JPWO2009041501A1 - ヘルペスウイルスの潜伏感染に関与する因子及びその利用 - Google Patents
ヘルペスウイルスの潜伏感染に関与する因子及びその利用 Download PDFInfo
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Abstract
Description
Kondo. K et al. Ltatent human herpesvirus 6 infection of human monocytes /macrophages (J Gen Virol 72:1401-1408, 1991) Kondo. K et al. Association of human herpesvirus 6 infection of the central nervous system with recurrence of febrile convulsions. (J Infect Dis 167:1197-1200, 1993.) Kondo. K et al. Identification of human herpesvirus 6 latency-associated transcripts. (J Virol. 76: 4145-4151, 2002) Kondo K et al. Recognition of a Novel Stage of Beta-Herpesvirus Latency in Human Herpesvirus 6. (J Virol. 77: 2258-2264, 2003) 近藤一博著、「ヘルペスウイルス感染と疲労」、ウイルス、第55巻 第1号 p9-18 2005
(a)配列番号1に示されるアミノ酸配列からなるタンパク質。
(b)配列番号1のアミノ酸配列において、1個又は数個のアミノ酸が置換、欠失、挿入、及び/又は付加されたアミノ酸配列からなり、かつ細胞内カルシウム濃度を上昇させる活性を有するタンパク質。
(a)配列番号1に示されるアミノ酸配列からなるタンパク質。
(b)配列番号1のアミノ酸配列において、1個又は数個のアミノ酸が置換、欠失、挿入、及び/又は付加されたアミノ酸配列からなり、かつ細胞内カルシウム濃度を上昇させる活性を有するタンパク質。
(i)(4)又は(5)に記載のタンパク質
(ii)(i)の部分断片
(iii)(i)又は(ii)を固定化した器具
(16)被験者が精神障害を有するか否かを診断する診断方法であって、(11)〜(13)のいずれかに記載の判定方法を用いて、該被験者において(6)に記載の抗体が存在しているか否かを判定する判定過程と、上記判定過程にて、(6)に記載の抗体が存在していると判定された場合、該被験者が慢性疲労症候群を罹患していると判断する判断過程と、を含む診断方法。
(i)(4)又は(5)に記載のタンパク質
(ii)(i)の部分断片
(iii)(i)又は(ii)を固定化した検出器具
(21)被験動物が精神障害のモデル動物として有用であるか否かを判定するモデル動物の判定方法であって、(18)に記載の診断方法により、上記被験動物が精神障害を有するか否かを診断する診断過程と、上記診断過程において、被験動物が精神障害を有することを指標として、上記被験動物が精神障害のモデル動物として有用であると判定する判定過程と、を備えるモデル動物の判定方法。
(1−1)構造
本発明は、ヘルペスウイルスの潜伏感染に関与する因子、より詳細にはヘルペスウイルスの潜伏感染時に特異的に発現するタンパク質及び該タンパク質をコードする遺伝子を提供するものである。ここで「ヘルペスウイルスの潜伏感染時に特異的に発現する」とは、ヘルペスウイルスが感染している宿主において、ヘルペスウイルスが潜伏感染している(増殖感染していない)際に、特異的に、ヘルペスウイルス由来の遺伝子又は遺伝子産物が発現することをいう。
本発明に係るタンパク質の機能について、上述のSITH−1タンパク質を例に挙げて詳細に説明する。
本発明に係る遺伝子及びタンパク質の取得方法(又は生産方法)は特に限定されるものではないが、代表的な方法として次に示す各方法を挙げることができる。
本発明に係るタンパク質を取得する方法(又はタンパク質の生産方法)は、上述したように特に限定されるものではないが、まず、本発明に係るタンパク質を含有する生物学的試料(例えば、細胞、組織、生物個体等)などから単純精製する方法を挙げることができる。また精製方法についても特に限定されるものではなく、公知の方法で細胞や組織から細胞抽出液を調製し、この細胞抽出液を公知の方法、例えばカラム等を用いて精製すればよい。例えば、細胞又は組織より抽出した粗タンパク質画分を高速液体クロマトグラフィー(HPLC)にかけ、本発明に係るタンパク質の精製・分離を行うことができる。
本発明に係る遺伝子を取得する方法(又は遺伝子の生産方法)も上述したように特に限定されるものではないが、例えば、ディファレンシャルスクリーニング(サブトラクションクローニング)を利用する方法を挙げることができる。この方法では、公知の技術に従って、試験管内での直接的ハイブリダイゼーションを繰り返し、目的のcDNA(本発明に係る遺伝子)を濃縮すればよい。
本発明に係る抗体は、本発明に係るタンパク質、例えば前記(a)又は(b)に記載のタンパク質、又はその部分ペプチドを抗原として、公知の方法によりポリクローナル抗体又はモノクローナル抗体として得られる抗体である。公知の方法としては、例えば、文献(Harlowらの「Antibodies : A laboratory manual(Cold Spring Harbor Laboratory, New York(1988))、岩崎らの「単クローン抗体 ハイブリドーマとELISA、講談社(1991)」」に記載の方法が挙げられる。このようにして得られる抗体は、本発明に係るタンパク質の検出・測定などに利用できる。
本発明に係る組換え発現ベクターは、上記(a)又は(b)に記載のタンパク質をコードする本発明の遺伝子を含むものである。例えば、cDNAが挿入された組換え発現ベクターが挙げられる。組換え発現ベクターの作製には、プラスミド、ファージ、又はコスミドなどを用いることができるが特に限定されるものではない。また、作製方法も公知の方法を用いて行えばよい。
本発明に係る形質転換体は、本発明に係る遺伝子が導入された形質転換体、すなわち、上記(3)欄に記載の組換え発現ベクターが導入された形質転換体である。ここで、「遺伝子が導入された」とは、公知の遺伝子工学的手法(遺伝子操作技術)により、対象細胞(宿主細胞)内に発現可能に導入されることを意味する。また、上記「形質転換体」とは、細胞・組織・器官のみならず、生物個体を含む意味である。
本発明に係る遺伝子検出器具は、本発明に係る遺伝子における少なくとも一部の塩基配列又はその相補配列をプローブとして用いたものである。遺伝子検出器具は、種々の条件下において、本発明に係る遺伝子の発現パターンの検出・測定などに利用することができる。
本発明に係る遺伝子検出器具に用いる基板の材質としては、オリゴヌクレオチドを安定して固定化することができるものであればよい。例えば、ポリカーボネートやプラスチックなどの合成樹脂、ガラス等を挙げることができるが、これらに限定されるものではない。基板の形態も特に限定されるものではないが、例えば、板状、フィルム状等の基板を好適に用いることができる。
本発明に係る遺伝子検出器具の基板表面に固定化されるオリゴヌクレオチドは、本発明に係る遺伝子の少なくとも一部分の塩基配列に基づくオリゴヌクレオチドであればよい。当該オリゴヌクレオチドとサンプル由来の核酸との間にハイブリダイゼーションが成立することにより、サンプル中に含まれている遺伝子を検出することが可能となる。なお、上記本発明に係る遺伝子の少なくとも一部分の塩基配列に基づくオリゴヌクレオチドを、以下「キャプチャーオリゴ」と称する場合もある。
オリゴヌクレオチドの基板表面への固定化法は特に限定されるものではなく、公知の方法を適宜選択して用いればよい。例えば、物理的吸着、電気的結合または分子共有結合などの一般的なハイブリダイゼーション法に用いられる手法が利用可能である。本発明に係る遺伝子検出器具においては、表面にカルボジイミド基又はイソシアネート基を有する基材を使用し(米国特許:US5,908,746、特開平8−23975号)、固定化することが好ましい。
本発明に係る検出器具は、本発明に係るタンパク質における少なくとも一部のアミノ酸配列をプローブとして用いたものである。すなわち、本発明に係るタンパク質又はその部分断片(フラグメント)を固定化した検出器具と換言できる。かかる検出器具は、種々の条件下において、本発明に係るタンパク質と相互作用する物質(ポリペプチド、核酸、抗体など)の検出・測定などに利用することができる。
本発明に係る遺伝子及びタンパク質は、上述のごとくヘルペスウイルスの潜伏感染時に特異的に発現するものであって、該タンパク質は、脳内アストロサイトなどのグリア細胞で発現させることにより宿主の精神障害を誘導できる機能を有すると考えられる。
このように、精神障害患者でのみ本発明に係るタンパク質に対する抗体が検出されるという現象の詳細な機構は未だ明らかではないが、かかる現象を利用することにより、精神障害を客観的に判断するのに資する判定方法や診断方法を提供することができる。また、同時に本発明は、判定キット、診断キット、モデル動物の作成方法、薬剤スクリーニング方法にも関するものである。以下、各方法について詳細に説明する。
本発明に係る判定方法は、本発明に係るタンパク質を認識する抗体、つまり上記(a)又は(b)に記載のタンパク質を認識する抗体が、被験対象生物中に存在するか否かを判定する方法であればよい。なお、用語「被験対象生物」とは、ヒト及びヒト以外の哺乳類の動物を意味する。
本発明に係る診断方法は、上記の判定方法を用いていればよく、その他の具体的な構成、条件等は特に限定されない。例えば、被験対象の患者又は被験動物において、本発明に係る抗体が存在することを指標として、当該被験対象の患者又は被験動物が精神障害に罹患していると判定することができる。また、本発明に係る抗体の定量値を指標として診断する場合、健常者における定量値(正常値)や典型的な精神障害患者の定量値(疾患値)を参考にして適切な閾値を設定し、該閾値を上回っているか、又は下回っていれば、精神障害である可能性が高いと診断することもできる。本発明では、精神障害の発症によって上記抗体の量が増加するため、例えば、健常者における定量値(正常値)を閾値として設定する場合、被験者の測定値がこの閾値を上回っていれば、精神障害である可能性が高いと判定し得る。
本発明に係る判定キット又は診断キットはそれぞれ、上記(7−1)欄で説明した判定方法又は上記(7−2)欄で説明した診断方法を実施するためのものであればよく、これに含まれる具体的な構成、材料、機器等は、特に限定されるものではない。具体的には、本発明に係る抗体を、免疫学的に検出するために、以下の(i)〜(iii)のいずれかの物質が含まれていることが好ましい。(i)本発明に係るタンパク質、(ii)(i)の部分断片(エピトープ保有ペプチドを含むことが好ましい)、(iii)(i)又は(ii)を固定化した検出器具。
本発明の診断方法は、ヒトを除く精神障害のモデル動物の作成法、有用性を判定する方法、及びこのようなモデル動物を用いた薬物スクリーニングにおいて、薬物の有効性を判定する方法に応用し得る。すなわち、精神障害のモデル動物の作成の場合には、実施例にもある様に、ベクターなどを用いて動物の脳内にSITH−1タンパク質を導入して作成することができる。また、精神障害のモデル動物の有用性を判定する場合には、前記判定方法や診断方法と同様に、本発明に係る抗体の有無に基づいて、被験動物が精神障害を発症しているか否かを判断し、該動物が精神障害を発症していれば、精神障害のモデル動物として有用であると判定することができる。
非特許文献1に示したHHV−6が潜伏感染しているマクロファージからメッセンジャーRNA(mRNA)を分離し、ランダムプライマーおよびsense transcriptsの逆転写用プライマーとしてIE4RBを、anti-sense transcriptの逆転写用にプライマーIE2FBを用いて逆転写反応を行った。その後逆転写産物(cDNA)を、プライマーIE4RBとIE2FBを用いてPCR法にて増幅し、その産物を内側のプライマーIE4RAとIE2FAを用いてdouble-nested PCR法にて増幅した。図1に、公知である増殖感染時のmRNAとSense transcript (H6LT)と、新規潜伏感染特異的遺伝子の位置関係および潜伏感染特異的タンパク質SITH−1のopen reading frameを示す。SITH−1および新規潜伏感染特異的遺伝子のシークエンス情報は、配列表参照。
IE4RB: 5‘GATGCTCCTTCTTCCACATTACTGG 3’
IE2FB: 5’ CATCCCATCAATTATTGGATTGCTGG 3’
IE2FA: 5' GAAACCAC- CACCTGGAATCAATCTCC 3'.
IE4RA: 5' GACACATTCTTGGAAGCGATGTCG 3'
N1: 5' GCTGGGTAGTCCCCACCTTTCTAGA 3'.
αF1: 5' CTGAAGCATGTAAGCACATCTCTTGC 3'
αR1: 5' GCTTCGAGATCAGTAGTGGTACG3'
<2.新規潜伏感染特異的遺伝子タンパク質SITH-1の機能解析>
タンパク質SITH−1の機能を検討するために、タンパク質SITH−1が細胞内で結合する宿主タンパク質の同定を行った。方法としては、タンパク質SITH−1をbaitとして、Yeast Two-hybrid法にてヒト胎児脳cDNAライブラリーのスクリーニングを行った。この結果を図4に示す。図4中、Aは、SITH−1とCAMLの結合により、強いβ−ガラクトシダーゼ発現のみられたyeastのクローンである。Bは、in vitroのpull-down assayにより、大腸菌で発現させたGST−SITH−1融合タンパク質により、大腸菌で発現させたCAMLが共沈させることができたことを、ウエスタンブロットと抗CAML抗体の染色により確認した図である。Cは、293T細胞にFLAGタグをつけたSITH−1とCAMLを、発現ベクターを用いて導入し、抗CAML抗体によってSITH−1を共沈させることができたことを、ウエスタンブロットと抗FLAG抗体の染色により確認した結果を示す図である。図4に示すように、タンパク質SITH−1がCalcium-signal modulating cyclophilin ligand (CAML)と強く結合することが示された(図4)。
次に、SITH−1と精神障害との関係を調べた。その結果を図7に示す。SITH−1に対する抗体は、非特許文献5などで報告してきた潜伏感染遺伝子タンパク質とは異なり、慢性疲労症候群患者そのものとの関連性は低かったが、精神障害を持つ患者では高率に抗体保有者が存在した。精神症状を伴う慢性疲労症候群(CFS)患者は、主として鬱症状を、小児のCFS患者は主として異常な興奮性を示す場合が多かった。双極I型は、症状の強い躁鬱病患者を表す。また、健常成人はSITH−1に対する抗体をほとんど保有していなかった。なお、抗体価は、SITH−1を発現させた293T細胞を抗原として、蛍光抗体法にて測定した。
SITH−1のopen reading frame上流にアストロサイトなどのグリア細胞で特異的に発現するglial fibrillary acidic protein (GFAP)プロモーターを付加したものを、アデノウイルスベクターまたはレトロウイルスベクターを用いて、生後間もなくマウスの脳内に注射した。約4〜5週後にマウスの行動を観察し、SITH-1導入による精神障害モデルマウスの成立を確認した。
次に、SITH−1のopen reading frameを、GFAPプロモーター下につなぎ、アデノウイルスベクターを用いて、マウスのグリア細胞で発現させ、3週間後にWheel running activity(滑車回し)にて自発運動量を測定した。結果を図11に示す。
続いて、SITH−1のopen reading frameを、GFAPプロモーター下につなぎ、レンチウイルスベクターを用いて、マウスのグリア細胞で発現させ、8週間後にWheel running activity(滑車回し)にて自発運動量を測定した。その結果を図12に示す。
SITH−1による診断が、うつ病を併発する他の疾患の診断にも有用であることを調べた。その結果を図13に示す。
Claims (23)
- 以下の(a)又は(b)に記載のタンパク質をコードする遺伝子。
(a)配列番号1に示されるアミノ酸配列からなるタンパク質。
(b)配列番号1のアミノ酸配列において、1個又は数個のアミノ酸が置換、欠失、挿入、及び/又は付加されたアミノ酸配列からなり、かつ細胞内カルシウム濃度を上昇させる活性を有するタンパク質。 - 配列番号2に示される塩基配列をオープンリーディングフレーム領域として有する遺伝子。
- 配列番号2に示される塩基配列からなるDNAと相補的な塩基配列からなるDNAとストリンジェントなハイブリダイゼーション条件下でハイブリダイズし、かつ細胞内カルシウム濃度を上昇させる活性を有するタンパク質をコードする遺伝子。
- 請求項1〜3のいずれか1項に記載の遺伝子にコードされるタンパク質。
- 以下の(a)又は(b)に記載のタンパク質。
(a)配列番号1に示されるアミノ酸配列からなるタンパク質。
(b)配列番号1のアミノ酸配列において、1個又は数個のアミノ酸が置換、欠失、挿入、及び/又は付加されたアミノ酸配列からなり、かつ細胞内カルシウム濃度を上昇させる活性を有するタンパク質。 - 請求項4又は5に記載のタンパク質を認識する抗体。
- 請求項1〜3のいずれか1項に記載の遺伝子を含む組換え発現ベクター。
- 請求項1〜3のいずれか1項に記載の遺伝子又は請求項7に記載の組換え発現ベクターを導入してなる形質転換体。
- 請求項1〜3のいずれか1項に記載の遺伝子における少なくとも一部の塩基配列又はその相補配列をプローブとして用いた遺伝子検出器具。
- 請求項4又は5に記載のタンパク質における、少なくとも一部のアミノ酸配列を有するポリペプチドをプローブとして用いた検出器具。
- 被験対象生物において、請求項6に記載の抗体が存在するか否かを判定することを特徴とする判定方法。
- 上記判定方法は、請求項4又は5に記載のタンパク質若しくはその部分断片を用いて、免疫学的に請求項6に記載の抗体が存在するか否かを検出することを特徴とする請求項11に記載の判定方法。
- 上記判定方法は、被験対象生物から分離された生物学的試料を用いて行われることを特徴とする請求項11又は12に記載の判定方法。
- 請求項11〜13のいずれか1項に記載の判定方法を行うための判定キット。
- 以下に示す(i)〜(iii)から選択される物質のうち、少なくとも1つの物質を含むことを特徴とする請求項14に記載の判定キット。
(i)請求項4又は5に記載のタンパク質
(ii)(i)の部分断片
(iii)(i)又は(ii)を固定化した器具 - 被験者が精神障害を有するか否かを診断する診断方法であって、
請求項11〜13のいずれか1項に記載の判定方法を用いて、該被験者において請求項6に記載の抗体が存在しているか否かを判定する判定過程と、
上記判定過程にて、請求項6に記載の抗体が存在していると判定された場合、該被験者が精神障害を有すると判断する判断過程と、を含むこと特徴とする診断方法。 - 上記診断方法は、被験者から分離された生物学的試料を用いて行われることを特徴とする請求項16に記載の診断方法。
- 被験動物が精神障害を有するか否かを診断する診断方法であって、
請求項11〜13のいずれか1項に記載の判定方法を用いて、該被験動物において請求項6に記載の抗体が存在しているか否かを判定する判定過程と、
上記判定過程にて、請求項6に記載の抗体が存在していると判定された場合、該被験動物が精神障害を有すると判断する判断過程と、を含むこと特徴とする診断方法。 - 請求項16〜18のいずれか1項に記載の診断方法を行うための診断キット。
- 以下に示す(i)〜(iii)から選択される物質のうち、少なくとも1つの物質を含むことを特徴とする請求項19に記載の診断キット。
(i)請求項4又は5に記載のタンパク質
(ii)(i)の部分断片
(iii)(i)又は(ii)を固定化した検出器具 - 被験動物が精神障害のモデル動物として有用であるか否かを判定するモデル動物の判定方法であって、
請求項18に記載の診断方法により、上記被験動物が精神障害を有するか否かを診断する診断過程と、
上記診断過程において、被験動物が精神障害を有することを指標として、上記被験動物が精神障害のモデル動物として有用であると判定する判定過程と、を備えることを特徴とするモデル動物の判定方法。 - 請求項1〜3のいずれか1項に記載の遺伝子、当該遺伝子産物、または請求項7に記載の組換え発現ベクターを導入してなることを特徴とするモデル動物。
- 向精神薬の候補物質をスクリーニングするスクリーニング方法であって、
精神障害のモデル動物に被験物質を与える過程と、
請求項18に記載の診断方法により、上記モデル動物の精神障害が治癒又は改善されたか否かを診断する過程と、
上記モデル動物の精神障害が治癒又は改善していることを指標として、上記被験物質が向精神薬の候補物質であると判定する過程と、を備えることを特徴とするスクリーニング方法。
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JP2013063090A Active JP5829228B2 (ja) | 2007-09-27 | 2013-03-25 | ヘルペスウイルスの潜伏感染に関与する因子及びその利用 |
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EP (2) | EP2199391B1 (ja) |
JP (4) | JP4920084B2 (ja) |
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CN (1) | CN101809153B (ja) |
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EP2199391B1 (en) * | 2007-09-27 | 2015-11-11 | Japan Tobacco, Inc. | Factor involved in latent infection with herpesvirus, and use thereof |
US9657324B1 (en) | 2008-10-03 | 2017-05-23 | Virus Ikagaku Kenkyusho Inc. | Method for treating or preventing mood disorders |
CA2756109A1 (en) * | 2009-03-31 | 2010-10-07 | Japan Tobacco Inc. | Method for detecting substance in biological sample |
EP2416159A4 (en) * | 2009-03-31 | 2012-05-30 | Japan Tobacco Inc | METHOD FOR DETECTING ANTIBODY AGAINST SITH-1 IN A BIOLOGICAL SAMPLE |
CN105705657B (zh) * | 2013-10-18 | 2020-07-28 | Seegene株式会社 | 基于利用杂交-捕捉和模板化寡核苷酸的探测和标记寡核苷酸切割及延伸分析的在固相中的靶核酸序列检测 |
US10067142B2 (en) | 2014-06-27 | 2018-09-04 | Japan Tobacco Inc. | Method for diagnosing, treating, or preventing mood disorder |
JP6623162B2 (ja) * | 2014-08-27 | 2019-12-18 | 株式会社ウイルス医科学研究所 | 疲労に関与する因子及びその利用 |
EP3398969A4 (en) * | 2015-12-28 | 2019-07-31 | Japan Tobacco, Inc. | METHOD FOR DIAGNOSING, TREATING OR PREVENTING MOOD DISORDERS |
CN105532575A (zh) * | 2016-01-14 | 2016-05-04 | 中国科学院昆明动物研究所 | 一种单纯疱疹病毒感染树鼩动物模型的构建、评估方法及其应用 |
CN109376816B (zh) * | 2018-09-11 | 2022-04-01 | 广州金域医学检验中心有限公司 | 一种病理切片质量监控方法及其装置 |
JP7264384B2 (ja) | 2019-03-29 | 2023-04-25 | 日本たばこ産業株式会社 | うつ病の評価を補助するための方法及びうつ病の治療法の効果の評価を補助するための方法、並びにうつ病若しくはうつ病の治療法の効果を評価するためのデータを取得する方法 |
JP2024065869A (ja) | 2022-10-31 | 2024-05-15 | 株式会社荏原製作所 | 基板処理装置、基板処理方法 |
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