JP2020524144A - 微生物性炎症を処置するための方法および組成物 - Google Patents
微生物性炎症を処置するための方法および組成物 Download PDFInfo
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Abstract
Description
明細書および添付の特許請求の範囲で使用される場合、単数形「1つ(a)」、「1つ(an)」および「その(the)」は、文脈上別段の指示がない限り、複数の指示対象を含む。したがって、例えば、「薬学的担体」への言及は、2つ以上のそのような担体および同類の物の混合物を含む。
本明細書に記載される組成物、キット、細胞、および方法に類似するまたは等価である組成物、キット、細胞、および方法を本発明の実行または試験において使用することが可能であるが、適切な組成物、キット、細胞、および方法が下に記載されている。本明細書で言及されるすべての刊行物、特許出願、および特許は参照によりその全体が組み込まれる。例えば、米国特許出願第14/349,918号明細書および米国特許第7,553,929号明細書は参照によりその全体が組み込まれる。矛盾する場合は、定義を含む本明細書が統制する。下で考察される特定の実施形態は説明的なものにすぎず、限定的であることを意図されていない。
対象(例えば、ヒト対象)において微生物性炎症を処置するための本明細書に記載される組成物、例えば、医薬組成物は、微生物性炎症を処置する(前記微生物性炎症から生じる血小板減少症または低グリコーゲン血症を処置することを含む)および/または組織、臓器、もしくは系において病原性微生物の負荷を低減するのに十分な治療有効量の核内輸送モディファイヤー(csN50、cSN50.1、cSN50.1ベータ、または配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、および/もしくは配列番号9に示されるNTM)ならびに薬学的に許容される担体を含む。同様に、対象(例えば、ヒト対象)において微生物性炎症を処置するための本明細書に記載される組成物は、微生物性炎症を有する対象においてSRTFおよびSREBPの核内レベルを低減するのに十分な治療有効量の核内輸送モディファイヤー(cSN50、cSN50.1、cSN50.1ベータ、または配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、および/もしくは配列番号9に示されるNTM)ならびに薬学的に許容される担体を含む。一部の態様では、組成物は抗菌剤をさらに含まない。
抗体を含む組成物は薬学的に許容される担体と組み合わせて治療的に使用することが可能である。
組成物を投与するのに効果的な投与量およびスケジュールは、経験的に決めてもよく、そのような決定を下すことは当技術分野の範囲内である。組成物の投与のための投与量範囲は、障害の症状が影響を受ける所望の効果を生み出すほどの大きさの範囲である。投与量は、望ましくない交差反応、アナフィラキシー反応などの有害な副作用を引き起こすほどの大きさであるべきではない。一般に、投与量は、患者の年齢、状態、性別および疾患の程度、投与経路、または他の薬物がレジメンに含まれているかどうかと共に変動し、当業者であればこれを決定することが可能である。投与量は、いかなる禁忌症(counterindication)の場合にも個々の医師が調整することが可能である。投与量は変動可能であり、1日または数日の間毎日1つまたは複数の用量投与で投与することが可能である。ガイダンスは、所与のクラスの医薬品の適切な投与量について文献に見出すことが可能である。例えば、抗体の適切な用量を選択する際のガイダンスは、抗体の治療的使用に関する文献、例えば、Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, N.J., (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp. 365-389に見出すことが可能である。単独で使用される抗体の典型的な1日投与量は、上記の要因に応じて、1日あたり約1μg/kg〜最大100mg/kg体重またはそれよりも多い範囲に及んでもよい。
本明細書に開示された遺伝子またはタンパク質のいかなる既知の変異体および誘導体または生じる可能性のある変異体および誘導体を定義する1つのやり方は、特定の既知の配列に対する相同性の点から変異体および誘導体を定義することによると理解されている。例えば、配列番号2はNTMの特定の配列を示している(cSN50.1)。具体的には、表明された配列に対して少なくとも70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99パーセントの相同性を有する本明細書で開示されたこれらのおよび他の遺伝子およびタンパク質の変異体が開示される。当業者であれば、2つのタンパク質または遺伝子などの核酸の相同性を判定する方法を容易に理解する。例えば、相同性は、相同性がその最も高いレベルであるように2つの配列を整列させた後で計算することが可能である。本明細書で使用される場合、配列相同性は配列同一性と互換的に使用される。
a)タンパク質変異体
本明細書で考察されるように、NTMの多数の変異体が知られており、本明細書では想定されている。タンパク質変異体および誘導体は当業者にはよく理解されており、アミノ酸配列改変を含むことが可能である。例えば、アミノ酸配列改変は典型的には3つのクラス:置換的、挿入的または欠失的変異体のうちの1つまたは複数に入る。挿入は、アミノおよび/またはカルボキシル末端融合ならびに単一または複数のアミノ酸残基の配列内挿入を含む。挿入は通常、アミノまたはカルボキシル末端融合の挿入よりも小さな挿入になり、例えば、およそ1〜4残基である。細胞透過性融合タンパク質誘導体(cell-penetrating fusion protein derivative)は、インビトロでの交差架橋によりターゲティング配列の細胞内送達を与えるのに十分大きなポリペプチドを融合させることにより、または融合物をコードするDNAで形質転換した組換え細胞培養により作成される。欠失は、タンパク質配列から1つまたは複数のアミノ酸残基を取り除くことを特徴とする。典型的には、タンパク質分子内のいずれか1つの部位で約2〜6以下の残基が欠失される。これらの変異体は通常、タンパク質をコードするDNAにおいてヌクレオチドを部位特異的変異誘発し、それによって変異体をコードするDNAを作成し、その後組換え細胞培養においてそのDNAを発現させることにより調製される。既知の配列を有するDNA中の所定の部位で置換突然変異を作成するための技法、例えば、M13プライマー変異誘発およびPCR変異誘発は周知である。アミノ酸置換は典型的には単一残基の置換であるが、いくつかの異なる位置で同時に起こることが可能であり、挿入は通常、およそ約1〜10アミノ酸残基であり、欠失は約1〜30残基の範囲に及ぶ。欠失または挿入は好ましくは、隣接する対、すなわち、2残基の欠失または2残基の挿入で行われる。置換、欠失、挿入またはそれらの任意の組合せを組み合わせて、最終構築物に到達してもよい。突然変異は配列をリーディングフレームから逸脱させてはならず、好ましくは第2のmRNA構造を作り出すおそれのある相補性領域を創り出さない。置換的変異体は、少なくとも1つの残基が取り除かれておりその場所に異なる残基が挿入されている変異体である。そのような置換は一般に、以下の表2および3に従って行われ、保存的置換と呼ばれる。
天然に存在するペプチドの逆立体異性体(opposite stereo isomer)、ならびにペプチド類似物の立体異性体が開示される。これらのアミノ酸は、tRNA分子に最適なアミノ酸を付与し、遺伝子構築物を操作し、例えば、アンバーコドンを利用して類似物アミノ酸を部位特異的なやり方でペプチド鎖中に挿入させることによりポリペプチド鎖中に容易に組み込むことが可能である。
核内輸送シャトルを標的にすることにより多微生物性敗血症(polymicrobial sepsis)において生存、クリアランス、および血小板減少症が改善される
多微生物性敗血症の実験モデルにおいて、cSN50.1を用いた核内輸送アダプターImpα5およびImpβ1の同時ターゲティングによりSRTFの核内移行が減弱され、肝臓において代謝的に重要なグリコーゲン貯蔵が維持されたことが本明細書で報告される。NTM処置により、血液、脾臓、および肺において細菌負荷が著しく低減され、血液中の炎症促進性サイトカインおよびケモカインが減弱され、血液中の正常な血小板数が維持され、微小血管損傷並びに肝臓の好中球浸潤の血漿マーカーが低減された。さらに、NTMと抗生物質療法を組み合わせると、死亡までの平均時間が著しく延長され、生存はほぼ2倍になった。
(1)NTMは肝細胞においてSRTFの核内輸送を減弱し、敗血症マウスの血液、脾臓、および肺において細菌負荷を低減する
グラム陰性菌は、単独でまたは他の微生物との組合せで、患者の3分の2で敗血症の原因となっているので、多微生物性敗血症の臨床的に関連するモデルが用いられた。この非外科的モデルでは、細菌豊富な腸内マイクロバイオームを用いて標準化チャレンジにより多微生物性腹膜炎が誘発される。新たに得られた腸内マイクロバイオームを、盲腸スラリー(CS)の形態で、腹腔内に注射し、それによって外科的創傷ならびに外科的腸管穿孔モデル(cecal ligation and puncture)に伴う腹膜腔中への盲腸内容物の制御されない溢流を回避した。最新で高度に可溶性の細胞透過性NTMペプチドであるcSN50.1を用いてSRTFの核内移行を制御すると、微小血管損傷の敗血症関連メディエーターの産生を低減し、血液および主要臓器での細菌のクリアランスを改善し、抗菌療法の有効性を増加させ、それによって生存を改善することができるという仮説を検証した。
敗血症の初期高炎症期(hyperinflammatory phase)の間、炎症促進性サイトカインTNF−αおよびIL−6、ならびにケモカイン単球走化性タンパク質1(MCP−1/CCL2)の血漿レベルは劇的に増加する。同時に、II型インターフェロン、インターフェロンガンマ(IFN−γ)は細胞媒介免疫応答を増強する。IFN−γはマクロファージ機能の特異的活性化因子であり、細菌感染に対して宿主免疫防御において調節的役割を果たす。注目すべきことに、抗IFN−γ抗体を投与すると、腹膜炎のラットモデルにおいて腹膜の細菌負荷が著しく減少した。IFN−γ刺激ヒト肺微小血管内皮細胞においておよび急性呼吸促拍症候群(ARDS)により悪化するグラム陰性菌敗血症を抱えた患者から得られたすべての血管の内皮において、微小血管完全性の中心的存在である血管内皮(VE)カドヘリンの発現の低減が観察された。IL−10などの抗炎症性サイトカインの産生も引き金となって炎症ホメオスタシス(inflammatory homeostasis)を修復する。増加したIL−10は、TNF−α発現を抑制し過剰な免疫応答を相殺するフィードバック機構を提供するが、IL−10の過剰産生は細菌クリアランスを低減する。IL−10の過剰産生が継続すると、敗血症の後期段階を特徴付ける免疫抑制環境に寄与する。しかし、炎症メディエーターの過剰産生が優勢な場合、その結果は血管機能障害、多臓器不全および死亡である。SRTFにより媒介される核シグナル伝達が減弱すると、TNF−α、MCP−1、およびIFN−γの血漿レベルの著しい抑制を伴い、一方、IL−6応答のパターンは依然として変化しなかった(図4A)。累積的に、敗血症誘発炎症促進性応答は、IL−6の注目すべき例外はあるが、NTMにより抑制され、これはホメオスタシス調節を維持するのに寄与する。
次に、多微生物性敗血症の急性期でのNTMの有益な作用が敗血症での全体的な生存に対してプラスの効果をもたらすことが可能かどうかを問うた。この仮説を検証するため、多微生物性敗血症のモデルにおいてNTM処置を抗菌療法と組み合わせた。図6に示されるように、重症感染症を処置するのに一般に使用されている広域スペクトルβラクタム抗生物質であるメロペネムのみで処置した動物間の生存は42時間での生存中央値で30%であった。これとは対照的に、メロペネム処置をNTMと組み合わせた場合、生存は55%まで著しく増加し、死亡までの平均時間は83時間まで伸びた(図6)。生存のこの増加は、手に負えない感染を抗菌療法単独では制御できない場合、NTMを用いて炎症促進性核シグナル伝達を標的にすると、敗血症において不可逆的な多臓器損傷が予防されることを示している。
本研究は、臨床的に関連のある実験モデルにおける多微生物性敗血症の動態および結果を、微生物病原性因子および内在性メディエーターにより引き起こされるゲノム嵐の原因であるストレス応答性転写因子の核内輸送を標的にすることにより改善することが可能であることを実証している。核への敗血症誘発シグナル伝達は、多臓器不全に寄与する血液および脈管系応答の原因である。機構的には、NTMは、敗血症に関与しているいくつかの細胞型の細胞膜を透過し、細胞質から核へのそれぞれSRTFおよびSREBPの移行により媒介される核シグナル伝達の原因であるImpα5およびImpβ1を標的にする。NTM、cSN50.1ペプチドによるImpα5およびImpβ1の選択的ターゲティングは、転写因子の両方の群により調節される種々の炎症促進性および代謝遺伝子の活性化を抑制するので、SRTFおよびSREBPの核内輸送は治療介入のための魅力的な標的である。NF−κBおよび他のSRTF(AP−1およびSTAT1)の核内移行を妨害することにより、NTMは、サイトカイン、ケモカイン、および細胞接着分子(セレクチン)の可溶性形態を含む炎症促進性メディエーターの発現を抑制した。注目すべきことに、抗菌療法の非存在下でのNTM処置は、腸内マイクロバイオームに由来する複数の微生物種のクリアランスを増強した。これは、細菌負荷の700倍の低減が得られた肺では特に注目すべきであった。NTM処置のそのような効果は、肺胞マクロファージの食細胞機能を損なうことが実証されているIL−10の初期抑制と関連する可能性がある。したがって、NTM増強細菌クリアランスは、核内輸送を標的化するこの様式が、肺および他の臓器での貪食細胞の機能に、または血液殺菌力に有害ではないことを示している。注目すべきことに、肝細胞におけるToll様受容体−4(TLR4)の細胞型特異的遺伝子破壊は、抗生物質療法なしでの腸管穿孔モデルにより引き起こされる多微生物性敗血症のモデルにおいて、増強されたマクロファージ食作用、低下した細菌レベル、および改善された生存をもたらした。したがって、核内輸送のNTMターゲティングは、細菌クリアランスの点でTLR4の遺伝子破壊に類似する転帰を達成する。
(1)ペプチド合成および精製
高度に可溶性の細胞透過性NTMペプチドcSN50.1は、別の場所に記載されている通りに合成し、精製し、フィルター殺菌した。
生後8週間のメスのC57B1/6Jマウス(Jackson Laboratories)をすべての実験で使用し処置群には無作為に割り当てた。生存および血液サイトカイン/ケモカイン分析では、すべてのマウスは体重1gあたり2mgのCSを腹腔内注射した(5.5×108CFU/kg)。CSはWynn et alに記載される通りに実験ごとに新たに調製した。手短に言えば、健康な生後6週間のメスのマウスを供給業者から到着後2週間未満で安楽死させ、その盲腸を単離し、盲腸内容物(「腸内マイクロバイオーム」)を押し出し、秤量して、5%ブドウ糖に80mg/mlの濃度で懸濁した(標準化盲腸スラリー、CS)。NTMペプチドcSN50.1は減菌水に溶解し、減菌生理食塩水に、0.45%w/vのNaCl中3.3mg/mlの最終濃度まで希釈した。マウスには、CSチャレンジ前30分で、並びにチャレンジ後30分、1.5時間、2.5時間、3.5時間、6時間、9時間、および12時間で、0.2mlの腹腔内注射によりNTM(cSN50.1ペプチド、0.66mg/注射)、またはビヒクル(0.45%w/vのNaCl)を与えた。NTM注射は54時間まで6時間ごとに、その後、12時間ごとに168時間目(CS7日後)の屠殺まで続いた。メロペネム(25mg/kg皮下注射で投与される)を用いた抗生物質療法は、CS後12時間で開始され、屠殺まで12時間ごとに続いた。血液試料(約40μL)は、CSチャレンジ前に、チャレンジ後2時間、6時間、12時間および24時間で伏在静脈からEDTA中に収集した。血漿は遠心分離により分離し、−80℃で保存した。マウスは実験期間中ずっと生存について入念にモニターされた。
核抽出物は凍結肝臓から調製した。手短に言えば、肝臓切片をNP−40なしで氷上、ダンス型ハンドホモジナイザー(Dounce hand homogenizer)で破壊し、抽出物調製前に1分間4000×gで核ペレット化した。それぞれの群(偽感染、CS感染+ビヒクルおよびCS感染+cSN50.1)中5マウス由来の抽出物を、Licor Odyssey Infrared Imaging System上で、ポリクローナルヤギ抗cFos(Santa Cruz)、モノクローナルマウス抗Y701リン酸化STAT1(Becton−Dickinson)ならびにポリクローナルウサギ抗NF−κBp50および抗NF−κB p65(Abcam)を使用する定量的免疫ブロッティングによりSRTFの核内移行について分析した。マウスモノクローナル抗TATA結合タンパク質(TBP、Abcam)を使用して、正規化のための核ローディングコントロール(nuclear loading control)としてTBPを測定した。
全血(50μl)は無菌PBSで1対1に希釈した。左肺および全脾臓を0.5mlの無菌PBS中でホモジナイズし、無菌PBS中で段階希釈した。試料はトリプチックソイ寒天+5%ヒツジ血液上に蒔いた。コロニーは37℃での一晩インキュベーション後に計数し、結果は1ミリリットルの血液、または臓器ホモジネートあたりのCFUで報告した。
細胞数測定ビーズアレイ(BD BioSciences)を使用して、マウス血漿中のIL−6、IL−10、MCP−1、TNFα、ならびに可溶性E−およびL−セレクチンを製造業者のプロトコールに従って測定し、バンダービルト大学のFlow Cytometry Coreにおいて分析した。IFN−γおよび可溶性P−セレクチンは、ELIZA(それぞれ、ThermoFisher Scientific and R&D Systems)によりマウス血漿中で測定した。
顕微鏡分析のために収集された組織は一晩ホルマリン中で固定し、次にルーチン的に加工し、パラフィンに包埋して、5ミクロンで薄片を作り、荷電スライドに載せた。病理学評価のためのスライドは、バンダービルト大学のTranslational Pathology Shared Resourceにおいて、PASで染色される、または好中球について免疫染色された。好中球についての免疫組織化学は、20分間Epitope Retrieval2溶液を使用して、Leica Bond Max(Leica Biosystems inc.Buffalo Grove、IL)上で実施された。スライドは、1:2000希釈で1時間抗好中球マーカー(カタログ番号ab2557、Abeam、Cambridge、MA)と一緒にインキュベートし、次に1:200希釈で15分間ウサギ抗ラット二次(BA−4001、Vector Laboratories、Inc.)中でインキュベートした。可視化のためにはBond Polymer Refine Detectionシステムを使用した。免疫染色スライドは、Leica Microsystems製の高スループットLeica SCN400スライドスキャナー自動デジタル画像システムを使用して、20倍拡大率で0.5μm/ピクセルの解像度まで画像化した。色彩、彩度、強度、サイズ、ラウンドネス、および軸長についての上位および下位閾値は、核の青色ヘマトキシリン染色と茶色DAB反応産物の両方について設定した。したがって、茶色(DAB)陽性細胞は青色(ヘマトキシリンのみ)陰性細胞と区別することが可能である。陽性茶色(DAB陽性)染色細胞のパーセンテージは、陽性細胞の全分析数を肝臓薄片中の全細胞数で除して計算された。全スライド画像化および免疫染色の定量化は、バンダービルト大学医療センターのDigital Histology Shared Resourceで実施された。
GraphPad Prismソフトウェアを統計解析のために使用した。24時間目での血球数、血液、肺ホモジネートおよび肝臓ホモジネート中の細菌数、好中球免疫染色、sP−セレクチンの血漿レベルならびに死亡までの平均時間は、ノンパラメトリックなマン・ホイットニーのU検定を使用して比較した。同じ動物から異なる時点で収集した血漿中のサイトカイン、ケモカイン、sL−セレクチンおよびsEセレクチンレベルは、サイダックポスト検定と一緒に反復測定二元配置ANOVAにより評価した。核抽出物中のSRTFはt−検定により解析した。生存データは、カプラン・マイヤー生存曲線としてプロットし、対数順位検定により解析した。データは平均±SEMとして提示し、<0.05のp値は有意であると見なした。
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Claims (24)
- 対象において微生物性炎症を処置する/阻害する/低減する方法であって、治療有効量の抗菌剤、および核内輸送モディファイヤー(NTM)を含む組成物を前記対象に投与することを含む方法。
- 前記NTMを含む組成物が前記抗菌剤を含まない、請求項1に記載の方法。
- 前記NTMを含む組成物が前記抗菌剤を含む、請求項1に記載の方法。
- 前記微生物性炎症が、急性炎症、亜急性炎、慢性炎症、臓器特異的炎症、全身性炎症、または敗血症である、請求項1に記載の方法。
- 前記NTMが、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6もしくは配列番号7、配列番号8、配列番号9、または配列番号16に示される配列を含む、請求項1に記載の方法。
- 前記微生物性炎症が、血液、脳、洞、上気道、または肺、心臓、骨髄、脾臓、肝臓、腎臓、尿路、膀胱、耳空洞、胃、腸、皮膚、目、歯、および/または歯肉に局在している、請求項1に記載の方法。
- 前記微生物性炎症がウイルス感染により引き起こされる、請求項1に記載の方法。
- 前記ウイルス感染が、単純ヘルペスウイルス1、単純ヘルペスウイルス2、水痘帯状疱疹ウイルス、エプスタイン・バーウイルス、サイトメガロウイルス、ヒトヘルペスウイルス6、痘瘡ウイルス、水疱性口内炎ウイルス、A型肝炎ウイルス、B型肝炎ウイルス、C型肝炎ウイルス、D型肝炎ウイルス、E型肝炎ウイルス、ライノウイルス、コロナウイルス、インフルエンザウイルスA、インフルエンザウイルスB、麻疹ウイルス、ポリオーマウイルス、ヒトパピローマウイルス、呼吸器多核体ウイルス、アデノウイルス、コクサッキーウイルス、デングウイルス、ムンプスウイルス、ポリオウイルス、狂犬病ウイルス、ラウス肉腫ウイルス、レオウイルス、黄熱病ウイルス、ジカウイルス、エボラウイルス、マールブルグウイルス、ラッサ熱ウイルス、東部ウマ脳炎ウイルス、日本脳炎ウイルス、セントルイス脳炎ウイルス、マレー渓谷熱ウイルス、西ナイルウイルス、リフトバレー熱ウイルス、ロタウイルスA、ロタウイルスB、ロタウイルスC、シンドビスウイルス、サル免疫不全ウイルス、ヒトT細胞白血病ウイルス1型、ハンタウイルス、風疹ウイルス、ヒト免疫不全ウイルス1型、およびヒト免疫不全ウイルス2型からなる群から選択されるウイルスによる感染である、請求項7に記載の方法。
- 前記微生物性炎症が細菌感染により引き起こされ、前記細菌感染を引き起こす細菌が炭疽菌(Bacillus anthracis)ではない、請求項1に記載の方法。
- 前記細菌感染が、結核菌(Mycobaterium tuberculosis)、マイコバクテリウム・ボビス(Mycobaterium bovis)、マイコバクテリウム・ボビス BCG株(Mycobaterium bovis strain BCG)、BCG亜株(BCG substrains)、マイコバクテリウム・アビウム(Mycobaterium avium)、マイコバクテリウム・イントラセルラーレ(Mycobaterium intracellular)、マイコバクテリウム・アフリカヌム(Mycobaterium africanum)、マイコバクテリウム・カンサシ(Mycobaterium kansasii)、マイコバクテリウム・マリヌム(Mycobaterium marinum)、マイコバクテリウム・ウルセランス(Mycobaterium ulcerans)、マイコバクテリウム・アビウム亜種パラ結核菌(Mycobaterium avium subspecies paratuberculosis)、ノカルジア・アステロイデス(Nocardia asteroides)、他のノカルジア種(Nocardia species)、在郷軍人病菌(Legionella pneumophila)、他のレジオネラ種(Legionella species)、アシネトバクター・バウマンニ(Acetinobacter baumanii)、チフス菌(Salmonella typhi)、サルモネラ菌(Salmonella enterica)、他のサルモネラ種(Salmonella species)、シゲラ・ボイディ(Shigella boydii)、志賀赤痢菌(Shigella dysenteriae)、ソンネ菌(Shigella sonnei)、シゲラ・フレックスネリ(Shigella flexneri)、他のシゲラ種(Shigella species)、ペスト菌(Yersinia pestis)、ヘモリチカ菌(Pasteurella haemolytica)、パスツレラ・マルトシダ(Pasteurella multocida)、他のパスツレラ種(Pasteurella species)、アクチノバチルス・プルロニューモニア(Actinobacillus pleuropneumoniae)、リステリア菌(Listeria monocytogenes)、リステリア・イバノビイ(Listeria ivanovii)、ウシ流産菌(Brucella abortus)、他のブルセラ種(Brucella species)、コウドリア・ルミナンチウム(Cowdria ruminantium)、ボレリア・ブルグドルフェリ(Borrelia burgdorferi)、ボルデテラ・アビウム(Bordetella avium)、百日咳菌(Bordetella pertussis)、気管支敗血症菌(Bordetella bronchiseptica)、ボルデテラ・トレマツム(Bordetella trematum)、ボルデテラ・ヒンジイ(Bordetella hinzii)、ボルデテラ・プテリ(Bordetella pteri)、ボルデテラ・パラペルツシス(Bordetella parapertussis)、ボルデテラ・アンソルピイ(Bordetella ansorpii)、他のボルデテラ種(Bordetella species)、鼻疽菌(Burkholderia mallei)、類鼻疽菌(Burkholderia psuedomallei)、セパシア菌(Burkholderia cepacian)、クラミジア・ニューモニエ(Chlamydia pneumoniae)、トラコーマクラミジア(Chlamydia trachomatis)、オウム病クラミジア(Chlamydia psittaci)、Q熱コクシエラ(Coxiella burnetii)、リケッチア種(Rickettsial species)、エーリキア種(Ehrlichia species)、黄色ブドウ球菌(Staphylococcus aureus)、表皮ブドウ球菌(Staphylococcus epidermidis)、肺炎球菌(Streptococcus pneumoniae)、化膿性連鎖球菌(Streptococcus pyogenes)、ストレプトコッカス・アガラクチア(Streptococcus agalactiae)、大腸菌(Escherichia coli)、コレラ菌(Vibrio cholerae)、カンピロバクター種(Campylobacter species)、髄膜炎菌(Neiserria meningitidis)、淋菌(Neiserria gonorrhea)、緑膿菌(Pseudomonas aeruginosa)、他のシュードモナス種(Pseudomonas species)、インフルエンザ菌(Haemophilus influenzae)、軟性下疳菌(Haemophilus ducreyi)、他のヘモフィルス種(Hemophilus species)、破傷風菌(Clostridium tetani)、他のクロストリジウム種(Clostridium species)、エンテロコルチカ菌(Yersinia enterolitica)、および他のエルシニア種(Yersinia species)からなる群から選択される細菌による感染である、請求項9に記載の方法。
- 前記微生物性炎症が真菌感染により引き起こされる、請求項1に記載の方法。
- 前記真菌感染が、カンジタ・アルビカンス(Candida albicans)、クリプトコッカス・ネオフォルマンス(Cryptococcus neoformans)、ヒストプラズマ・カプスラーツム(Histoplama capsulatum)、アスペルギルス・フミガーツス(Aspergillus fumigatus)、ココシジオイデス・イミチス(Coccidiodes immitis)、南アメリカ分芽菌(Paracoccidiodes brasiliensis)、ブラストミセス・デルマチチジス(Blastomyces dermitidis)、ニューモシスシス・カリニ(Pneumocystis carinii)、ペニシリウム・マルネッフェイ(Penicillium marneffi)、およびアルテルナリア・アルテナータ(Alternaria alternata)からなる群から選択される真菌による感染である、請求項11に記載の方法。
- 前記微生物性炎症が寄生虫感染により引き起こされる、請求項1に記載の方法。
- 前記寄生虫感染が、トキソプラズマ原虫(Toxoplasma gondii)、熱帯熱マラリア原虫(Plasmodium falciparum)、三日熱マラリア原虫(Plasmodium vivax)、四日熱マラリア原虫(Plasmodium malariae)、他のプラスモディウム種(Plasmodium species)、エントアメーバ・ヒストリチカ(Entamoeba histolytica)、ネグレリア・フォーレリ(Naegleria fowleri)、リノスポリジウム・セーベリ(Rhinosporidium seeberi)、ランブル鞭毛虫(Giardia lamblia)、ぎょう虫(Enterobius vermicularis)、エンテロビウス・グレゴリイ(Enterobius gregorii)、回虫(Ascaris lumbricoides)、ズビニ鉤虫(Ancylostoma duodenale)、アメリカ鉤虫(Necator americanus)、クリプトスポリジウム種(Cryptosporidium spp.)、トリパノソーマ・ブルセイ(Trypanosoma brucei)、トリパノソーマ・クルージ(Trypanosoma cruzi)、森林型熱帯リーシュマニア(Leishmania major)、他のリーシュマニア種(Leishmania species)、広節裂頭条虫(Diphyllobothrium latum)、小型条虫(Hymenolepis nana)、縮小条虫(Hymenolepis diminuta)、単包条虫(Echinococcus granulosus)、多包条虫(Echinococcus multilocularis)、フォーゲル包条虫(Echinococcus vogeli)、ヤマネコ条虫(Echinococcus oligarthrus)、肝吸虫(Clonorchis sinensis);クロノルキス・ビベリニ(Clonorchis viverrini)、肝蛭(Fasciola hepatica)、巨大肝蛭(Fasciola gigantica)、槍形吸虫(Dicrocoelium dendriticum)、肥大吸虫(Fasciolopsis buski)、横川吸虫(Metagonimus yokogawai)、タイ肝吸虫(Opisthorchis viverrini)、ネコ肝吸虫(Opisthorchis felineus)、膣トリコモナス(Trichomonas vaginalis)、アカントアメーバ種(Acanthamoeba species)、インターカラーツム住血吸虫(Schistosoma intercalatum)、ビルハルツ住血吸虫(Schistosoma haematobium)、日本住血吸虫(Schistosoma japonicum)、マンソン住血吸虫(Schistosoma mansoni)、他のシストソーマ種(Schistosoma species)、トリコビルハルツ住血吸虫(Trichobilharzia regenti)、旋毛虫(Trichinella spiralis)、旋毛虫ブリトビ(Trichinella britovi)、旋毛虫ネルソニ(Trichinella nelsoni)、旋毛虫ナティバ(Trichinella nativa)、およびエントアメーバ・ヒストリチカ(Entamoeba histolytica)からなる群から選択される寄生虫による感染である、請求項13に記載の方法。
- 血液、脳、洞、上気道、または肺、心臓、骨髄、脾臓、肝臓、腎臓、尿生殖器官、膀胱、耳空洞、胃、腸、皮膚、目、歯、または歯肉において微生物負荷を低減する方法であって、NTMを含む治療有効量の組成物を対象に投与することを含む方法。
- 対象において血小板減少症に関連する微生物性炎症を処置する/阻害する/低減する方法であって、NTMを含む治療有効量の組成物を前記対象に投与することを含む方法。
- 感染を有する対象の炎症部位の細胞において、ストレス応答転写因子(SRTF)のレベルを低減する方法であって、核内輸送モディファイヤー(NTM)を含む治療有効量の組成物を前記対象に投与することを含む方法。
- 前記NTMが配列番号2を含む、請求項17に記載の方法。
- 前記SRTFが、NF−κB、STAT1α、またはAP−1を含む、請求項17に記載の方法。
- 前記NF−κBが、NF−κB1、NF−κB RelAまたはそれらの組合せである、請求項19に記載の方法。
- ステロール調節エレメント結合タンパク質(SREBP)が、微生物性炎症に関与する細胞の核中で低減される、請求項16に記載の方法。
- 前記細胞が、顆粒球、単球、マクロファージ、樹状細胞、自然リンパ球系細胞、B細胞、NK細胞、T細胞、内皮細胞または上皮細胞である、請求項17に記載の方法。
- 対象において抗菌剤の治療効果を増加させる方法であって、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6もしくは配列番号7、配列番号8、配列番号9、または配列番号16に示される配列を含むNTMを前記対象に投与することを含む方法。
- 対象において微生物性炎症関連低グリコーゲン血症を低減する/阻害する/予防する方法であって、NTMを前記対象に投与することを含む方法。
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