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令和4年度

We investigated the inhibitory effect of extracts of blackcurrant (Ribes nigrum L.) from New Zealand and Poland on 4 strains of influenza virus (IFV) by the inhibition of virus adsorption ; pandemic flu from 2009-2010 (IFV-AH1pdm), Hong Kong flu (IFV-AH3), oseltamivir phosphate- resistant Russian flu (IFV-AH1tam r ) and influenza virus type B (IFV-B). The inhibitory effect of the extracts of blackcurrant or blueberry on the infectivity of the virion were evaluated by the inhi- bition of virus adsorption on the cell surface (adsorption-inhibitory assay). Three percent solutions of the blackcurrant extracts from New Zealand and Poland were enough to disinfect more than half of IFV-AH1pdm and IFV-B, and 10 % solutions from both regions disinfected all IFV strains com- pletely. Our previous study showed that the antiviral effect of the blackcurrant differed according to viral species. Here we showed that although the antiviral effect of Blackcurrant was slightly dif- ferent within viral strains from one species, the extract of Blackcurrant could disinfect all of 4 IFV strains we examined. The extracts of blackcurrant showed definite potential for use as a disinfec- tant and antiseptic agent to prevent IFV infection.

The localization of hepatitis C virus (HCV) proteins in cells leads to several problems. The translocase of outer mitochondrial membrane 70 (TOM70) is a mitochondrial import receptor. In this study, TOM70 expression was induced by HCV infection. TOM70 overexpression induced resistance to tumor necrosis factor-alpha (TNF-α)-mediated apoptosis but not to Fas-induced apoptosis in HepG2 cells. TOM70 was found to be induced by the HCV non-structural protein (NS)3/4A protein, and silencing of TOM70 decreased the levels of the NS3 and Mcl-1 proteins. These results indicate that TOM70 can directly interact with the NS3 protein. In hepatoma cells, silencing of TOM70 induced apoptosis and increased caspase-3/7 activity but did not modify caspase-8 and caspase-9 activity. TOM70 silencing-induced apoptosis was impaired in HCV NS3/4A protein-expressing cells. Thus, this study revealed a novel finding, that is, TOM70 is linked with the NS3 protein and the apoptotic response.

application/pdf, Human infl uenza virus causes an annual epidemic infection. After infl uenza virus infection in the airway, infection sometimes spreads with severe neurologic complication and multiple organ failure, resulting in high mortality. In the process of viral spread from the lungs to other organs, signifi cant up-regulated trpsin was observed in various organs. Up-regulated trypsin eff ectively converted precursor of the viral envelope hemagglutinin（ HA） into HA1 and HA2 subunits. The proteolytic activation of HA is a prerequisite for virus multiplication. Administration of the inhibitors of trypsin as new approaches for the treatment of infl uenza virus infection eff ectively suppressed viral multiplication. Almost vaccines for infl uenza virus infection are administered i.m. or s.c., which induce IgG-mediated protection in the systemic immune compartment, but this immunization off ers insuffi cient protection on the mucosal surface at the initial site of viral multiplication. To improve protective mucosal immunity, intranasal vaccination has been studied. The powerful mucosal adjuvants reported are toxin based, such as cholera toxin and Escherichia coli heat-labile toxin, but these enterotoxins cause severe side eff ects. We recently found natural mucosal adjuvant, pulmonary surfactant, in the lungs. Intranasal administration of infl uenza vaccine combined with Surfacten, a modifi ed pulmonary surfactant free of antigenic c-type lectins, induced high protective mucosal immunity in the airway and systemic immune responses in the blood, the effi cacy of both protective immunities by Surfacten being equivalent to those by cholera toxin. In this symposium, we reported the eff ects of Surfacten on mucosal and systemic immunities., 弘前医学. 59(Suppl.), 2007, p.S19-S25

application/pdf, Human parvovirus B19 （B19） is single stranded DNA virus, that causes erythema infectinosum in infant and/or acute onset polyarthritis in adult. We present the evidence showing the role of B19 on the etiopathogy of rheumatoid arthritis（ RA）.（ 1） B19 DNA could be frequently amplifi ed in the samples from rheumatoid joints. The detection B19 RNA and B19 protein VP1 was specific for RA, and positive at T cells, B cells, macrophages and follicular dendritic cells in rheumatoid synovium. （ 2） B19 infection or transduction of B19 NS1gene caused TNFα, IL-6 and IL-8 production through activating AP1 and AP2 in macrophages or macrophage celll line U937. We also found Ku80 as a novel receptor for B19 on T cells, macrophages or erythroblasts. B19 used clathrin on the surface at their cell entry and caused enhanced actin polymerization, resulting in the migration of T cells. （ 3） B19-transgenic mice became susceptible to type II collagen-induced polyarthritis that is a model of RA. We also experienced 12 cases who developed RA after acute B19 infection. （ 4） Half of RA cases had a defective neutralizing ability to B19., 弘前医学. 59(Suppl.), 2007, p.S12-S18

Background & Aims: Helicobacter pylori CagA-positive strain is associated with gastric adenocarcinoma. CagA is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation at the EPIYA sites by Src family kinases (SFKs). Owing to homologous recombination within the 3'-region of the cagA gene, 4 distinct EPIYA sites, each of which is defined by surrounding sequences, are variably assembled in both number and order among CagA proteins from different clinical H pylori isolates. Tyrosine-phosphorylated CagA specifically binds and deregulates SHP-2 via the Western CagA-specific EPIYA-C or East Asian CagA-specific EPIYA-D site, and C-terminal Src kinase (Csk) via the EPIYA-A or EPIYA-B site. Here we investigated the influence of EPIYA-repeat polymorphism on the CagA activity. Methods: A series of EPIYA-repeat variants of CagA were expressed in AGS gastric epithelial cells and the ability of individual CagA to bind SHP-2 or Csk was determined by the sequential immunoprecipitation and immunoblotting method. Results: CagA proteins carrying multiple EPIYA-C or EPIYA-D sites bound and deregulated SHP-2 more strongly than those having a single EPIYA-C or EPIYA-D. Furthermore, the ability of CagA to bind Csk was correlated with the number of EPIYA-A and EPIYA-B sites. Because Csk inhibits SFK, CagA with greater Csk-binding activity more strongly inhibited Src-dependent CagA phosphorylation and more effectively attenuated induction of cell elongation caused by CagA-SHP-2 interaction. Conclusions: EFIYA-repeat polymorphism of CagA greatly influences the magnitude and duration of phosphorylation-dependent CagA activity, which may determine the potential of individual CagA as a bacterial virulence factor that directs gastric carcinogenesis

HIV/AIDS、SARS、鳥インフルエンザといった新興感染症、薬剤耐性を持った病原体の出現によって問題が深刻化している結核、マラリア等再興感染症への関心が世界で高まっている。感染症の予防や治療はそれを個人に施すことのプラスの効果が国境を超えてスピル・オーバーすることが多く、国際公共財としての性質を持っている。また、新薬・ワクチンの成分・製法に関する情報および、感染症の流行に関する情報は典型的な公共財であり、誰しもがフリー・ライドするインセンティブを持っている。したがって、これら公共財の過少供給の問題を解決するためには国際的な協調行動が必要である。 世界の感染症対策は、感染がより大規模に広まっている発展途上国を中心としたものにならざるを得ない。現在これをリードしているのはアメリカであり、日本はWHOへの出資については存在感を示しているものの、それ以外の機関への出資や二国間協力の面において、少なくとも今現在においては貢献度が大きいと見られていない。また、新薬・ワクチン開発については日本の財政的な面での貢献は全く目立たない。 国際的な感染症対策に関する日本の印象を高めるためには、沖縄感染症イニシアティブの際になされたような形で金銭的貢献度を再び高める、あるいは、国際的に必要と考えられているものの他国が協力を決めていない分野への貢献をいち早く宣言する、等の対応が考えられる。

Two New York (NY) strains of the West Nile (WN) virus were plaque-purified and four variants that had different amino acid sequences at the N-linked glycosylation site in the envelope (E) protein sequence were isolated. The E protein was glycosylated in only two of these strain variants. To determine the relationship between E protein glycosylation and pathogenicity of the WN virus, 6-week-old mice were infected subcutaneously with these variants. Mice infected with viruses that carried the glycosylated E protein developed lethal infection, whereas mice infected with viruses that carried the non-glycosylated E protein showed low mortality. In contrast, intracerebral infection of mice with viruses carrying either the glycosylated or non-glycosylated forms of the E protein resulted in lethal infection. These results suggested that E protein glycosylation is a molecular determinant of neuroinvasiveness in the NY strains of WN virus.

本稿において、我々は疫学の研究領域に文化人類学がどのように貢献してきたかについて２つの歴史的事例を検討する。次に今日の疫学における最大の実践的課題のひとつであるHIV感染症に対して、文化人類学者の挑戦について紹介する。

米国における25歳から45歳までの死亡原因の第一位は, 1993年以降エイズになり以後も増え続けている。しかし, この病気の感染から発病までの潜伏期は平均的に13年といわれており, 1993年の死亡者は, 1981年頃に感染したことになる。1981年といえば米国においてまさにエイズ第1号が報告された年であり, 決して現在のこの姿が予見されていたわけではない。この疫学的事実が, 実はこの病気の最も恐ろしいところである。しかし, 近年この病気の病態が明らかになってきたことと, 抗HIV薬が次々に開発されてきたことから, 先進国においては治療環境は格段の進歩を見せている。これらの国においては, 慢性病としてかなり長期にわたりコントロール可能な病気になりつつある。しかし, 低開発国におけるこの病気のコントロールのためにはワクチン開発が重要である。

1995年および1996年の2年間の呼吸器感染症由来インフルエンザ菌について検討した。洗浄喀痰培養における本菌の分離頻度はエピソード別平均32.3%, 症例別平均29.3%であり, 常に最上位を占めていた。由来病名の確認された菌株の疾患分類による分離頻度は急性気管支炎→反復・遷延性気管支炎→慢性気管支炎の順で増加し, その結果は従来の報告を裏付けるものであった。過去5年間の生物型別の分布では, II型(35.4%)>III型(32.4%)>I型(16.4%)で, この3つの生物型で全体の84.2%を占めていた。感受性分布ではアンピシリン耐性菌(ABPC;MIC≧1.56μg/ml)が27.7%を占めていたが, β-L変生のアンピシリン耐性菌は11.8%に過ぎず, 残りのβ-L非産生アンピシリン耐性菌(15.9%)が前回(1980-1991年)の中村らの報告の値(1.3%)と比べて著しく増加していた。この事実はインフルエンザ菌のβ-Lの変化を含めた, 耐性機構の変容を示唆しており, 今後の感受性の動向に注意しつつ適切な抗菌薬を選択することが重要だと考えられた。, Three hundred and thirty-nine (339) strains of H. influenzas dominantly isolated from respiratory tract in these 2 years were analyzed. These were isolated by the method of washed sputum culture. The rate of isolation of H. influenzas was higher than any other pathogens in respiratory tract infection. Chronic bronchitis had high isolation rate of H. influenzae. Biotype distribution of the strains was as follows: type I 16.4%, II 35.4%, III 32.4%, IV 5.4%, V 8.3%, VI 1.2%, VII 0.5%, VIII 0.5%.0 Among these strains 11.8% were β-lactamase positive, and 15.9% were β-lactamase negative ampicillin-resistant strains (BLNARs). An increase in the prevalence of BLNARs from 1.3 0n 1980-1991 to 15.9 139698200n 1995-1996.

Haemophilus influenzae (H. influenzae)標準株を用いて, 3社の抗血清とCounter-immunoelectrophoresis (CIE)での基礎的検討を行ったうえで, 健常小児鼻咽腔より検出されたH. influenzae株と, 当科における下気道感染症由来株について血清型の検討を行った。小学4年生154名中19名の鼻咽腔からH. influenzaeが分離された。これより5名のHaemophilus influenzae type b (Hib)保菌者を除いた14名14株(1症例1株)のうち, nontypeable 13株, 不明1株であった。同様に0〜3歳児342名中27名からH. influenzaeが分離され, このうちHib保菌者は3名, 残りの24名24株のうちnontypeable 22株, type e 1株, 不明1株であった。1996年1月から12月までに洗浄喀痰より有意に分離された下気道感染症由来H. influenzae 208株から, 等しい生物型を持つ同一症例由来株を除いた116株について型別を行った。莢膜株は8株あり, type b 3株, type d 1株, type f 4株であった。莢膜株8株のうち, 5歳と6歳児に由来したtype f 2株を除く6株は低γグロブリン血症を有する慢性気管支炎症例(8〜28歳)出来であった。下気道感染症由来株はnontypeableが大部分を占め, 莢膜株は少数に過ぎなかったが, 慢性気管支炎を呈する比較的高年齢の低γグロブリン血症患者より検出される傾向にあった。, We serotyped Haemophilus influenzae (H. influenzas) isolated from nasopharynx of healthy children and washed sputum from patients with lower respiratory tract infection by using counterimmunoelectrophoresis (CIE) and one commercial antiserum, which was selected among three commercial antisera. Of 154 cases in the 4th grade healthy children, 5 had been proved H. influenzae type b (Hib) carriers, 14 H. influenzae strains (one strain each case) were isolated from their nasopharynx, including 13 nontypeable strains and one unknown strain. In the same method, of 342 3-year and under-old healthy infants and children, 3 had been proved Hib carriers, 24 H. influenzae strains were isolated, including 22 nontypeable strains, one type e and one unknown strain. Of 208 H. influenzae strains dominantly isolated from washed sputum in 1996, 116 strains were serotyped and 92 strains were excluded because these biotypes had corresponded to those ones in each case. Eight strains were identified serotypeable (3 type b, 1type d, and 4 type f). In these 8 strains, 6 typeable strains came from 4 cases aged 8 to 28 years having chronic bronchitis with hypogammaglobulinemia, and 2 type f strains came from 2 children aged 5 and 6 years without immunodeficiency. In conclusion, almost all the H. influenzae strains isolated from patients with lower respiratory tract infection proved to be nontypeable, however, several typeable strains came from relatively old cases diagnosed as chronic bronchitis since their childhood due to hypogammaglobulinemia.

Serological survey of influenza virus was performedanlong two groups of nursing school students,one (group 1) was the sophomores who entered in1979 and 1980, the other (group 2) was those whoentered in 1992 and 1994.Decrease in antibody positivity rate among thegroup 2, in particular in the rate of high titer ofantibody was observed, as compared with thegroup 1 who were brought up in the period of highprevalence of influenza vaccination. The resultsindicated that the lower positivity rate amonggroup 2 was associated with the low vaccinationrate in their childhood.Since the recommendation of advisory committeeon immunization practice was revised in 1994,people who received influenza vaccine have beendecreasing. It is accordingly estimated that seropositivityrate become low in young generationyear by year.Nursing school students who have good opportunityto contact many patients should be vaccinatedagainst influenza to protect high risk group frominfluenza infection., 近年我が国のインフルエンザワクチンの接種率は急激に低下した.1992年,94年入学の看護学部2年次学生の血清について抗インフルエンザ抗体測定を行い.1979年,80年入学生の抗体測定成績と比較した.学童期のワクチン接種率の高かった時代の1979年,80年入学生に比し92年,94年入学生では,抗体保有率,特に高抗体保有率は低下しており,ワクチン接種率の低下を反映した成績であった.1994年の予防接種法の改訂にともない,今後の学生はさらに抗体保有率の低下することが予想される.ハイリスク群に対する院内感染防止対策として,ハイリスク群との接触率の高い臨床実習生に対するインフルエンザワクチンの接種の必要性について検討を行った.

「老いの感染症」を考える時,病原体と宿主の両者について別々に考察を加える必要がある。我々は,そうすることにより,いかにして感染症を防ぐか,あるいは悪化しないようにどのようにしたらよいかを知ることができる。

地球温暖化により、疾病媒介生物がこれまで生息していなかった地域に活動範囲を広げ、その生物が媒介する病気は深刻な問題となっている。また、気候変動との関連性は明らかではないが、新型インフルエンザウイルスの予兆も人類の脅威となっている。本論文では、細胞培養技術を用い、特に培養細胞とウイルスの相互関係に着目した、新しい医薬品の開発研究について論述する。