JP4494974B2 - イヌおよびヒトエールリヒア症の免疫診断のためのp153およびp156抗原ならびにその使用 - Google Patents
イヌおよびヒトエールリヒア症の免疫診断のためのp153およびp156抗原ならびにその使用 Download PDFInfo
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- JP4494974B2 JP4494974B2 JP2004550409A JP2004550409A JP4494974B2 JP 4494974 B2 JP4494974 B2 JP 4494974B2 JP 2004550409 A JP2004550409 A JP 2004550409A JP 2004550409 A JP2004550409 A JP 2004550409A JP 4494974 B2 JP4494974 B2 JP 4494974B2
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Description
本出願は、2002年11月4日に出願し現在は放棄している米国仮特許出願第60/423,573号の利益を主張する。
連邦政府補助金の説明
本発明は、一部、国立アレルギー・感染症研究所(National Institute of Allergy and Infectious Diseases)の助成金第AI31431号のもと、連邦政府による補助金を用いてなされたものである。したがって、連邦政府は本発明において一定の権利を有する。
発明の分野
本発明は一般に、分子および免疫診断の分野に関する。より具体的には、本発明は、イヌエールリヒア症およびヒト単球性エールリヒア症の種特異的診断に有用である、エールリヒア・カニス(Ehrlichia canis)およびエールリヒア・シャフェエンシス(Ehrlichia chaffeensis)の種特異的免疫反応性タンパク質オーソログ(約200 kDa)に関する。
イヌ単球性エールリヒア症は、主としてリケッチア病原体、エールリヒア・カニスに起因する、世界全域に分布する、潜在的に致死性のイヌのダニ媒介疾患である(Huxsoll et al., 1970)。E. カニスは単核およびマクロファージに対する向性を示す偏性細胞内細菌であり(Nyindo et al., 1971)、脊椎動物宿主において持続的感染を確立する(Harrus et al., 1998)。本疾患は、3段階により特徴づけられる:2〜4週間持続する急性期;イヌは数年間一貫して感染したままであり得るが、臨床的徴候を示さない無症状期、その後の、多くのイヌにおいて骨髄形成不全および予後不良により疾患が徐々に悪化する慢性期(Troy et al., 1990)。
エールリヒア・カニスの免疫反応性の強い43 kDタンパク質(p43)が同定された(米国特許第6,355,777号)。p43は免疫診断抗原として、間接蛍光抗体試験と比較して96%の精度を有し、これによりE. カニス感染の種特異的診断が提供される。さらなる研究から、E. カニスp43は、エールリヒア種において記載されている中で最も大きな免疫反応性タンパク質である、予想分子量153 kDを有するタンパク質のN末端部分を表すことが明らかになった。組換え発現させたp153断片のタンパク質ゲル電気泳動による解析から、予想よりも大きな分子量(約10〜30%)であることおよびN末端およびC末端断片における糖グリカンの存在が実証され、p153が糖タンパク質であることが示された。
E. カニスp43遺伝子配列は以前に1173-bpとして報告されたが(米国特許第6,355,777号)、さらなる解析から、DNA配列決定の誤りで人工的な終止コドンが生じ、切断型の遺伝子配列が得られたことが明らかになった。プライマー-アダプター遺伝子歩行法により、元のp43クローンの2.4-kbpの下流にあるさらなる4.5-kbp配列を決定した。不完全なp43遺伝子配列を完全にし、予想分子量153 kDを有するタンパク質(p153と命名)をコードする4263-bpのオープンリーディングフレームが明らかになった。153遺伝子の上流には、E. カニスとE. シャフェエンシスとの間に高い核酸相同性(それぞれ87%および90%)を有する、デオキシグアノシン三リン酸三リン酸加水分解酵素をコードするオープンリーディングフレーム、およびp153遺伝子に先行する遺伝子間非コード領域が存在する。
E. カニスp153タンパク質およびE. シャフェエンシスp156タンパク質の特徴づけ
以前に記載した通りに(McBride et al., 2001;米国特許第6,355, 777号)、λZap II発現ライブラリーからE. カニスp43タンパク質遺伝子を同定した。元の2.4-kbクローンは、デオキシグアノシン三リン酸三リン酸加水分解酵素遺伝子をコードするオープンリーディングフレーム(ORF)および切断されたp43遺伝子断片に先行する下流の229-bp遺伝子間スペースからなった。プライマー-アダプターPCR法により、鋳型としてE.カニスゲノムDNA(Jake, North Carolina株)を用いて、p43オープンリーディングフレームの完全な配列を決定した。増幅に用いたプライマーを用いて単位複製配列を直接配列決定するか、または配列解析のためにTOPO/TAにクローニングした。E.カニスp43クローン(2.4-kb)全体を用いてE. シャフェエンシスゲノム配列のBLASTn検索を行うことにより、E. シャフェエンシスオーソログ(p156遺伝子) が同定された。
E. カニスp153のN末端(p43)部分を含むクローンの強い免疫反応性により、その最初の同定および特徴づけが導かれた(McBride et al., 2001)。イヌにおけるE. カニスに対する抗体を検出するための間接蛍光抗体試験の結果と比較した場合、p43は優れた感度および特異性を示した。さらに、抗組換えp43ポリクローナル抗体がE. シャフェエンシス感染DH82細胞と反応しなかったため、p43により種特異的検出が提供されると考えられた。遺伝子的に異なり低いアミノ酸相同性を有するE. シャフェエンシスのp153オーソログ(p156)が同定されたことから、p43タンパク質が種特異的抗原であり、ひいては優れた種特異的免疫診断抗原となるという以前の知見が支持される。主要な線状B細胞エピトープがp153タンパク質のN末端領域(p43)およびC末端領域に存在する。
Claims (13)
- エールリヒア・カニス(Ehrlichia canis)免疫反応性表面タンパク質p153をコードするDNAであって、SEQ ID NO: 2のアミノ酸配列を有するp153タンパク質をコードするDNA。
- 請求項1記載のDNAおよび細胞におけるDNA発現のために必要な制御要素を含むベクター。
- 請求項2記載のベクターで形質転換した宿主細胞。
- 細菌細胞、哺乳動物細胞、植物細胞、および昆虫細胞からなる群より選択される、請求項3記載の宿主細胞。
- SEQ ID NO: 2に示されるアミノ酸配列を有する、エールリヒア・カニス免疫反応性表面タンパク質p153。
- エールリヒア・シャフェエンシス(Ehrlichia chaffeensis)免疫反応性表面タンパク質p156をコードするDNAであって、SEQ ID NO: 1のアミノ酸配列を有するp156タンパク質をコードするDNA。
- 請求項6記載のDNAおよび細胞におけるDNA発現のために必要な制御要素を含むベクター。
- 請求項7記載のベクターで形質転換した宿主細胞。
- 細菌細胞、哺乳動物細胞、植物細胞、および昆虫細胞からなる群より選択される、請求項8記載の宿主細胞。
- SEQ ID NO: 1に示されるアミノ酸配列を有する、エールリヒア・シャフェエンシス免疫反応性表面タンパク質p156。
- 以下の段階を含む、イヌがエールリヒア種に感染しているかどうかを判定する方法:
該イヌの血液からDNAを抽出する段階;
SEQ ID NO: 2に示されるアミノ酸配列を有するp153タンパク質をコードするエールリヒア・カニスp153遺伝子またはSEQ ID NO: 1に示されるアミノ酸配列を有するp156タンパク質をコードするエールリヒア・シャフェエンシスp156遺伝子に特異的なオリゴヌクレオチドプライマーを用いて、該DNAにおいてPCR増幅を行う段階であって、該オリゴヌクレオチドプライマーは、SEQ ID NO: 1に示されるアミノ酸配列をコードするヌクレオチド配列もしくはその相補ヌクレオチド配列の一部からなるヌクレオチドを含むか、またはSEQ ID NO: 2に示されるアミノ酸配列をコードするヌクレオチド配列もしくはその相補ヌクレオチド配列の一部からなるヌクレオチドを含む、段階;
得られたPCR産物を大きさにより分離する段階;および
適切な大きさの増幅産物を検出する段階であって、適切な大きさの増幅産物の陽性検出によりエールリヒア・カニスまたはエールリヒア・シャフェエンシスによる感染が示される、段階。 - PCR産物がゲル電気泳動により検出される、請求項11記載の方法。
- 以下を含む、イヌがエールリヒア種に感染しているかどうかを判定するためのキット:
(a) 血液からDNAを抽出するための試薬;
(b) SEQ ID NO: 2に示されるアミノ酸配列をコードするヌクレオチド配列もしくはその相補ヌクレオチド配列の一部からなるヌクレオチドを含むp153特異的オリゴヌクレオチド、またはSEQ ID NO: 1に示されるアミノ酸配列をコードするヌクレオチド配列もしくはその相補ヌクレオチド配列の一部からなるヌクレオチドを含むp156特異的オリゴヌクレオチド;および
(c) PCR増幅のための試薬。
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US42357302P | 2002-11-04 | 2002-11-04 | |
PCT/US2003/034916 WO2004042037A1 (en) | 2002-11-04 | 2003-11-04 | P153 and p156 antigens for the immunodiagnosis of canine and human ehrlichioses and uses thereof |
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US7842474B2 (en) | 2005-04-04 | 2010-11-30 | Idexx Laboratories, Inc. | Ehrlichia canis DIVA (differentiate infected from vaccinated animals) |
WO2006107924A2 (en) * | 2005-04-04 | 2006-10-12 | Idexx Laboratories, Inc. | Ehrlichia canis diva (differentiate infected from vaccinated animals) |
CA2612302C (en) | 2005-06-16 | 2015-07-28 | Research Development Foundation | Immunoreactive protein orthologs of ehrlichia canis and e. chaffeensis |
PT2187958T (pt) | 2007-09-11 | 2017-03-17 | Yissum Res Dev Company Of The Hebrew Univ Of Jerusalem | Vacina atenuada de erliquiose |
WO2009039414A2 (en) | 2007-09-21 | 2009-03-26 | Idexx Laboratories, Inc. | Methods and compositions for detection of ehrlichia chaffeensis (vlpt) |
EP2045816A1 (en) * | 2007-10-01 | 2009-04-08 | Paul Scherrer Institut | Fast readout method and swiched capacitor array circuitry for waveform digitizing |
EP2664344B1 (en) | 2007-10-31 | 2019-02-27 | Idexx Laboratories, Inc. | Ehrlichia canis diva (differentiate infection from vaccinated animals) |
JP5677703B2 (ja) * | 2008-01-10 | 2015-02-25 | リサーチ ディベロップメント ファウンデーション | Ehrlichiachaffeensisにのためのワクチンおよび診断 |
AU2010321790B2 (en) | 2009-11-20 | 2016-08-04 | Zoetis Services Llc | Peptides, devices, and methods for the detection of Ehrlichia antibodies |
CN103200960B (zh) * | 2010-07-02 | 2019-04-23 | 英特维特国际股份有限公司 | 针对犬埃利希体的疫苗和相关方法 |
US9651546B2 (en) | 2012-10-11 | 2017-05-16 | Abaxis, Inc. | Peptides, devices, and methods for the detection of ehrlichia antibodies |
US9194870B2 (en) | 2014-01-21 | 2015-11-24 | Abaxis, Inc. | Peptides, devices, and methods for the detection of Anaplasma antibodies |
US9442112B2 (en) | 2014-04-04 | 2016-09-13 | Abaxis, Inc. | Compositions and methods for identifying Ehrlichia species |
US20220356231A1 (en) * | 2019-07-12 | 2022-11-10 | Research Development Foundation | Ehrlichia vaccines and immunogenic compositions |
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US6653128B2 (en) * | 1996-10-17 | 2003-11-25 | University Of Florida | Nucleic acid vaccines against rickettsial diseases and methods of use |
US6403093B1 (en) | 1997-03-21 | 2002-06-11 | Mayo Foundation For Medical Education And Research | Methods to detect granulocytic ehrlichiosis |
US6207169B1 (en) * | 1997-03-21 | 2001-03-27 | Corixa Corporation | Compounds and methods for the diagnosis and treatment of Ehrlichia infection |
US6436399B1 (en) * | 1998-04-09 | 2002-08-20 | The Ohio State University Research Foundation | Nucleic acid encoding the major outer membrane protein of the causative agent of human granulocytic ehrlichiosis and peptides encoded thereby |
WO1999052370A1 (en) * | 1998-04-09 | 1999-10-21 | The Ohio State Research Foundation | Nucleic acids encoding outer membrane protein of human granulocytic ehrlichiosis agent |
US6043085A (en) * | 1998-08-27 | 2000-03-28 | Research Development Foundation | Ehrlichia canis 120-kDa immunodominant antigenic protein and gene |
US6544517B1 (en) * | 1998-09-18 | 2003-04-08 | The Ohio State University Research Foundation | Outer membrane protein of Ehrlichia canis and Ehrlichia chaffeensis |
US6355777B1 (en) * | 2000-04-28 | 2002-03-12 | Research Development Foundation | P43 antigen for the immunodiagnosis of canine ehrlichiosis and uses thereof |
US6512005B2 (en) * | 2001-02-28 | 2003-01-28 | Taro Pharmaceutical Industries, Ltd. | Process for synthesis of pure warfarin acid, warfarin alkali metal salts and corresponding clathrates |
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US7204992B2 (en) | 2007-04-17 |
US7754224B2 (en) | 2010-07-13 |
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ATE372378T1 (de) | 2007-09-15 |
US20070218082A1 (en) | 2007-09-20 |
BRPI0315980B1 (pt) | 2016-03-29 |
CN101294162B (zh) | 2011-03-30 |
DE60316189T2 (de) | 2007-12-20 |
DE60316189D1 (de) | 2007-10-18 |
AU2003290575B2 (en) | 2009-10-29 |
KR20050084679A (ko) | 2005-08-26 |
EP1581638A4 (en) | 2005-12-28 |
CN1735684A (zh) | 2006-02-15 |
ES2293057T3 (es) | 2008-03-16 |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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LAPS | Cancellation because of no payment of annual fees |