human-placental-decidual-organ-cultures-to-study-infections-at

Human Placental and Decidual Organ Cultures to Study Infections at the Maternal-fetal Interface

The placenta shows a large degree of interspecies anatomic variability. To best understand biology and pathophysiology of the human placenta, it is ...

Benioff Children’s Hospital

University of California, San Francisco

Infections f&oelig;to-placentaire repr&eacute;sentent une cause majeure de complications de la grossesse, et encore les m&eacute;canismes mol&eacute;culaires et cellulaires sous-jacents de la transmission verticale sont mal compris. Listeria monocytogenes, un pathog&egrave;ne intracellulaire facultatif, fait partie d&#39;un groupe d&#39;agents pathog&egrave;nes connus pour causer des infections f&oelig;to-placentaires chez les humains et autres mammif&egrave;res. Le but de cette &eacute;tude &eacute;tait d&#39;&eacute;valuer les m&eacute;canismes possibles de transmission verticale de L. monocytogenes. Les humains et les cochons d&#39;Inde ont un placenta de hemochorial, o&ugrave; une seule couche de trophoblastes fetally d&eacute;riv&eacute;es s&eacute;pare maternel de la circulation foetale. Nous avons caract&eacute;ris&eacute; l&#39;infection &agrave; L. monocytogenes de l&#39;unit&eacute; f&oelig;to-placentaire dans un mod&egrave;le cobaye enceinte en primaires trophoblastes humaines et lign&eacute;es cellulaires d&eacute;riv&eacute;es de trophoblaste. Les manifestations cliniques de la list&eacute;riose dans l&#39;enceintes des cobayes et le tropisme de L. monocytogenes au placenta de cobaye ressemblent &agrave; celles des humains. Syst&egrave;mes de culture de cellules trophoblastiques &eacute;taient permissives de croissance list&eacute;riales et cellule &agrave; diffuser et r&eacute;v&egrave;le que L. monocytogenes d&eacute;ficientes en internaline A, un facteur de virulence que l&#39;invasion des cellules non phagocytaires, la m&eacute;diation a &eacute;t&eacute; 100 fois d&eacute;fectueux dans l&#39;invasion. Toutefois, le franchissement de la barri&egrave;re f&oelig;to-placentaire dans le mod&egrave;le cobaye &eacute;tait ind&eacute;pendante d&#39;internaline A, sugg&eacute;rant un r&ocirc;le n&eacute;gligeable pour INTERNALINE m&eacute;diation directe invasion du trophoblaste in vivo. Une meilleure compr&eacute;hension de la transmission verticale de L. monocytogenes aidera &agrave; concevoir des moyens plus efficaces de pr&eacute;vention de la maladie et de traitement.

List&eacute;riose chez le cobaye enceinte : un mod&egrave;le de transmission verticale.

Listeriose in der Schwangerschaft Meerschweinchen: ein Modell der vertikalen &#xDC;bertragung.

&#x80CE;&#x513F;-&#x80CE;&#x76D8;&#x611F;&#x67D3;&#x5360;&#x598A;&#x5A20;&#x5E76;&#x53D1;&#x75C7;&#x7684;&#x4E3B;&#x8981;&#x539F;&#x56E0;&#x548C;&#x5782;&#x76F4;&#x4F20;&#x64AD;&#x7684;&#x5206;&#x5B50;&#x548C;&#x7EC6;&#x80DE;&#x673A;&#x5236;&#x8FD8;&#x4E0D;&#x751A;&#x4E86;&#x89E3;&#x3002;&#x517C;&#x6027;&#x7EC6;&#x80DE;&#x5185;&#x81F4;&#x75C5;&#x83CC;&#x3001; &#x674E;&#x65AF;&#x7279;&#x83CC;&#x662F;&#x4E00;&#x7EC4;&#x5DF2;&#x77E5;&#x4F1A;&#x5BFC;&#x81F4;&#x80CE;&#x513F;-&#x80CE;&#x76D8;&#x611F;&#x67D3;&#x4EBA;&#x7C7B;&#x548C;&#x5176;&#x4ED6;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x7684;&#x75C5;&#x539F;&#x4F53;&#x4E4B;&#x4E00;&#x3002;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x7684;&#x76EE;&#x7684;&#x662F;&#x674E;&#x65AF;&#x7279;&#x7684;&#x8BC4;&#x4F30;&#x5782;&#x76F4;&#x4F20;&#x67D3;&#x7684;&#x53EF;&#x80FD;&#x673A;&#x5236;&#x3002;&#x4EBA;&#x7C7B;&#x548C;&#x8C5A;&#x9F20; hemochorial &#x80CE;&#x76D8;&#xFF0C;&#x5DF2;&#x5C06;&#x4EA7;&#x5987;&#x80CE;&#x513F;&#x5FAA;&#x73AF;&#x4ECE; fetally &#x6D3E;&#x751F;&#x6ECB;&#x517B;&#x7684;&#x5355;&#x4E2A;&#x56FE;&#x5C42;&#x5206;&#x5F00;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7279;&#x70B9; L.&#x674E;&#x65AF;&#x7279;&#x83CC;&#x611F;&#x67D3;&#x7684;&#x80CE;&#x513F;-&#x80CE;&#x76D8;&#x5355;&#x4F4D;&#x5728;&#x598A;&#x5A20;&#x8C5A;&#x9F20;&#x6A21;&#x578B;&#x548C;&#x4E3B;&#x6ECB;&#x517B;&#x7EC6;&#x80DE;&#x548C;&#x6ECB;&#x517B;&#x5C42;&#x6D3E;&#x751F;&#x7684;&#x5355;&#x5143;&#x683C;&#x7684;&#x884C;&#x3002;&#x5728;&#x6000;&#x5B55;&#x7684;&#x51E0;&#x5185;&#x4E9A;&#x732A;&#x674E;&#x6C0F;&#x6746;&#x83CC;&#x75C5;&#x7684;&#x4E34;&#x5E8A;&#x8868;&#x73B0;&#x4E0E;&#x674E;&#x65AF;&#x7279;&#x5230;&#x51E0;&#x5185;&#x4E9A;&#x732A;&#x80CE;&#x76D8;&#x53D6;&#x5411;&#x7684;&#x5999;&#x97F3;&#x4EBA;&#x7C7B;&#x3002;&#x6ECB;&#x517B;&#x5C42;&#x7EC6;&#x80DE;&#x57F9;&#x517B;&#x4F53;&#x7CFB;&#x662F;&#x7EB5;&#x5BB9; listerial &#x589E;&#x957F;&#x548C;&#x5355;&#x5143;&#x683C;&#x4F20;&#x64AD;&#x548C;&#x53D1;&#x73B0;&#x674E;&#x65AF;&#x7279; internalin A&#xFF0C;&#x4ECB;&#x5BFC; nonphagocytic &#x7EC6;&#x80DE;&#x4FB5;&#x88AD;&#x7684;&#x6BD2;&#x529B;&#x56E0;&#x5B50;&#x6709;&#x4E0D;&#x8DB3;&#x4E4B;&#x5904;&#x662F; 100-fold &#x5728;&#x5165;&#x4FB5;&#x5B58;&#x5728;&#x7F3A;&#x9677;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x8FC7;&#x5883;&#x7684;&#x8C5A;&#x9F20;&#x6A21;&#x578B;&#x4E2D;&#x7684;&#x80CE;&#x513F;-&#x80CE;&#x76D8;&#x5C4F;&#x969C;&#x662F;&#x72EC;&#x7ACB;&#x7684; internalin&#xFF0C;&#x8FD9;&#x8868;&#x660E; internalin &#x4ECB;&#x5BFC;&#x7684;&#x6ECB;&#x517B;&#x7EC6;&#x80DE;&#x5728;&#x4F53;&#x5185;&#x76F4;&#x63A5;&#x5165;&#x4FB5;&#x53EF;&#x4EE5;&#x5FFD;&#x7565;&#x4E0D;&#x8BA1;&#x7684;&#x4F5C;&#x7528;&#x3002;&#x674E;&#x65AF;&#x7279;&#x7684;&#x5782;&#x76F4;&#x4F20;&#x64AD;&#x8FDB;&#x4E00;&#x6B65;&#x4E86;&#x89E3;&#x5C06;&#x6709;&#x52A9;&#x4E8E;&#x8BBE;&#x8BA1;&#x66F4;&#x52A0;&#x6709;&#x6548;&#x7684;&#x6CBB;&#x7597;&#x548C;&#x9884;&#x9632;&#x75BE;&#x75C5;&#x7684;&#x624B;&#x6BB5;&#x3002;

&#x5728;&#x6000;&#x5B55;&#x7684;&#x51E0;&#x5185;&#x4E9A;&#x732A;&#x674E;&#x6C0F;&#x6746;&#x83CC;&#x75C5;&#xFF1A; &#x6A21;&#x578B;&#x7684;&#x5782;&#x76F4;&#x4F20;&#x64AD;&#x3002;

Feto-placental infections represent a major cause of pregnancy complications, and yet the underlying molecular and cellular mechanisms of vertical transmission are poorly understood. Listeria monocytogenes, a facultative intracellular pathogen, is one of a group of pathogens that are known to cause feto-placental infections in humans and other mammals. The purpose of this study was to evaluate possible mechanisms of vertical transmission of L. monocytogenes. Humans and guinea pigs have a hemochorial placenta, where a single layer of fetally derived trophoblasts separates maternal from fetal circulation. We characterized L. monocytogenes infection of the feto-placental unit in a pregnant guinea pig model and in primary human trophoblasts and trophoblast-derived cell lines. The clinical manifestations of listeriosis in the pregnant guinea pigs and the tropism of L. monocytogenes to the guinea pig placenta resembled those in humans. Trophoblast cell culture systems were permissive for listerial growth and cell-to-cell spread and revealed that L. monocytogenes deficient in internalin A, a virulence factor that mediates invasion of nonphagocytic cells, was 100-fold defective in invasion. However, crossing of the feto-placental barrier in the guinea pig model was independent of internalin A, suggesting a negligible role for internalin-mediated direct invasion of trophoblasts in vivo. Further understanding of vertical transmission of L. monocytogenes will help in designing more effective means of treatment and disease prevention.

Listeriosis in the pregnant guinea pig: a model of vertical transmission.

Infezioni feto-placentare rappresentano delle principali cause di complicazioni durante la gravidanza, e ancora i sottostanti meccanismi molecolari e cellulari della trasmissione verticale sono scarsamente compreso. Listeria monocytogenes, un patogeno intracellulare facoltativo, &egrave; uno di un gruppo di agenti patogeni che sono noti per causare infezioni feto-placentare in esseri umani ed altri mammiferi. Lo scopo di questo studio era di valutare i possibili meccanismi di trasmissione verticale di L. monocytogenes. Gli esseri umani e porcellini d&#39;India hanno una placenta hemochorial, dove un singolo strato di trofoblasto fetally derivata separa materna dalla circolazione fetale. Abbiamo caratterizzato infezione da L. monocytogenes dell&#39;unit&agrave; feto-placentare in un modello di cavia incinta e trofoblasto umano primario e linee cellulari derivate dal trofoblasto. Le manifestazioni cliniche della listeriosi in gravidanza cavie e il tropismo di L. monocytogenes alla placenta cavia assomigliava a quelli negli esseri umani. Sistemi di coltura di cellule di trofoblasto sono stati permissivi per la crescita listerial e cella a diffusa e ha rivelato che L. monocytogenes carenti in internalin A, un fattore di virulenza che media l&#39;invasione delle cellule nonphagocytic, era 100 volte difettosi all&#39;invasione. Tuttavia, attraversamento della barriera feto-placenta nel modello della cavia &egrave; stato indipendente di internalin una, suggerendo un ruolo trascurabile di internalin-mediata diretta invasione del trofoblasto in vivo. Ulteriore comprensione della trasmissione verticale di L. monocytogenes aiuter&agrave; nella progettazione pi&ugrave; efficaci mezzi di prevenzione trattamento e malattia.

Listeriosi in gravidanza cavia: un modello di trasmissione verticale.

&#x80CE;&#x76E4;&#x611F;&#x67D3;&#x598A;&#x5A20;&#x5408;&#x4F75;&#x75C7;&#x306E;&#x4E3B;&#x8981;&#x306A;&#x539F;&#x56E0;&#x3092;&#x8868;&#x3057;&#x3001;&#x307E;&#x3060;&#x5782;&#x76F4;&#x611F;&#x67D3;&#x306E;&#x57FA;&#x306B;&#x306A;&#x308B;&#x5206;&#x5B50;&#x30FB;&#x7D30;&#x80DE;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x3088;&#x304F;&#x7406;&#x89E3;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2;&#x83CC;&#x306F;&#x901A;&#x6027;&#x7D30;&#x80DE;&#x5185;&#x75C5;&#x539F;&#x4F53;&#x306F;&#x3001;&#x4EBA;&#x9593;&#x3068;&#x4ED6;&#x306E;&#x54FA;&#x4E73;&#x52D5;&#x7269;&#x306E;&#x80CE;&#x76E4;&#x611F;&#x67D3;&#x75C7;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3059;&#x3053;&#x3068;&#x304C;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x75C5;&#x539F;&#x4F53;&#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x306E; 1 &#x3064;&#x3067;&#x3059;&#x3002;&#x5782;&#x76F4;&#x611F;&#x67D3;&#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2;&#x306E;&#x53EF;&#x80FD;&#x306A;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x8A55;&#x4FA1;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30D2;&#x30C8;&#x3084;&#x30E2;&#x30EB;&#x30E2;&#x30C3;&#x30C8; hemochorial &#x80CE;&#x76E4;&#x3001;fetally &#x6D3E;&#x751F;&#x30C8;&#x30ED;&#x30DB;&#x30D6;&#x306E;&#x5358;&#x4E00;&#x306E;&#x5C64;&#x304C;&#x6BCD;&#x4F53;&#x80CE;&#x5150;&#x5FAA;&#x74B0;&#x304B;&#x3089;&#x5206;&#x96E2;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005; &#x306F;&#x3001;L. &#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2;&#x611F;&#x67D3;&#x80CE;&#x76E4;&#x30E6;&#x30CB;&#x30C3;&#x30C8;&#x598A;&#x5A20;&#x30E2;&#x30EB;&#x30E2;&#x30C3;&#x30C8; &#x30E2;&#x30C7;&#x30EB;&#x3068;&#x30D7;&#x30E9;&#x30A4;&#x30DE;&#x30EA;&#x3072;&#x3068;&#x57F9;&#x990A;&#x30C8;&#x30ED;&#x30DB;&#x30D6; &#x30E9;&#x30B9;&#x30C8;&#x304A;&#x3088;&#x3073;&#x7D68;&#x6BDB;&#x7531;&#x6765;&#x7D30;&#x80DE;&#x682A;&#x306E;&#x7279;&#x5FB4;&#x3002;&#x598A;&#x5A20;&#x4E2D;&#x306E;&#x30E2;&#x30EB;&#x30E2;&#x30C3;&#x30C8;&#x306B;&#x304A;&#x3051;&#x308B;&#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2;&#x75C7;&#x306E;&#x81E8;&#x5E8A;&#x75C7;&#x72B6;&#x3068;&#x89AA;&#x548C;&#x6027;&#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2; &#x30E2;&#x30EB;&#x30E2;&#x30C3;&#x30C8;&#x80CE;&#x76E4;&#x3078;&#x306E;&#x30D2;&#x30C8;&#x306E;&#x3082;&#x306E;&#x306B;&#x985E;&#x4F3C;&#x3057;&#x3066;&#x3044;&#x305F;&#x3002;&#x7D68;&#x6BDB;&#x7D30;&#x80DE;&#x57F9;&#x990A;&#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x3060;&#x3063;&#x305F; listerial &#x306E;&#x6210;&#x9577;&#x306E;&#x305F;&#x3081;&#x306E;&#x5BDB;&#x5BB9;&#x3068;&#x7D30;&#x80DE;&#x306B;&#x5E83;&#x304C;&#x308A;&#x3001;internalin A&#x3001;nonphagocytic &#x7D30;&#x80DE;&#x306E;&#x6D78;&#x6F64;&#x3092;&#x5A92;&#x4ECB;&#x3059;&#x308B;&#x75C5;&#x539F;&#x6027;&#x56E0;&#x5B50;&#x6B20;&#x4E4F;&#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2; 100 &#x304C;&#x660E;&#x3089;&#x304B;&#x306B;&#x306A;&#x3063;&#x305F;&#x4FB5;&#x653B;&#x306B;&#x6B20;&#x9665;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x30E2;&#x30EB;&#x30E2;&#x30C3;&#x30C8; &#x30E2;&#x30C7;&#x30EB;&#x306B;&#x304A;&#x3051;&#x308B;&#x80CE;&#x76E4;&#x30D0;&#x30EA;&#x30A2;&#x306E;&#x6A2A;&#x65AD;&#x304C; internalin &#x306E;&#x72EC;&#x7ACB;&#x3057;&#x3066;&#x3044;&#x305F;&#x306F;&#x3001;internalin &#x3092;&#x4ECB;&#x3057;&#x305F;&#x76F4;&#x63A5;&#x6D78;&#x6F64;&#x306E;&#x30C8;&#x30ED;&#x30DB;&#x30D6; in vivo &#x306E;&#x53D6;&#x308B;&#x306B;&#x8DB3;&#x3089;&#x306A;&#x3044;&#x5F79;&#x5272;&#x306F;&#x3001;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2;&#x306E;&#x5782;&#x76F4;&#x611F;&#x67D3;&#x306E;&#x3055;&#x3089;&#x306A;&#x308B;&#x7406;&#x89E3;&#x6CBB;&#x7642;&#x3068;&#x75BE;&#x75C5;&#x4E88;&#x9632;&#x306E;&#x3088;&#x308A;&#x52B9;&#x679C;&#x7684;&#x306A;&#x624B;&#x6BB5;&#x306E;&#x8A2D;&#x8A08;&#x306B;&#x5F79;&#x7ACB;&#x3061;&#x307E;&#x3059;&#x3002;

&#x598A;&#x5A20;&#x4E2D;&#x306E;&#x30E2;&#x30EB;&#x30E2;&#x30C3;&#x30C8;&#x306B;&#x304A;&#x3051;&#x308B;&#x30EA;&#x30B9;&#x30C6;&#x30EA;&#x30A2;&#x75C7;: &#x7E26;&#x4F1D;&#x9054;&#x306E;&#x30E2;&#x30C7;&#x30EB;&#x3002;

Feto &#xD0DC; &#xBC18; &#xAC10;&#xC5FC; &#xC784;&#xC2E0; &#xD569;&#xBCD1;&#xC99D;&#xC758; &#xC8FC;&#xC694; &#xC6D0;&#xC778;&#xC774; &#xB098;&#xD0C0;&#xB0B4;&#xACE0; &#xC544;&#xC9C1; &#xC218;&#xC9C1; &#xC804;&#xC1A1;&#xC758; &#xAE30;&#xBCF8; &#xBD84;&#xC790; &#xBC0F; &#xC138;&#xD3EC; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC81C;&#xB300;&#xB85C; &#xC774;&#xD574;. Listeria monocytogenes, &#xC758;&#xC0AC; &#xC138;&#xD3EC;&#xB0B4; &#xBCD1;&#xC6D0; &#xCCB4;, &#xBCD1;&#xC6D0; &#xCCB4;&#xC5D0; &#xC778;&#xAC04;&#xACFC; &#xB2E4;&#xB978; &#xD3EC;&#xC720;&#xB3D9;&#xBB3C;&#xC5D0; &#xC788;&#xB294; feto &#xD0DC; &#xBC18; &#xAC10;&#xC5FC;&#xC744; &#xC77C;&#xC73C;&#xD0A4;&#xB294; &#xAC83;&#xC73C;&#xB85C; &#xC54C;&#xB824;&#xC9C4; &#xADF8;&#xB8F9; &#xC911; &#xD558;&#xB098;&#xC785;&#xB2C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xC758; &#xBAA9;&#xC801;&#xC740; L. monocytogenes&#xC758; &#xC218;&#xC9C1; &#xC804;&#xC1A1; &#xAC00;&#xB2A5;&#xD55C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xD3C9;&#xAC00; &#xD588;&#xB2E4;. &#xC778;&#xAC04;&#xACFC; &#xAE30;&#xB2C8; &#xD53C;&#xADF8;&#xB294; hemochorial &#xD0DC; &#xBC18; &#xCE35; fetally &#xD30C;&#xC0DD;&#xB41C; trophoblasts &#xBAA8;&#xC131; &#xD0DC;&#xC544; &#xC21C;&#xD658;&#xC5D0;&#xC11C; &#xBD84;&#xB9AC;. &#xC6B0;&#xB9AC;&#xB294; L. monocytogenes &#xAC10;&#xC5FC; &#xC784;&#xC2E0; &#xAE30;&#xB2C8; &#xB3FC;&#xC9C0; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xACE0; &#xC8FC; &#xC778;&#xAC04;&#xC758; trophoblasts trophoblast &#xD30C;&#xC0DD; &#xC140; &#xB77C;&#xC778;&#xC5D0;&#xC11C; feto placental &#xB2E8;&#xC704;&#xC758; &#xD2B9;&#xC9D5;. Listeriosis &#xC784;&#xC2E0;&#xD55C; &#xAE30;&#xB2C8; &#xD53C;&#xADF8;&#xC5D0;&#xC11C;&#xC758; &#xC784;&#xC0C1; &#xBC1C;&#xD604; &#xBC0F; &#xAE30;&#xB2C8; &#xB3FC;&#xC9C0; &#xD0DC; &#xBC18;&#xC5D0; L. monocytogenes tropism &#xB2EE;&#xC740; &#xC778;&#xAC04;&#xC5D0;&#xC11C; &#xB4E4;. Trophoblast &#xC140; &#xBB38;&#xD654; &#xC2DC;&#xC2A4;&#xD15C;&#xC740; listerial &#xC131;&#xC7A5;&#xC5D0; &#xB300; &#xD55C; &#xD5C8;&#xC6A9; &#xBC0F; &#xC140; &#xD655;&#xC0B0; &#xBC0F; internalin A, nonphagocytic &#xC140;&#xC758; &#xCE68;&#xACF5;&#xC744; &#xC911;&#xC7AC; &#xD558;&#xB294; &#xB3C5;&#xC131; &#xC778;&#xC790; &#xACB0;&#xD54D; L. monocytogenes&#xB294; 100 &#xCE68;&#xACF5;&#xC5D0; &#xACB0;&#xD568;&#xC774; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xAE30;&#xB2C8; &#xB3FC;&#xC9C0; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; feto placental &#xBC29; &#xBCBD;&#xC758; &#xAD50;&#xCC28;&#xC810;&#xC740; internalin&#xC758; &#xB3C5;&#xB9BD;, trophoblasts vivo&#xC5D0;&#xC11C;&#xC758; &#xC9C1;&#xC811; &#xCE68;&#xACF5; internalin &#xC911;&#xC7AC;&#xC5D0; &#xB300; &#xD55C; &#xC0AC;&#xC18C;&#xD55C; &#xC5ED;&#xD560;&#xC744; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;. L. monocytogenes&#xC758; &#xC218;&#xC9C1; &#xC804;&#xC1A1;&#xC758; &#xC790;&#xC138;&#xD55C; &#xC774;&#xD574; &#xBCF4;&#xB2E4; &#xD6A8;&#xACFC;&#xC801;&#xC778; &#xCE58;&#xB8CC; &#xBC0F; &#xC9C8;&#xBCD1; &#xC608;&#xBC29; &#xC218;&#xB2E8;&#xC744; &#xC124;&#xACC4;&#xC5D0; &#xB3C4;&#xC6C0;&#xC774; &#xB429;&#xB2C8;&#xB2E4;.

&#xC784;&#xC2E0;&#xD55C; &#xAE30;&#xB2C8; &#xD53C;&#xADF8;&#xC5D0;&#xC11C; listeriosis: &#xC218;&#xC9C1; &#xC804;&#xC1A1; &#xBAA8;&#xB378;.

Feto-placentaria infecciones representan una causa importante de complicaciones del embarazo, y todav&iacute;a los mecanismos moleculares y celulares subyacentes de la transmisi&oacute;n vertical se entienden mal. Listeria monocytogenes, un pat&oacute;geno intracelular facultativo, es uno de un grupo de agentes pat&oacute;genos que causan infecciones del feta-placentarias en humanos y otros mam&iacute;feros. El prop&oacute;sito de este estudio fue evaluar los posibles mecanismos de transmisi&oacute;n vertical de L. monocytogenes. Los seres humanos y conejillos de Indias tienen una placenta hemochorial, donde una sola capa de trofoblastos fetally derivadas separa maternal de la circulaci&oacute;n fetal. Caracterizamos infecci&oacute;n de L. monocytogenes de la unidad feta-placentaria en un modelo de embarazadas conejillo de Indias y en trofoblastos humanos primarios y l&iacute;neas celulares derivadas de trofoblasto. Las manifestaciones cl&iacute;nicas de la listeriosis en los embarazadas de conejillos de Indias y el tropismo de L. monocytogenes a la placenta de conejillo de Indias se asemejaron a los seres humanos. Sistemas de cultivo de c&eacute;lulas trofobl&aacute;sticas fueron permisivos para el crecimiento listerial y c&eacute;lula a c&eacute;lula y revel&oacute; que L. monocytogenes deficientes en internalin A, un factor de virulencia que media la invasi&oacute;n de las c&eacute;lulas nonphagocytic, era centesimal defectuoso en la invasi&oacute;n. Sin embargo, el cruce de la barrera feta-placentaria en el modelo de conejillo de Indias fue independiente de internalin, sugiriendo un papel insignificante para una invasi&oacute;n directa mediada por internalin de trofoblastos in vivo. Mayor comprensi&oacute;n de la transmisi&oacute;n vertical de L. monocytogenes ayudar&aacute;n en el dise&ntilde;o de medios m&aacute;s eficaces de tratamiento y prevenci&oacute;n de enfermedades.

Listeriosis en el embarazo de conejillo de Indias: un modelo de transmisi&oacute;n vertical.

Listeria monocytogenes causes foodborne outbreaks that lead to infection in human and other mammalian fetuses. To elucidate the molecular and cellular mechanisms involved in transplacental transmission, we characterized placental-fetal infection in pregnant guinea pigs inoculated with wild-type (wt) or mutant L. monocytogenes strains. The wt strain increased in number in the placenta by >1000-fold during the first 24 h after inoculation--an increase that was unparalleled in other maternal organs. The ActA- mutant, which is impaired in cell-to-cell spread and attenuated in maternal organs, increased in the placenta by a similar amount, although, in fetal infection, the number of ActA- mutant bacteria was 100-fold lower, compared with that of the wt strain. Furthermore, a mutant impaired in vacuolar escape was rapidly eliminated from maternal organs but persisted in the placenta. We concluded that cell-to-cell spread facilitates maternal-to-fetal transmission. Furthermore, the placenta provides a protective niche for growth of L. monocytogenes.

Growth of Listeria monocytogenes in the guinea pig placenta and role of cell-to-cell spread in fetal infection.

Infection with Listeria monocytogenes is a significant health problem during pregnancy. This study evaluates the role of trafficking between maternal organs and placenta in a pregnant guinea pig model of listeriosis. After intravenous inoculation of guinea pigs, the initial ratio of bacteria in maternal organs to placenta was 10(3)-10(4):1. Rapid increase of bacteria in the placenta changed the ratio to 1:1 after 24 h. Utilizing two wild-type strains, differentially marked by their susceptibility to erythromycin, we found that only a single bacterium was necessary to cause placental infection, and that L. monocytogenes trafficked from maternal organs to the placenta in small numbers. Surprisingly, bacteria trafficked in large numbers from the placenta to maternal organs. Bacterial growth, clearance, and transport between organs were simulated with a mathematical model showing that the rate of bacterial clearance relative to the rate of bacterial replication in the placenta was sufficient to explain the difference in the course of listeriosis in pregnant versus nonpregnant animals. These results provide the basis for a new model where the placenta is relatively protected from infection. Once colonized, the placenta becomes a nidus of infection resulting in massive reseeding of maternal organs, where L. monocytogenes cannot be cleared until trafficking is interrupted by expulsion of the infected placental tissues.

Listeria monocytogenes traffics from maternal organs to the placenta and back.

Listeria monocytogenes is an important cause of maternal-fetal infections and serves as a model organism to study these important but poorly understood events. L. monocytogenes can infect non-phagocytic cells by two means: direct invasion and cell-to-cell spread. The relative contribution of each method to placental infection is controversial, as is the anatomical site of invasion. Here, we report for the first time the use of first trimester placental organ cultures to quantitatively analyze L. monocytogenes infection of the human placenta. Contrary to previous reports, we found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection by either internalin-mediated invasion or cell-to-cell spread. Instead, extravillous cytotrophoblasts-which anchor the placenta in the decidua (uterine lining) and abundantly express E-cadherin-served as the primary portal of entry for L. monocytogenes from both extracellular and intracellular compartments. Subsequent bacterial dissemination to the villous stroma, where fetal capillaries are found, was hampered by further cellular and histological barriers. Our study suggests the placenta has evolved multiple mechanisms to resist pathogen infection, especially from maternal blood. These findings provide a novel explanation why almost all placental pathogens have intracellular life cycles: they may need maternal cells to reach the decidua and infect the placenta.

Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes.

La placenta fornisce funzioni critiche di trasporto tra le circolazioni materne e fetale durante lo sviluppo intrauterino. Formazione di questa interfaccia si basa su coordinato interazioni tra fattori trascrizionali, epigenetiche e ambientali. Qui descriviamo questi meccanismi nel contesto della differenziazione delle cellule della placentale (trofoblasto) e sintetizzare le conoscenze attuali su come interagiscono fra loro per generare una placenta funzionale. Lo sviluppo di una comprensione di questi percorsi contribuisce a un miglioramento dei nostri modelli per lo studio della biologia del trofoblasto e getta luce sull&#39;eziologia delle complicazioni durante la gravidanza e la programmazione in utero delle malattie degli adulti.

La placenta: integrazione trascrizionale, epigenetica e fisiologica durante lo sviluppo.

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The placenta provides critical transport functions between the maternal and fetal circulations during intrauterine development. Formation of this interface relies on coordinated interactions among transcriptional, epigenetic, and environmental factors. Here we describe these mechanisms in the context of the differentiation of placental cells (trophoblasts) and synthesize current knowledge about how they interact to generate a functional placenta. Developing an understanding of these pathways contributes to an improvement of our models for studying trophoblast biology and sheds light on the etiology of pregnancy complications and the in utero programming of adult diseases.

The placenta: transcriptional, epigenetic, and physiological integration during development.

Le placenta fournit des fonctions de transport essentiel entre les circulations maternelles et f&oelig;tales au cours du d&eacute;veloppement intra-ut&eacute;rin. La formation de cette interface s&#39;appuie sur la coordonn&eacute;e interactions entre facteurs transcriptionnels, &eacute;pig&eacute;n&eacute;tiques et environnementales. Nous d&eacute;crivons ici ces m&eacute;canismes dans le cadre de la diff&eacute;renciation des cellules placentaires (trophoblaste) et de synth&eacute;tiser les connaissances actuelles sur la fa&ccedil;on dont elles interagissent pour g&eacute;n&eacute;rer un placenta fonctionnel. D&eacute;velopper une compr&eacute;hension de ces voies contribue &agrave; une am&eacute;lioration de nos mod&egrave;les pour l&#39;&eacute;tude de la biologie de trophoblaste et fait la lumi&egrave;re sur l&#39;&eacute;tiologie des complications de la grossesse et de la programmation dans l&#39;ut&eacute;rus des maladies de l&#39;adulte.

Le placenta : int&eacute;gration transcriptionnelle &eacute;pig&eacute;n&eacute;tique et physiologique au cours du d&eacute;veloppement.

Die Plazenta stellt wichtige Transportfunktionen zwischen der m&uuml;tterlichen und fetalen Zirkulation w&auml;hrend der intrauterinen Entwicklung. Bildung dieser Schnittstelle basiert auf koordinierte Interaktionen zwischen transkriptionelle, epigenetische und umweltbedingten Faktoren. Hier beschreiben wir diese Mechanismen im Zusammenhang mit der Differenzierung der Plazenta Zellen (Trophoblasten) und aktuelle Kenntnisse &uuml;ber deren Interaktion um eine funktionale Plazenta generieren zu synthetisieren. Entwickeln ein Verst&auml;ndnis f&uuml;r diese Pfade tr&auml;gt zu einer Verbesserung unserer Modelle f&uuml;r Trophoblast Biologie zu studieren und wirft Licht auf die &Auml;tiologie der Komplikationen w&auml;hrend der Schwangerschaft und in der Geb&auml;rmutter Programmierung von Erwachsenen Krankheiten.

Die Plazenta: transkriptionelle, epigenetische und physiologische Integration w&auml;hrend der Entwicklung.

&#xD0DC; &#xBC18; &#xC790;&#xAD81;&#xB0B4; &#xAC1C;&#xBC1C; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xC0B0; &#xBAA8;&#xC640; &#xD0DC;&#xC544; &#xC21C;&#xD658; &#xC0AC;&#xC774; &#xC911;&#xC694; &#xD55C; &#xC804;&#xC1A1; &#xAE30;&#xB2A5;&#xC744; &#xC81C;&#xACF5;&#xD569;&#xB2C8;&#xB2E4;. &#xC774; &#xC778;&#xD130;&#xD398;&#xC774;&#xC2A4;&#xC758; &#xD615;&#xC131; transcriptional, epigenetic, &#xADF8;&#xB9AC;&#xACE0; &#xD658;&#xACBD; &#xC694;&#xC778; &#xAC04;&#xC758; &#xD611;&#xC870; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0; &#xC758;&#xC874;&#xD569;&#xB2C8;&#xB2E4;. &#xD0DC; &#xBC18; &#xC138;&#xD3EC; (trophoblasts)&#xC758; &#xCC28;&#xBCC4;&#xD654;&#xC758; &#xCEE8;&#xD14D;&#xC2A4;&#xD2B8;&#xC5D0;&#xC11C; &#xC774;&#xB7EC;&#xD55C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC124;&#xBA85; &#xD558; &#xACE0; &#xC5EC;&#xAE30; &#xACE0; &#xAE30;&#xB2A5;&#xC131; &#xD0DC; &#xBC18; &#xC0DD;&#xC131;&#xC5D0; &#xC791;&#xC6A9; &#xD558;&#xB294; &#xBC29;&#xBC95;&#xC5D0; &#xB300; &#xD55C; &#xD604;&#xC7AC; &#xC815;&#xBCF4;&#xB97C; &#xC885;&#xD569;. &#xC774;&#xB7EC;&#xD55C; &#xACBD;&#xB85C; &#xB300; &#xD55C; &#xC774;&#xD574;&#xB97C; &#xAC1C;&#xBC1C; trophoblast &#xC0DD;&#xBB3C;&#xD559;&#xC744; &#xACF5;&#xBD80; &#xD558;&#xB294; &#xAC83;&#xC5D0; &#xB300; &#xD55C; &#xC6B0;&#xB9AC;&#xC758; &#xBAA8;&#xB378;&#xC758; &#xAC1C;&#xC120;&#xC5D0; &#xAE30;&#xC5EC; &#xD558; &#xACE0; &#xC784;&#xC2E0; &#xD569;&#xBCD1;&#xC99D;&#xC758; &#xBCD1; &#xC778; &#xBC0F; &#xC131;&#xC778; &#xBCD1;&#xC758; utero &#xD504;&#xB85C;&#xADF8;&#xB798;&#xBC0D;&#xC5D0; &#xBE5B;&#xC774; sheds.

&#xD0DC; &#xBC18;: transcriptional epigenetic, &#xD558; &#xACE0; &#xC0DD;&#xB9AC; &#xC801; &#xD1B5;&#xD569; &#xAC1C;&#xBC1C; &#xD558;&#xB294; &#xB3D9;&#xC548;.

La placenta proporciona funciones de transporte cr&iacute;tico entre las circulaciones maternas y fetales durante el desarrollo intrauterino. Formaci&oacute;n de esta interfaz se basa en interacciones coordinadas entre factores transcripcionales, epigen&eacute;ticas y ambientales. Aqu&iacute; describimos estos mecanismos en el contexto de la diferenciaci&oacute;n de c&eacute;lulas de la placenta (trofoblastos) y sintetizar los conocimientos actuales sobre c&oacute;mo interact&uacute;an para generar una placenta funcional. Desarrollar una comprensi&oacute;n de estas v&iacute;as contribuye a una mejora de nuestros modelos para el estudio de la biolog&iacute;a del trofoblasto y arroja luz sobre la etiolog&iacute;a de las complicaciones del embarazo y la programaci&oacute;n en el &uacute;tero de enfermedades del adulto.

La placenta: integraci&oacute;n transcripcional, epigen&eacute;tica y fisiol&oacute;gica durante el desarrollo.

Listeria monocytogenes is a facultative intracellular bacterial pathogen that can infect the placenta, a chimeric organ made of maternal and fetal cells. Extravillous trophoblasts (EVT) are specialized fetal cells that invade the uterine implantation site, where they come into direct contact with maternal cells. We have shown previously that EVT are the preferred site of initial placental infection. In this report, we infected primary human EVT with L. monocytogenes. EVT eliminated ∼80% of intracellular bacteria over 24-hours. Bacteria were unable to escape into the cytoplasm and remained confined to vacuolar compartments that became acidified and co-localized with LAMP1, consistent with bacterial degradation in lysosomes. In human placental organ cultures bacterial vacuolar escape rates differed between specific trophoblast subpopulations. The most invasive EVT-those that would be in direct contact with maternal cells in vivo-had lower escape rates than trophoblasts that were surrounded by fetal cells and tissues. Our results suggest that EVT present a bottleneck in the spread of L. monocytogenes from mother to fetus by inhibiting vacuolar escape, and thus intracellular bacterial growth. However, if L. monocytogenes is able to spread beyond EVT it can find a more hospitable environment. Our results elucidate a novel aspect of the maternal-fetal barrier.

Invasive extravillous trophoblasts restrict intracellular growth and spread of Listeria monocytogenes.

Toxoplasma gondii is a ubiquitous, obligate intracellular parasite capable of crossing the placenta to cause spontaneous abortion, preterm labor, or significant disease in the surviving neonate. Exploration of the cellular and histological components of the placental barrier is in its infancy, and both how and where T. gondii breaches it are unknown. The human placenta presents two anatomical interfaces between maternal cells and fetal cells (trophoblasts): (i) the villous region where maternal blood bathes syncytialized trophoblasts for nutrient exchange and (ii) the maternal decidua, where mononuclear, extravillous trophoblasts anchor the villous region to the uterus. Using first-trimester human placental explants, we demonstrate that the latter site is significantly more vulnerable to infection, despite presenting a vastly smaller surface. This is consistent with past findings concerning two vertically transmitted viruses and one bacterium. We further explore whether three genetically distinct T. gondii types (I, II, and III) are capable of preferential placental infection and survival in this model. We find no difference in these strains' ability to infect placental explants; however, slightly slower growth is evident in type II (Prugniaud [Pru]) parasites relative to other cell types, although this did not quite achieve statistical significance.

Tissue barriers of the human placenta to infection with Toxoplasma gondii.

Listeria monocytogenes causes a serious food-borne disease due to its ability to spread from the intestine to other organs, a process that is poorly understood. In this study we used 20 signature-tagged wild-type clones of L. monocytogenes in guinea pigs in combination with extensive quantitative data analysis to gain insight into extraintestinal dissemination. We show that L. monocytogenes colonized the liver in all asymptomatic animals. Spread to the liver occurred as early as 4 h after ingestion via a direct pathway from the intestine to the liver. This direct pathway contributed significantly to the bacterial load in the liver and was followed by a second wave of dissemination via the mesenteric lymph nodes (indirect pathway). Furthermore, bacteria were eliminated in the liver, whereas small intestinal villi provided a niche for bacterial replication, indicating organ-specific differences in net bacterial growth. Bacteria were shed back from intestinal villi into the small intestinal lumen and reinfected the Peyer's patches. Together, these results support a novel dissemination model where L. monocytogenes replicates in intestinal villi, is shed into the lumen, and reinfects intestinal immune cells that traffic to liver and mesenteric lymph nodes, a process that occurs even during asymptomatic colonization.

Oral infection with signature-tagged Listeria monocytogenes reveals organ-specific growth and dissemination routes in guinea pigs.

Placental infections are major causes of maternal and fetal disease. This review introduces a new paradigm for placental infections based on current knowledge of placental defenses and how this barrier can be breached. Transmission of pathogens from mother to fetus can occur at two sites of direct contact between maternal cells and specialized fetal cells (trophoblasts) in the human placenta: firstly, maternal immune and endothelial cells juxtaposed to extravillous trophoblasts in the uterine implantation site and secondly, maternal blood surrounding the syncytiotrophoblast (SYN). Recent findings suggest that the primary vulnerability is in the implantation site. We explore evidence that the placental SYN evolved as a defense against pathogens, and that inflammation-mediated spontaneous abortion may benefit mother and pathogen.

Pathogens and the placental fortress.

During human pregnancy, placental trophoblasts differentiate and syncytialize into syncytiotrophoblasts that sustain progesterone production [1]. This process is accompanied by mitochondrial fragmentation and cristae remodeling [2], two facets of mitochondrial apoptosis, whose molecular mechanisms and functional consequences on steroidogenesis are unclear. Here we show that the mitochondria-shaping protein Optic atrophy 1 (Opa1) controls efficiency of steroidogenesis. During syncytialization of trophoblast BeWo cells, levels of the profission mitochondria-shaping protein Drp1 increase, and those of Opa1 and mitofusin (Mfn) decrease, leading to mitochondrial fragmentation and cristae remodeling. Manipulation of the levels of Opa1 reveal an inverse relationship with the efficiency of steroidogenesis in trophoblasts and in mouse embryonic fibroblasts where the mitochondrial steroidogenetic pathway has been engineered. In an in vitro assay, accumulation of cholesterol is facilitated in the inner membrane of isolated mitochondria lacking Opa1. Thus, Opa1-dependent inner membrane remodeling controls efficiency of steroidogenesis.

Optic atrophy 1-dependent mitochondrial remodeling controls steroidogenesis in trophoblasts.

Host defense and tolerance: unique challenges in the placenta.

Fetal syncytiotrophoblasts form a unique fused multinuclear surface that is bathed in maternal blood, and constitutes the main interface between fetus and mother. Syncytiotrophoblasts are exposed to pathogens circulating in maternal blood, and appear to have unique resistance mechanisms against microbial invasion. These are due in part to the lack of intercellular junctions and their receptors, the Achilles heel of polarized mononuclear epithelia. However, the syncytium is immune to receptor-independent invasion as well, suggesting additional general defense mechanisms against infection. The difficulty of maintaining and manipulating primary human syncytiotrophoblasts in culture makes it challenging to investigate the cellular and molecular basis of host defenses in this unique tissue. Here we present a novel system to study placental pathogenesis using murine trophoblast stem cells (mTSC) that can be differentiated into syncytiotrophoblasts and recapitulate human placental syncytium. Consistent with previous results in primary human organ cultures, murine syncytiotrophoblasts were found to be resistant to infection with Listeria monocytogenes via direct invasion and cell-to-cell spread. Atomic force microscopy of murine syncytiotrophoblasts demonstrated that these cells have a greater elastic modulus than mononuclear trophoblasts. Disruption of the unusually dense actin structure--a diffuse meshwork of microfilaments--with Cytochalasin D led to a decrease in its elastic modulus by 25%. This correlated with a small but significant increase in invasion of L. monocytogenes into murine and human syncytium. These results suggest that the syncytial actin cytoskeleton may form a general barrier against pathogen entry in humans and mice. Moreover, murine TSCs are a genetically tractable model system for the investigation of specific pathways in syncytial host defenses.

Placental syncytium forms a biophysical barrier against pathogen invasion.

We report a case in which placental abruption occurred at 16 weeks following first trimester diagnosis and treatment for typhoid fever. Unexpectedly Salmonella enterica serovar Typhi (S. Typhi) was found in fetal tissues at autopsy. Using information from the murine model of typhoid fever in pregnancy, we draw parallels between S. Typhi and L. monocytogenes to develop a plausible hypothesis to explain how this organism was able to cross the placenta in the first trimester to cause abruption, inflammation, and expulsion of the fetus and placenta. We hope that this model for understanding placental infections by the hematogenous route helps to raise awareness that organisms not typically associated with TORCH infection can nevertheless cause placental infection and pregnancy loss.

Anna I. Bakardjiev

Benioff Children’s Hospital

Human Placental and Decidual Organ Cultures to Study Infections at the Maternal-fetal Interface