuchi,
Nobuyuki Harada,
Kazuo Kobayashi, Sohkichi Matsumoto
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ABSTRACT: CD4(+)CD25(+) regulatory T (Treg) cells cause immune suppression by inhibiting T cell effector functions and play pivotal roles not only in self-tolerance but also in immune response to parasitic microbial pathogens. Mycobacteria are major parasitic bacterial pathogens, but the role of CD4(+)CD25(+) Treg cells in mycobacterial infection is not yet defined. In this study we found that, at the early stage of infection, depletion of CD25(+) cells reduced both bacterial load and granuloma formation in mice infected with Mycobacterium tuberculosis strains, such as M. tuberculosis Erdman or M. tuberculosis Kurono. However, at a later stage of infection, bacterial burden and histopathology were similar regardless of depletion of CD25(+) cells. Severe combined immunodeficient (SCID) mice reconstituted with CD4(+)CD25(-) T cells alone or a combination of CD4(+)CD25(+) and CD4(+)CD25(-) T cells showed similar bacterial loads and survival kinetics after infection with M. tuberculosis Erdman. Consistent with in vivo data, in vitro studies revealed that mycobacterial antigens, purified protein derivative of tuberculin (PPD), failed to induce the suppressive function of CD4(+)CD25(+) Treg cells to CD4(+)CD25(-) effector T cells, as demonstrated by the lack of response of CD4(+)CD25(+) T cells to PPD, in mice chronically infected with Mycobacterium bovis bacillus Calmette-Guérin and M. tuberculosis. Our data show that CD4(+)CD25(+) Treg cells have a transient effect at the early stage of mycobacterial infection but, contrary to the expectation, have little impact on the overall course of infection.
International Immunology 02/2010; 22(3):179-89. · 3.41 Impact Factor
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ABSTRACT: Mycobacterial DNA-binding protein 1 (MDP1) is a major protein antigen in mycobacteria and induces protective immunity against Mycobacterium tuberculosis infection in mice. In this study we determined murine T-cell epitopes on MDP1 with MDP1 DNA immunization in mice. We analyzed interferon-gamma production from the MDP1 DNA-immune splenocytes in response to 20-mer overlapping peptides covering MDP1 protein. We identified several CD4+ T-cell epitopes in three inbred mouse strains and one CD8+ T-cell epitope in C57BL/6 mice. These T-cell epitopes would be feasible for analysis of the role of MDP1-specific T-cells in protective immunity and for future vaccine design against M. tuberculosis infection.
Vaccine 02/2010; 28(8):2020-5. · 3.77 Impact Factor
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Yukio Hirayama,
Mamiko Yoshimura,
Yuriko Ozeki,
Isamu Sugawara,
Tadashi Udagawa,
Satoru Mizuno,
Naoki Itano,
Koji Kimata,
Aki Tamaru,
Hisashi Ogura,
Kazuo Kobayashi, Sohkichi Matsumoto
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ABSTRACT: In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobacterial infection was established and found that pathogenic mycobacteria can grow by utilizing hyaluronan as a carbon source. Both mouse and human possess 3 kinds of hyaluronan synthases (HAS), designated HAS1, HAS2, and HAS3. Utilizing individual HAS-transfected cells, we show that HAS1 and HAS3 but not HAS2 support growth of mycobacteria. We found that the major hyaluronan synthase expressed in the lung is HAS1, and that its expression was increased after infection with Mycobacterium tuberculosis. Histochemical analysis demonstrated that hyaluronan profoundly accumulated in the granulomatous legion of the lungs in M. tuberculosis-infected mice and rhesus monkeys that died from tuberculosis. We detected hyaluronidase activity in the lysate of mycobacteria and showed that it was critical for hyaluronan-dependent extracellular growth. Finally, we showed that L-Ascorbic acid 6-hexadecanoate, a hyaluronidase inhibitor, suppressed growth of mycobacteria in vivo. Taken together, our data show that pathogenic mycobacteria exploit an intrinsic host-protective molecule, hyaluronan, to grow in the respiratory tract and demonstrate the potential usefulness of hyaluronidase inhibitors against mycobacterial diseases.
PLoS Pathogens 10/2009; 5(10):e1000643. · 9.13 Impact Factor
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ABSTRACT: The late endosomal marker Rab7 has been long believed to be absent from the phagosome containing Mycobacterium tuberculosis (M.tb) in macrophage, but the detail kinetics remains elusive. Here, we found that Rab7 is transiently recruited to and subsequently released from M.tb phagosomes. For further understanding of the effect of Rab7 dissociation from the phagosome, we examined the localization of lysosomal markers on the phagosome in the macrophage expressing a dominant-negative Rab7. The localization of lysosomal associated membrane protein-2 (LAMP-2) on the phagosome was Rab7-independent, while that of cathepsin D was Rab7-dependent. These results agree with the localization of each lysosomal marker on M.tb phagosome at 6h postinfection-i.e., LAMP-2, but not cathepsin D localized on the majority of M.tb phagosomes. These results suggest that the dissociation of Rab7 from M.tb phagosome is the important process in inhibition of phagolysosome biogenesis.
Biochemical and Biophysical Research Communications 08/2009; 387(2):272-7. · 2.48 Impact Factor
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ABSTRACT: A population-based study of Mycobacterium tuberculosis isolated from homeless tuberculosis patients was performed during 2002-2004 in Osaka City, Japan. The data show that the ancient Beijing subfamily was predominant, whereas clustered isolates based on refined variable number of tandem repeats genotyping (19 loci) mainly belonged to the modern Beijing subfamily, suggesting its increased transmissibility.
Tuberculosis (Edinburgh, Scotland) 07/2009; 89(4):252-5. · 2.54 Impact Factor
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Mitsuhiro Okazaki,
Kiyofumi Ohkusu,
Hiroyuki Hata,
Hiroaki Ohnishi,
Keiko Sugahara,
Chizuko Kawamura,
Nagatoshi Fujiwara, Sohkichi Matsumoto,
Yukiko Nishiuchi,
Kouichi Toyoda,
Hajime Saito,
Shota Yonetani,
Yoko Fukugawa,
Masayuki Yamamoto,
Hiroo Wada,
Akiko Sejimo,
Akio Ebina,
Hajime Goto,
Takayuki Ezaki,
Takashi Watanabe
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ABSTRACT: A novel, non-pigmented, slow-growing mycobacterium was identified on the basis of biochemical and nucleic acid analyses, as well as growth characteristics. Three isolates were cultured from clinical samples (two from sputum and one from pus in lymph nodes) obtained from three immunocompetent patients with infections. Bacterial growth occurred at 28-42 degrees C on Middlebrook 7H11-OADC agar. The isolates showed negative results for Tween hydrolysis, nitrate reductase, semiquantitative catalase, urease activity, 3 day arylsulfatase activity, pyrazinamidase, tellurite reduction and niacin accumulation tests, but positive results for 14 day arylsulfatase activity and heat-stable catalase tests. The isolates contained alpha-, keto-, and dicarboxymycolates in their cell walls. Sequence analysis revealed that all isolates had identical, unique 16S rRNA sequences. Phylogenetic analysis of the 16S rRNA, rpoB, hsp65 and sodA gene sequences confirmed that these isolates are unique but closely related to Mycobacterium celatum. DNA-DNA hybridization of the isolates demonstrated less than 50 % reassociation with M. celatum and Mycobacterium branderi. On the basis of these findings, a novel species designated Mycobacterium kyorinense sp. nov. is proposed. The type strain is KUM 060204(T) (=JCM 15038(T)=DSM 45166(T)).
International journal of systematic and evolutionary microbiology 07/2009; 59(Pt 6):1336-41. · 2.27 Impact Factor
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Yukiko Nishiuchi,
Aki Tamura,
Seigo Kitada,
Takahiro Taguri, Sohkichi Matsumoto,
Yoshitaka Tateishi,
Mamiko Yoshimura,
Yuriko Ozeki,
Narumi Matsumura,
Hisashi Ogura,
Ryoji Maekura
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ABSTRACT: Medical treatment of pulmonary Mycobacterium avium complex (MAC) disease does not always provide curative effects and is frequently hampered by recurrence. This suggests the presence of a reservoir for MAC in the environment surrounding patients. We previously reported the recovery of MAC isolates from the residential bathrooms of outpatients. In the present study, to ascertain the colonizing sites and the possibility of an MAC reservoir in the bathrooms of patients, we tested the recovery and the genetic diversity of MAC isolates from 6 sites of specimens, including 2 additional sampling sites, inside the showerhead and the bathtub inlet, in the residential bathrooms of patients with pulmonary MAC disease. MAC isolates were recovered from 15 out of the 29 bathrooms (52%), including specimens from 14 bathtub inlets and 3 showerheads. Nearly half of these bathrooms (7/15) contained MAC strains that were identical or similar to their respective clinical isolates Additionally, in 5 out of 15 bathrooms, polyclonal colonization was revealed by pulsed-field gel electrophoresis. The results imply that colonization of MAC organisms in the bathrooms of MAC patients occurs predominantly in the bathtub inlets, and there is thus a risk of infection and/or reinfection for patients via use of the bathtub and other sites in the bathroom.
Japanese journal of infectious diseases 06/2009; 62(3):182-6. · 1.49 Impact Factor
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Hiroyuki Saiga,
Junichi Nishimura,
Hirotaka Kuwata,
Megumi Okuyama, Sohkichi Matsumoto,
Shintaro Sato,
Makoto Matsumoto,
Shizuo Akira,
Yasunobu Yoshikai,
Kenya Honda,
Masahiro Yamamoto,
Kiyoshi Takeda
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ABSTRACT: Mycobacterium tuberculosis invades alveolar epithelial cells as well as macrophages. However, the role of alveolar epithelial cells in the host defense against M. tuberculosis remains unknown. In this study, we report that lipocalin 2 (Lcn2)-dependent inhibition of mycobacterial growth within epithelial cells is required for anti-mycobacterial innate immune responses. Lcn2 is secreted into the alveolar space by alveolar macrophages and epithelial cells during the early phase of respiratory mycobacterial infection. Lcn2 inhibits the in vitro growth of mycobacteria through sequestration of iron uptake. Lcn2-deficient mice are highly susceptible to intratracheal infection with M. tuberculosis. Histological analyses at the early phase of mycobacterial infection in Lcn2-deficient mice reveal increased numbers of mycobacteria in epithelial cell layers, but not in macrophages, in the lungs. Increased intracellular mycobacterial growth is observed in alveolar epithelial cells, but not in alveolar macrophages, from Lcn2-deficient mice. The inhibitory action of Lcn2 is blocked by the addition of endocytosis inhibitors, suggesting that internalization of Lcn2 into the epithelial cells is a prerequisite for the inhibition of intracellular mycobacterial growth. Taken together, these findings highlight a pivotal role for alveolar epithelial cells during mycobacterial infection, in which Lcn2 mediates anti-mycobacterial innate immune responses within the epithelial cells.
The Journal of Immunology 01/2009; 181(12):8521-7. · 5.79 Impact Factor
