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 - Basic Medicine (Core Departments) - Infectious Diseases and Immunology
The clinical outcome of infection is the result of a battle between bacterial virulence factors and the host defense system. It is becoming increasingly important to understand the basic mechanism of bacteria-host interaction under the current situation where bacteria acquire antibiotic resistance. We have been particularly interested in the intracellular parasitic bacteria that are capable of escaping the macrophage killing. Our aim is to elucidate the molecular mechanism of survival of Listeria and Mycobacteria, representative intracellular parasitic bacteria, and the host immune response to these microbes.

  Masao Mitsuyama, M.D., Ph.D.
Research and Education
1. Virulence factor of Listeria and the host response
The ability of Listeria monocytogenes to evade the intracellular killing by macrophages depends mainly on its virulence locus called LIPI-1. By constructing the deficient mutant for the genes locating in this locus, we have found that LLO encoded by hly plays a critical role in the induction of host cytokine response in addition to its role for cytosolic invasion. The precise relationship between the LLO structure and the cytokine-inducing ability has been analyzed and reported. Our current research is trying to clarify the molecular mechanism in inflammasome formation and induction of type I interferon in infected macrophages by using construction of various mutant or recombinant strains, mice deficient for candidate genes or SiRNA.
2. Virulence factor of Mycobacteria and the host response
One of the major candidates for the virulence of M. tuberculosis is RD1 locus that encodes various protein probably comprising a type VII secretion system. By using RD1 deficient mutant and complemented strains, we have found that RD1 is involved in the host cell necrosis and induction of IL-1α,β processing. We are now trying to find out how the effector proteins encoded by RD1 locus induce such response of host macrophages. Another candidate is PPE proteins in one of which we have found the inhibitory activity for host cytokine response. Our recent studies have revealed that PD1/PDL-1 pathway of the host plays a pivotal role in the pathophysiology of infected mice. Thus, mycobacterial virulence factors and host response are under investigation from a various point of view.
As our laboratory has a number of students from abroad, we use English at our journal club or data discussion.

Professor Masao Mitsuyama

Ikuo Kawamura

Kohsuke Tsuchiya,
Hideki Hara
TEL +81-75-753-4441, 4448
FAX +81-75-753-4446
Construction of recombinant L. monocytogenes strains differing in hly gene, the growth of each strain inside macrophages (immunofluorescence microscopy) and the ability to induce caspase-1 activation (western blotting).
2 RD1 region of M. tuberculosis plays an essential role in the induction of host cell necrosis, processing and secretion of IL-1a and IL-1b in infected macrophages.
Lab Staffs (as of February, 2011)
Recent Publications
1. Yamamoto T, Hara H, Tsuchiya K, Sakai S, Fang R, Matsuura M, Nomura T, Sato F, Mitsuyama M, Kawamura I : Listeria monocytogenes strain-specific impairment of the TetR regulator underlies the drastic increase in cyclic di-AMP secretion and interferon beta-inducing ability. Infect Immun 80 (7) : in press, 2012.
2. Matsuura M, Kawasaki K, Kawahara K, Mitsuyama M : Evasion of human innate immunity without antagonizing TLR4 by mutant Salmonella enterica serovar Typhimurium having penta-acylated lipid A. Innate Immun 18 : in press, 2012.
3. Fang R, Tsuchiya K, Kawamura I, Shen Y, Hara H, et al & Mitsuyama M : Critical roles of ASC inflammasomes in caspase-1 activation and host immune resistance to Streptococcus pneumoniae infection. J. Immunol.187 : 4890-4899, 2011
4. Daim S, Kawamura I, Tsuchiya K, Hara H, Kurenuma T, Shen Y, Dewamitta S, Sakai S, Nomura S, Qu H, Mitsuyama M : Expression of the Mycobacterium tuberculosis PPE37 protein in Mycobacterium smegmatis induces low tumour necrosis factor alpha and interleukin 6 production in murine macrophages. J. Med. Microbiol. 60 : 582-591, 2011.
5. Sakai S, Kawamura I, Okazaki T, Tsuchiya K, Uchiyama R & Mitsuyama M : PD-1-PD-L1 pathway impairs Th1 immune response in the late stage of infection with Mycobacterium bovis bacillus Calmette-Guérin. Int. Immunol. 22: 915-925, 2010.
6. Tsuchiya K, Hara H, Kawamura I, Nomura T, Yamamoto T, Daim S, Dewamitta SR, Shen Y, Fang R, Mitsuyama M : Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J. Immunol. 185: 1186-1195, 2010.
7. Dewamitta SR, Nomura T, Kawamura I, Hara H, Tsuchiya K, et al, Mitsuyama M. : Listeriolysin O-dependent bacterial entry into the cytoplasm is required for calpain activation and interleukin-1 alpha secretion in macrophages infected with Listeria monocytogenes. Infect. Immun. 78 : 1884-1894, 2010.