Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli.
Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli.
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DOI：
10.1371/journal.ppat.1006471
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发表时间：
2017-07
期刊：
影响因子：
6.7
通讯作者：
Guerrant RL
中科院分区：
文献类型：
--
作者：
Bartelt LA;Bolick DT;Mayneris-Perxachs J;Kolling GL;Medlock GL;Zaenker EI;Donowitz J;Thomas-Beckett RV;Rogala A;Carroll IM;Singer SM;Papin J;Swann JR;Guerrant RL
不同的肠道病原体暴露与儿童营养不良有关。为了阐明肠道微生物在营养不良期间相互作用的机制途径，我们使用小鼠蛋白质缺乏来开发一种新的共肠道病原体肠病模型。关注营养不良儿童常见的肠道病原体，贾第鞭毛虫和肠聚集性大肠杆菌（EAEC），我们提供了新的见解交叉病原体特异性机制，增强营养不良。我们首次表明，在蛋白质营养不良期间，肠道微生物群允许贾第虫持续定植，同时导致生长障碍。尽管肠道损伤的信号，如IL 1 α，贾第虫感染的小鼠缺乏促炎性肠道反应，类似于地方性小儿贾第虫感染。相反，贾第虫干扰微生物宿主的蛋白质水解的共代谢产物在生长障碍，而主机烟酰胺利用的适应，相应的生长恢复增加。EAEC促进肠道炎症和髓样细胞活化的标志物。在合并感染期间，肠道炎症信号传导和对EAEC的细胞募集反应与贾第虫介导的骨髓细胞活化减少一起被保留。相反，EAEC破坏宿主能量消耗调节反应的标志，贾第虫，作为主机的代谢适应似乎耗尽。在共病原体感染和营养不良过程中整合免疫学和代谢特征，我们开发了一个工作机制模型，说明累积的饮食诱导和病原体引发的微生物扰动如何导致宿主越来越浪费。营养不良的儿童暴露于多种连续的，往往是持久的肠道病原体。已知肠道微生物破坏和炎症有助于营养不良的发病机制，但共同病原体如何相互作用，与常驻微生物群或与宿主改变这些途径尚不清楚。使用一种新的肠道共感染模型与贾第虫和肠聚集性大肠杆菌在小鼠喂养蛋白质缺乏的饮食，我们确定主机的生长和肠道免疫反应的差异介导的病原体-微生物的相互作用，包括寄生虫介导的变化，肠道微生物宿主共代谢，并在共感染过程中改变免疫反应。我们的数据模型如何早期生活累积肠道病原体暴露逐步破坏肠道免疫和宿主代谢在关键的发展时期。此外，在这种共感染模型中的研究揭示了对目前常见但知之甚少的肠道病原体如贾第鞭毛虫的致病性的环境和微生物决定因素的新见解，这可能不符合基于单一病原体设计的模型的微生物发病机制的现有范式。
Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host. Malnourished children are exposed to multiple sequential, and oftentimes, persistent enteropathogens. Intestinal microbial disruption and inflammation are known to contribute to the pathogenesis of malnutrition, but how co-pathogens interact with each other, with the resident microbiota, or with the host to alter these pathways is unknown. Using a new model of enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli in mice fed a protein deficient diet, we identify host growth and intestinal immune responses that are differentially mediated by pathogen-microbe interactions, including parasite-mediated changes in intestinal microbial host co-metabolism, and altered immune responses during co-infection. Our data model how early life cumulative enteropathogen exposures progressively disrupt intestinal immunity and host metabolism during crucial developmental periods. Furthermore, studies in this co-infection model reveal new insights into environmental and microbial determinants of pathogenicity for presently common, but poorly understood enteropathogens like Giardia lamblia, that may not conform to existing paradigms of microbial pathogenesis based on single pathogen-designed models.
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影响因子：
3.7
作者：
Guerrant RL;Leite AM;Pinkerton R;Medeiros PH;Cavalcante PA;DeBoer M;Kosek M;Duggan C;Gewirtz A;Kagan JC;Gauthier AE;Swann J;Mayneris-Perxachs J;Bolick DT;Maier EA;Guedes MM;Moore SR;Petri WA;Havt A;Lima IF;Prata MM;Michaleckyj JC;Scharf RJ;Sturgeon C;Fasano A;Lima AA
通讯作者：
Lima AA
影响因子：
15.9
作者：
Bartelt, Luther A.;Roche, James;Guerrant, Richard
通讯作者：
Guerrant, Richard
影响因子：
25.7
作者：
CUOMO, R;PUMPO, R;BUDILLON, G
通讯作者：
BUDILLON, G
DOI：
10.1097/00005176-200408000-00005
发表时间：
2004-08-01
影响因子：
2.9
作者：
Campbell, DI;McPhail, G;Jeffries, DJ
通讯作者：
Jeffries, DJ
DOI：
10.1093/cid/ciw391
发表时间：
2016-09-15
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Donowitz JR;Alam M;Kabir M;Ma JZ;Nazib F;Platts-Mills JA;Bartelt LA;Haque R;Petri WA Jr
通讯作者：
Petri WA Jr