Department of Pathophysiology and Host Defense

The Department of Pathophysiology and Host Defense comprises divisions of Pathophysiology, Immunology, Animal Experiment and Senior Researcher section. In the Divisions of Pathophysiology and Immunology, we aim to analyse infection, development, and recurrence of tuberculosis and other mycobacterial diseases at molecular levels. We also try to elucidate their pathophysiological mechanisms.

The Division of Animal Experiment supports basic research using experimental animals. The Senior Researcher section is responsible for projects on novel anti-mycobacterial drugs and combinational chemotherapy and implementation of pharmacological studies.

Collaborative research projects with developing countries

We have been conducting collaborative researches with Vietnamese institutes through NCGM-BMH Medical Collaboration Center for more than 10 years. Our research projects include host immunogenetics; host-pathogen interactions; and clinical epidemiology on mycobacterial infection, development, and recurrence of the disease. Particularly, control of multi-drug resistant tuberculosis is an important target.

Figure 1: Presentation of the current status of collaborative research on tuberculosis in front of representatives in Hanoi Lung Hospital and District TB centres.

Research on human susceptibility genes and molecular pathogenesis of airway infectious/inflammatory diseases

We have been investigating the functional significance of airway defense genes and their polymorphisms. We have so far identified novel mucin genes on the human sixth chromosome and characterization of these genes is underway. Our target genes include beta-defensins and interferon-inducible anti-viral genes as well. This would help us to understand pathogenesis of airway infectious/inflammatory diseases widely.

Figure 2 : Novel mucin or mucin-like genes, PBMUCL1 and PBMUCL2 located in the candidate region for chronic airway diseases. These genetic polymorphisms might affect human airway defense mechanisms.

Unique strategy of intracellular parasitism of Mycobacterium tuberculosis

M. tuberculosis is an intracellular bacterium, which can proliferate within phagocytosed macrophages. M. tuberculosis gains this ability by escaping from the killing and digesting mechanisms of macrophages. We have been studying the unique strategy of its intracellular parasitism by investigating the membrane trafficking in infected macrophages.

Figure 3 : Autophagosome formation around M. tuberculosis in macrophages. Coronin-1a is an actin-binding protein in host cells. Knockdown of Coronin-1a leads autophagosome formation (green and red) around M. tuberculosis (blue) in macrophages.

Novel anti-TB drug development and pharmacological research of the new combination TB chemotherapy regimen

This project focuses on the development of novel anti-TB drug(s) and next generation combination regimen(s) to shorten the treatment duration for TB, and aims to create the future short course 3-4 months TB chemotherapy. We have established drug PK-analysis system by LC/MS-MS; now totally 32 drugs (approved anti-TB drugs, and novel candidates) are available. In combination with LC/MS-MS analysis system and the molecular imaging device, we have been investigating high throughput in vivo evaluation system to screen various drug-combination regimens. Recently, our project has had a collaborative relationship with Japanese pharmaceutical companies and TB Alliance (USA) to accelerate GHIT Fund (Global Health and Innovative Technology Fund) projects, as a collaboration partner and a screening platform in Japan.

Figure 4 : Inside of the animal facility Biosafety Level Three (BSL3) laboratory for infection study.

Publication list in the past five years

Noguchi S, Hamano E, Matsushita I, Hijikata M, Ito H, Nagase T, Keicho N. Differential effects of a common splice site polymorphism on the generation of OAS1 variants in human bronchial epithelial cells. Hum Immunol 74 (3): 395-401, 2013.

Noguchi S, Hijikata M, Hamano E, Matsushita I, Ito H, Ohashi J, Nagase T, Keicho N. MxA transcripts with distinct first exons and modulation of gene expression levels by single-nucleotide polymorphisms in human bronchial epithelial cells. Immunogenetics 65 (2): 107-14, 2013.

Pitabut N, Sakurada S, Tanaka T, Ridruechai C, Tanuma J, Aoki T, Kantipong P, Piyaworawong S, Kobayashi N, Dhepakson P, Yanai H, Yamada N, Oka S, Okada M, Khusmith S, Keicho N. Potential function of granulysin, other related effector molecules and lymphocyte subsets in patients with TB and HIV/TB coinfection. Int J Med Sci 10 (8): 1003-1014, 2013.

Hang NT, Maeda S, Lien LT, Thuong PH, Hung NV, Thuy TB, Nanri A, Mizoue T, Hoang NP, Cuong VC, Ngoc KT, Sakurada S, Endo H, Keicho N. Primary drug-resistant tuberculosis in Hanoi, Viet Nam: present status and risk factors. PLoS One 8 (8): e71867, 2013.

Hung NV, Ando H, Thuy TT, Kuwahara T, Hang NT, Sakurada S, Thuong PH, Lien LT, Keicho N. Clonal expansion of Mycobacterium tuberculosis isolates and coexisting drug resistance in patients newly diagnosed with pulmonary tuberculosis in Hanoi, Vietnam. BMC Res Notes 6:444, 2013.

Hang NT, Matsushita I, Shimbo T, Hong LT, Tam DB, Lien LT, Thuong PH, Cuong VC, Hijikata M, Kobayashi N, Sakurada S, Higuchi K, Harada N, Endo H, Keicho N. Association between tuberculosis recurrence and interferon-γ response during treatment. J Infect 69 (6): 616-626, 2014.

Hijikata M, Matsushita I, Hang NT, Maeda S, Thuong PH, Tam DB, Shimbo T, Sakurada S, Cuong VC, Lien LT, Keicho N. Age-dependent association of mannose-binding lectin polymorphisms with the development of pulmonary tuberculosis in Viet Nam. Hum Immunol 75 (8): 840-846, 2014.

Maeda S, Hang NT, Lien LT, Thuong PH, Hung NV, Hoang NP, Cuong VC, Hijikata M, Sakurada S, Keicho N. Mycobacterium tuberculosis strains spreading in Hanoi, Vietnam: Beijing sublineages, genotypes, drug susceptibility patterns, and host factors. Tuberculosis 94 (6): 649-656, 2014.

Hang NT, Maeda S, Keicho N, Thuong PH, Endo H. Sublineages of Mycobacterium tuberculosis Beijing genotype strains and unfavorable outcomes of anti-tuberculosis treatment. Tuberculosis 95 (3): 336-342, 2015.

Jeong S, Patel N, Edlund CK, Hartiala J, Hazelett DJ, Itakura T, Wu PC, Avery RL, Davis JL, Flynn HW, Lalwani G, Puliafito CA, Wafapoor H, Hijikata M, Keicho N, Gao X, Argüeso P, Allayee H, Coetzee GA, Pletcher MT, Conti DV, Schwartz SG, Eaton AM, Fini ME. Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. Invest Ophthalmol Vis Sci 56 (4): 2737-2748, 2015.

Matsushita I, Hang NT, Hong LT, Tam DB, Lien LT, Thuong PH, Cuong VC, Hijikata M, Kobayashi N, Sakurada S, Higuchi K, Harada N, Keicho N. Dynamics of immune parameters during the treatment of active tuberculosis showing negative interferon-gamma response at the time of diagnosis. Int J Infect Dis 40:39-44, 2015.

Yatagai Y, Hirota T, Sakamoto T, Yamada H, Masuko H, Kaneko Y, Iijima H, Naito T, Noguchi E, Tamari M, Kubo M, Takahashi A, Konno S, Makita H, Nishimura M, Hijikata M, Keicho N, Homma S, Taguchi Y, Azuma A, Kudoh S, Hizawa N. Variants nearby the HLA complex group 22 gene confer increased susceptibility to late-onset asthma in Japanese populations. J Allergy Clin Immunol 138 (1): 281-283.e13, 2016.

Nakauchi A, Wong JH, Mahasirimongkol S, Yanai H, Yuliwulandari R, Mabuchi A, Liu X, Mushiroda T, Wattanapokayakit S, Miyagawa T, Keicho N, Tokunaga K. Identification of ITPA as a susceptibility gene to young-onset Tuberculosis on Chromosome 20. Human Genome Variation 3:15067, 2016.

Hijikata M, Matsushita I, Hang NT, Thuong PH, Tam DB, Maeda S, Sakurada S, Cuong VC, Lien LT, Keicho N. Influence of the polymorphism of the DUSP14 gene on the expression of immune-related genes and development of pulmonary tuberculosis. Genes and Immunity 17 (4): 207-212, 2016.

Thuong PH, Tam DB, Sakurada S, Hang NT, Hijikata M, Hong LT, Ngoc PT, Anh PT, Cuong VC, Matsushita I, Lien LT and Keicho N. Circulating granulysin levels in healthcare workers and latent tuberculosis infection estimated using interferon-gamma release assays. BMC Infectious Diseases 16 (1): 580, 2016.

Wada T, Hijikata M, Maeda S, Hang NT, Thuong PH, Hoang NP, Hung NV, Keicho N. Complete genome sequences of three representative Mycobacterium tuberculosis Beijing family strains belonging to distinct genotype clusters in Hanoi, Vietnam, during 2007–2009. Genome Announc 5 (27):2017. pii: e00510-17.

Wada T, Hijikata M, Maeda S, Hang NT, Thuong PH, Hoang NP, Hung NV, Keicho N. Complete genome sequence of a Mycobacterium tuberculosis strain belonging to the EAI family in the Indo-Oceanic lineage, isolated in Hanoi, Vietnam. Genome Announc 5 (24):2017. pii: e00509-17.

Horita Y, Doi N. Comparative study of the effects of antituberculosis drugs and antiretroviral drugs on cytochrome P450 3A4 and P-glycoprotein.Antimicrob Agents Chemother 58 (6): 3168-3176, 2014.

Horita Y, Maeda S, Kazumi Y, Doi N. In vitro susceptibility of Mycobacterium tuberculosis isolates to an oral carbapenem alone or in combination with -lactamase inhibitors.Antimicrob Agents Chemother 58 (11): 7010-7014, 2014.

Disratthakit A, Prammananan T, Tribuddharat C, Thaipisuttikul I, Doi N, Leechawengwongs M, Chaiprasert A. Role of gyrB Mutation in Pre-extensively and Extensively Drug-Resistant Tuberculosis in Thai Clinical Isolates. Antimicrob Agents Chemother 60 (9): 5188-5197, 2016

3-1-24 Matsuyama, Kiyose-shi, Tokyo 204-8533 Japan