JP7365328B2 - 酸素感受性グラム陽性細菌の保護に使用されるポリペプチド - Google Patents
酸素感受性グラム陽性細菌の保護に使用されるポリペプチド Download PDFInfo
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- JP7365328B2 JP7365328B2 JP2020501467A JP2020501467A JP7365328B2 JP 7365328 B2 JP7365328 B2 JP 7365328B2 JP 2020501467 A JP2020501467 A JP 2020501467A JP 2020501467 A JP2020501467 A JP 2020501467A JP 7365328 B2 JP7365328 B2 JP 7365328B2
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Description
発明者らは、hReg3αレクチンの濃度をhReg3αトランスジェニックマウスの胃腸管(GIT)内腔中で増大させると、腸内細菌叢の組成の顕著な変化が誘導され、宿主の腸炎に対する耐性が顕著に改善することを示した。実際に、DSS(デキストラン硫酸ナトリウム)に暴露したhReg3α-トランスジェニックマウスは、大腸炎の兆候を殆ど呈さず、強固な粘膜障壁を保持し、完全な生存率を達成した。hReg3αは、特に高度に酸素感受性の細菌の生存率を促進することにより、大腸炎において腸上皮細胞に対する強力な抗酸化活性、特に原核細胞において作用する組換え人Reg3α(rcREG3α)のROS除去活性を呈した。
(i)小腸の炎症;
(ii)酸素、特に反応性酸素種への暴露;
の1つ以上に対抗して、酸素感受性グラム陽性細菌を保護する。
本発明の他の態様において、上記Reg3αポリペプチドは、微生物叢に関連する疾患及び/又は障害を予防又は治療するために使用される。
上記定義は、非治療的用途にも適用される。
MLPPMALPSVSWMLLSCLMLLSQVQGEEPQRELPSARIRCPKGSKAYGSHCYALFLSPKSWTDADLACQKRPSGNLVSVLSGAEGSFVSSLVKSIGNSYSYVWIGLHDPTQGTEPNGEGWEWSSSDVMNYFAWERNPSTISSPGHCASLSRSTAFLRWKDYNCNVRLPYVCKFTD
MEEPQRELPSARIRCPKGSKAYGSHCYALFLSPKSWTDADLACQKRPSGNLVSVLSGAEGSFVSSLVKSIGNSYSYVWIGLHDPTQGTEPNGEGWEWSSSDVMNYFAWERNPSTISSPGHCASLSRSTAFLRWKDYNCNVRLPYVCKFTD
EEPQRELPSARIRCPKGSKAYGSHCYALFLSPKSWTDADLACQKRPSGNLVSVLSGAEGSFVSSLVKSIGNSYSYVWIGLHDPTQGTEPNGEGWEWSSSDVMNYFAWERNPSTISSPGHCASLSRSTAFLRWKDYNCNVRLPYVCKFTD
IRCPKGSKAYGSHCYALFLSPKSWTDADLACQKRPSGNLVSVLSGAEGSFVSSLVKSIGNSYSYVWIGLHDPTQGTEPNGEGWEWSSSDVMNYFAWERNPSTISSPGHCASLSRSTAFLRWKDYNCNVRLPYVCKFTD
恒常的及び炎症条件下でのhReg3αにおけるトランスジェニックマウスにおける腸内微生物叢の組成及び腸障壁の完全性に対する人Reg3α(hReg3α)の効果を試験した。炎症は、デキストラン硫酸ナトリウム(DSS)の経口吸収によって誘導した。上部GITにおける酸及び内腔プロテアーゼによるhReg3αタンパク質の分解を防ぐため、予め作製したマウスアルブミン遺伝子プロモーターのコントロール下肝細胞中でhReg3αを発現するホモ接合トランスジェニックC57BL/6マウスを使用した。これらのマウスにおいて、hReg3αタンパク質は胆管内及び胃腸管(GIT)内に流れ込むことが示された。トランスジェニック肝細胞は、hReg3αを側底膜を通じて血管内に分泌し、頂端膜を通じて毛細胆管内に分泌した。
hReg3αトランスジェニックマウスにおける微生物叢の変化は、グラム陽性及びグラム陰性細菌の間の比率の大幅な増大に対応した。これは、報告されていたhReg3αの選択的抗グラム陽性細菌抑制活性と整合し難い。hReg3αの抗酸化活性がhReg3αトランスジェニックマウスの腸内微生物系の変化の重要な因子であると予想された。そのメカニズムは、Clostridia幾つかのと同様に、厳しい嫌気性グラム陽性細菌に有利なhReg3αによって呈される選択圧であり得る。この見解を立証するため、インビトロで原核生物における全長組換えヒトReg3αタンパク質(rcReg3α)の抗酸化効率を試験した。使用した組換えタンパク質は、真核細胞における抗炎症能力及び炭水化物結合選択性に関して化学的及び生物学的に活性である。まず、グラム陽性腸内共生細菌Enterococcus faecalisを培養し、対数増殖期の間ROS発生剤(パラコート)でストレスを掛けた。200mMパラコートへの暴露は、E. faecalisに対し強力な殺細菌効果を有していた。E. faecalisの対数増殖は10μMのrcReg3αの添加によって保存され、パラコートによって発生したROSがrcReg3αの存在下効率的に減少することを示唆する。これは、ROS特異的蛍光プローブH2-DCFDA及びヨウ化プロビジウムDNA染色を用いたフローサイトメトリー測定によって実証された。若干の細菌凝集が見られたが、従来の報告に反してに対するE. faecalis殺細菌活性は無かった。この相違は細菌株によるかもしれないが、Reg3αの殺細菌活性の欠如は、トランスジェニックマウスの腸内微生物叢中で見られたグラム陽性細菌の増加と一致する。
IBD患者のバランスの崩れた微生物叢は、Sutterellaceae, Prevotellaceae及びEnterobacteriaceae(Proteobacteria門)の増加並びにRuminococcaceae及びLachnospiraceae (主な酪酸塩生産共生生物を含む)の減少によって最も特徴付けられる。腸内微生物叢の組成の類似の変化は、遺伝的に感受性のマウスモデルにおける大腸炎にも関連する。hReg3αトランスジェニックマウスの腸内微生物叢に大なり小なり逆の変化が起こっているという事実は、hReg3αにより形成された微生物叢は健康に有益な影響を有することを示唆する。
腸炎に対するhReg3αによって整えられた微生物叢の保護作用を評価するため、コハウジングによってhReg3αトランスジェニックマウスからWTマウスに便微生物叢を移動させた。3週齢の離乳したWTマウスを同齢のhReg3αトランスジェニックマウスと8週間コハウジングし、DSSで処理した。対照群はWTマウスのみ飼育したものである。コハウジング期間の終了時、コハウジングしたWT(CoH-MT)マウスの腸内微生物叢の組成は、細菌の科レベルでhReg3αトランスジェニックマウスのプロファイルへの顕著なシフトを呈し、便の稠度及び出血、腸障壁の完全性及び生存率において、DSS誘導大腸炎の明確な緩和が見られた。
腸内の先天的免疫分子が腸障壁機能及び腸内微生物叢の恒常性においてそれらの多面的な活性を通じて重要な役割を果たすことは、一般に受け入れられている。また、それは腸内微生物叢と腸上皮障壁との間の共生的相互作用を不安定化するため、それらの機能的発現の不調が、慢性炎症性腸疾患の重要な寄与因子であることも広く信じられている。しかしながら、それらの操作が宿主微生物叢恒常性を保存する助けとなり、腸の炎症を防止するかどうかは、尚も立証されていない。この研究において、トランスジェニックマウスのhReg3αレクチンの内腔濃度の増大が、腸内微生物叢の組成の顕著な変化を誘導し、腸の炎症に対する宿主の耐性を劇的に改善することが示された。実際に、DSSに暴露したhReg3αトランスジェニックマウスは、大腸炎の兆候を殆ど呈さず、強固な粘膜障壁を保持し、完全な生存を達成した。大腸上皮における炎症応答及び酸化ストレスが、WTマウスと比較してDSS処理されたhReg3αトランスジェニックマウスにおいてより減少し、これは、hReg3αが、大腸炎の間腸上皮細胞に対して強力な抗酸化活性を呈することを示唆している。また、インビトロでの研究において、組換えヒトReg3α(rcReg3α)のROS排除活性が、特に、高度に酸素感受性の細菌の生存を促進することにより、原核細胞に対して作用したことも示された。
rcReg3αの静脈内投与はhReg3αトランスジェニックマウスとは反対にWTマウスにおいてDSS誘導大腸炎を改善しなかった
炎症条件下WTマウスに1日あたり4.2μgの組換えヒトReg3α(rcReg3α)を静脈内投与した効果を試験した。炎症は、デキストラン硫酸ナトリウム(DSS)の経口摂取により誘導された。これらの結果は、マウスアルブミン遺伝子プロモーターの制御下で肝細胞中にhReg3αを発現するホモ接合トランスジェニックC57BL/6マウスと比較された。トランスジェニック肝細胞は、hReg3αを側底膜を通じて血管内に分泌し、頂端膜を通じて毛細胆管内に分泌した。
hReg3αトランスジェニックマウスは抗生物質治療後のDSS誘導大腸炎に対しより良好な耐性を有する
抗生物質による微生物叢の分解は炎症の悪化や腸及び腸外に有害な効果をもたらす。WTマウス及びhReg3αトランスジェニックマウスにバンコマイシン及びゲムシタビンの2つの抗生物質(Abx)を3日間投与して、その後DSS誘導大腸炎を起こした場合の効果を試験した。バンコマイシンは、細菌細胞壁に結合し細胞膜の透過性を変化させることによって殆どのグラム陽性生物を殺す三環式糖ペプチドである。これはまた細菌のRNA合成も阻害する。ゲンタマイシンは、好気性グラム陰性桿菌を標的とする広範囲のアミノグリコシド系抗生物質である。
hReg3αの直腸内投与が大腸炎のWTマウスにおける結腸のダメージ及び炎症を減少した
大腸炎のWTマウスにおけるrcReg3αの直腸内投与の効果を評価した。100μgのrcReg3α(rcReg3α;n=14)又は同体積の緩衝剤(n=15)を、トリニトロベンゼンスルホン酸(TNBS)投与の前日及び当日に送達した。
Claims (4)
- 酸素感受性グラム陽性細菌のエクスビボ増殖を促進するための、配列番号1、配列番号2、配列番号3及び配列番号4に記載される配列からなる群から選択されるアミノ酸配列、又はこれと90%以上の同一性を有する配列を含み、かつ酪酸塩生成細菌の生存及び増殖率を増大し、酪酸塩の濃度を増大する活性を有する、Reg3αポリペプチドの使用。
- 前記酸素感受性グラム陽性細菌がClostridiales目のものである、請求項1に記載のReg3αポリペプチドの使用。
- 前記酸素感受性グラム陽性細菌が、Ruminococcaceae及び/又はLachnospiraceaeに属する、請求項1に記載のReg3αポリペプチドの使用。
- 前記酸素感受性グラム陽性細菌が、Faecalibacterium prausnitzii及び/又はRoseburia intestinalisに属する、請求項1に記載のReg3αポリペプチドの使用。
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