Research Institute for Microbial Diseases

Suita, Japan

Research Institute for Microbial Diseases

Suita, Japan

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Kawakami K.,Nagasaki Kawatana Medical Center | Ohkusa Y.,National Institute of Infectious Disease | Kuroki R.,Nagasaki Kawatana Medical Center | Tanaka T.,Nagasaki Kawatana Medical Center | And 5 more authors.
Vaccine | Year: 2010

To determine the clinical efficacy and cost-saving effect of pneumococcal polysaccharide vaccine (PPV) against community-acquired pneumonia (CAP), an open-label, randomized clinical trial was conducted involving 786 Japanese subjects older than 65 years of age receiving a routine influenza vaccine during the 2-year period. Study subjects were randomly assigned to either a PPV group (n= 394) or to a non-PPV group (n= 392). The incidence, admission and the medical cost for all-cause pneumonia were compared between these two groups. PPV vaccination significantly reduced the incidence of admission for all-cause pneumonia for subjects older than 75 years of age (41.5%, P= 0.039) and for those who had difficulty walking (62.7%, P= 0.005), but not for all study subjects older than 65 years of age (P= 0.183), for the 2-year period. The Kaplan-Meier survival curves for subjects who had difficulty walking free from all-cause pneumonia demonstrated a significant difference (P= 0.0146) between the two groups. PPV vaccination significantly reduced medical costs for all study subjects during the first year period (P= 0.027). Our present data demonstrated that PPV was effective for all-cause pneumonia for study subjects older than 75 years of age, although the effect was not significant for all study subjects older than 65 years of age. © 2010 Elsevier Ltd.


Matsubara T.,Osaka University | Ikeda F.,Osaka University | Hata K.,Osaka University | Nakanishi M.,Osaka University | And 4 more authors.
Journal of Bone and Mineral Research | Year: 2010

A tyrosine kinase, c-Src, that plays an indispensable role in ruffled border formation and bone resorption is constitutively active in osteoclasts. However, to date, the molecular mechanism underlying increased c-Src activity in osteoclasts is unknown. To address this, we first examined the expression levels and subcellular localization of Csk, a negative regulatory kinase for c-Src. We found that the expression level of Csk in osteoclasts was comparable with that of other tissues. However, in osteoclasts, Csk was hardly localized in lipid rafts, where c-Src is highly expressed. Interestingly, expression of Cbp, which recruits Csk into lipid rafts through physical interaction with Csk, was very low in osteoclasts compared with other tissues. To understand the importance of Cbp in osteoclasts, we introduced Cbp into osteoclasts using an adenovirus gene delivery system. Introduction of Cbp stimulated recruitment of Csk into lipid rafts and suppressed c-Src activity in a dose-dependent manner. Furthermore, introduction of Cbp markedly inhibited formation of actin rings and bone-resorbing activity in osteoclasts. In addition, treatment with RANKL and overexpression of TRAF6 or NFAT2 inhibited Cbp expression in the osteoclastogenic cell line RAW264.7 along with osteoclastic differentiation. NFAT2 overexpression also inhibited Cbp expression in spleen macrophages. Collectively, our results indicate that reduction in Cbp expression is responsible for maintaining high c-Src activity in osteoclasts. These findings contribute to an understanding of the unique regulatory system for c-Src in osteoclasts. © 2010 American Society for Bone and Mineral Research.


PubMed | Osaka University, Shimadzu Corporation and Research Institute for Microbial Diseases
Type: | Journal: Nature communications | Year: 2016

Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H


PubMed | Research Institute for Microbial Diseases, University of New South Wales and University of Southern Denmark
Type: Journal Article | Journal: Reproduction (Cambridge, England) | Year: 2016

IZUMO1 is a protein found in the head of spermatozoa that has been identified as essential for sperm-egg fusion. Its binding partner in the egg has been discovered (JUNO); however, the roles of several domains within IZUMO1 remain unexplored. One such domain is the C-terminus, which undergoes major phosphorylation changes in the cytoplasmic portion of the protein during rat epididymal transit. However, the cytoplasmic tail of IZUMO1 in many species is highly variable, ranging from 55 to one amino acid. Therefore, to understand the role of the cytoplasmic tail of IZUMO1 in mouse, we utilised the gene manipulation system of CRISPR/Cas9 to generate a point mutation resulting in a premature stop codon, producing mice with truncated IZUMO1. Mice without the cytoplasmic tail of IZUMO1 showed normal fertility but decreased the amount of protein, indicating that whilst this region is important for the expression level of IZUMO1, it is dispensable for fertilisation in the mouse.


PubMed | Oita University, Research Institute for Microbial Diseases, Aichi Cancer Institute and National Center for Geriatrics and Gerontology
Type: Journal Article | Journal: The Journal of pathology | Year: 2016

We have previously reported that Salvador homologue 1 (SAV1), a component of the Hippo pathway, is significantly down-regulated in high-grade clear cell renal cell carcinoma (ccRCC) due to 14q copy number loss, and that this down-regulation contributes to the proliferation and survival of renal tubular epithelial cells through activation of Yes-associated protein 1 (YAP1), a downstream target of the Hippo pathway. However, the impact of SAV1 loss on the proliferation and survival of kidney cells in vivo remained to be determined. To address this issue, we generated kidney-specific Sav1-knockout (Cdh16-Cre;Sav1(fl/fl) ) mice. Sav1 deficiency enhanced the proliferation of renal tubular epithelial cells in Cdh16-Cre;Sav1(fl/fl) mice, accompanied by nuclear localization of Yap1, suggesting suppression of the Hippo pathway. Sav1 deficiency in renal tubules also caused structural and cellular abnormalities of the epithelial cells, including significant enlargement of their nuclei. Furthermore, Cdh16-Cre;Sav1(fl/fl) mice developed both glomerular and tubular cysts. Although lining cells of the glomerular cysts showed no atypia, those of the tubular cysts showed variations in cell size and nuclear shape, which became more severe as the mice aged. In aged Cdh16-Cre;Sav1(fl/fl) mice, we observed focal disruption of proximal tubules and perivascular lymphocytic infiltration. In conclusion, Sav1 is required for the maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to the acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling.


Murakami H.,Research Institute for Microbial Diseases | Wang Y.,Research Institute for Microbial Diseases | Hasuwa H.,Osaka University | Maeda Y.,Research Institute for Microbial Diseases | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

Glycosylphosphatidylinositol (GPI) is a complex glycolipid that serves as a membrane anchor for many cell-surface proteins, such as Thy-1 and CD48. GPI-anchored proteins (GPI-APs) play important roles in many biological processes, such as signal transduction and cell-cell interaction, through their association with lipid rafts. Fatty acid remodeling of GPI-APs in the Golgi apparatus is required for their efficient association with lipid rafts, i.e., the unsaturated fatty acid at the sn-2 position of the PI moiety is exchanged for the saturated fatty acid by PGAP2 and PGAP3. To investigate the immunological role of the fatty acid remodeling of GPI-APs, we generated a Pgap3 knockout mouse. In this mouse, GPI-APs are expressed on the cell surface without fatty acid remodeling, and fail to associate with lipid rafts. Male Pgap3 knockout mice were born alive at a ratio lower than expected from Mendel's law, whereas the number of female mice followed Mendel's law. All mice exhibited growth retardation and abnormal reflexes such as limb grasping. We focused T cell function in these mice and found that T cell development in the absence of Pgap3 was normal. However, the response of T cells was enhanced in Pgap3 knockout mice in both in vitro and in vivo studies, including alloreactive response, antigen-specific immune response, and experimental autoimmune encephalomyelitis. Cross-linking of Thy-1 in wild-type cells inhibited the signal transduced by the T cell receptor (TCR), whereas cross-linking of Thy-1 in Pgap3 knockout cells enhanced the TCR signal. These results suggest that GPI-APs localized in lipid rafts may modulate signaling through the TCR. © 2011 Elsevier Inc.


Rotaviruses are the most common cause of severe diarrhea and kill hundreds of thousands of infants a year. Although current vaccines are effective in preventing aggravation of rotaviruses, the development of more effective vaccines at lower cost is expected. Technology cannot study well how rotaviruses invade and replicate in a cell. To identify which genes are crucial for the infection of rotaviruses, scientists at the Research Institute for Microbial Diseases at Osaka University report a new plasmid-based reverse genetics system. The study can be read in Proceedings of the National Academy of Sciences of the United States of America. "Reverse genetics allows us to generate artificially engineered viruses", says Associate Professor Takeshi Kobayashi, who led the study. "Using reverse genetics, we can mutate a gene and see its effects on the virus," he added. Reverse genetics systems have been developed for a wide number of viruses to study the conditions in which a virus thrives, but systems for multiple-segmented RNA-based viruses like rotaviruses have proven more difficult. Kobayashi's group solved this problem by including two viral proteins, FAST and VV capping enzyme, into their plasmid-based system. Taking advantage, the researchers tested their system by mutating a single protein of rotaviruses, NSP1, finding that they could decrease viral replication. Through comprehensive testing of all proteins in future studies, Kobayashi expects to find the key determinants that make rotaviruses a severe pubic threat. "We could modify the propagation and pathogenicity of the rotavirus", he said. Kobayashi is optimistic about how plasmid-based reverse genetics system will bring new innovations to combat rotaviruses. "Because no one could synthesize rotaviruses artificially, less is known about the replication and pathogenesis." He expects the system will increase the number of labs working on rotaviruses and lead to more effective vaccines. Explore further: Researchers find chink in the armor of viral 'tummy bug' More information: Yuta Kanai et al. Entirely plasmid-based reverse genetics system for rotaviruses, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1618424114


News Article | February 24, 2017
Site: www.eurekalert.org

Rotaviruses are the most common cause of severe diarrhea and kill hundreds of thousands of infants a year. Although current vaccines are effective in preventing aggravation of rotaviruses, the development of more effective vaccines at lower cost is expected. Technology cannot study well how rotaviruses invade and replicate in a cell. To identify which genes are crucial for the infection of rotaviruses, scientists at the Research Institute for Microbial Diseases at Osaka University report a new plasmid-based reverse genetics system. The study can be read in Proceedings of the National Academy of Sciences of the United States of America. "Reverse genetics allows us to generate artificially engineered viruses", says Associate Professor Takeshi Kobayashi, who led the study. "Using reverse genetics, we can mutate a gene and see its effects on the virus," he added. Reverse genetics systems have been developed for a wide number of viruses to study the conditions in which a virus thrives, but systems for multiple-segmented RNA-based viruses like rotaviruses have proven more difficult. Kobayashi's group solved this problem by including two viral proteins, FAST and VV capping enzyme, into their plasmid-based system. Taking advantage, the researchers tested their system by mutating a single protein of rotaviruses, NSP1, finding that they could decrease viral replication. Through comprehensive testing of all proteins in future studies, Kobayashi expects to find the key determinants that make rotaviruses a severe pubic threat. "We could modify the propagation and pathogenicity of the rotavirus", he said. Kobayashi is optimistic about how plasmid-based reverse genetics system will bring new innovations to combat rotaviruses. "Because no one could synthesize rotaviruses artificially, less is known about the replication and pathogenesis." He expects the system will increase the number of labs working on rotaviruses and lead to more effective vaccines.


Sugawara Y.,Research Institute for Microbial Diseases | Yutani M.,Research Institute for Microbial Diseases | Amatsu S.,Research Institute for Microbial Diseases | Matsumura T.,Research Institute for Microbial Diseases | Fujinaga Y.,Research Institute for Microbial Diseases
PLoS ONE | Year: 2014

Botulinum neurotoxin (BoNT) inhibits neurotransmitter release in motor nerve endings, causing botulism, a condition often resulting from ingestion of the toxin or toxin-producing bacteria. BoNTs are always produced as large protein complexes by associating with a non-toxic protein, non-toxic non-hemagglutinin (NTNH), and some toxin complexes contain another non-toxic protein, hemagglutinin (HA), in addition to NTNH. These accessory proteins are known to increase the oral toxicity of the toxin dramatically. NTNH has a protective role against the harsh conditions in the digestive tract, while HA is considered to facilitate intestinal absorption of the toxin by intestinal binding and disruption of the epithelial barrier. Two specific activities of HA, carbohydrate and E-cadherin binding, appear to be involved in these processes; however, the exact roles of these activities in the pathogenesis of botulism remain unclear. The toxin is conventionally divided into seven serotypes, designated A through G. In this study, we identified the amino acid residues critical for carbohydrate and E-cadherin binding in serotype B HA. We constructed mutants defective in each of these two activities and examined the relationship of these activities using an in vitro intestinal cell culture model. Our results show that the carbohydrate and E-cadherin binding activities are functionally and structurally independent. Carbohydrate binding potentiates the epithelial barrier-disrupting activity by enhancing cell surface binding, while E-cadherin binding is essential for the barrier disruption. © 2014 Sugawara et al.

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