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An Oral Inoculation Infant Rabbit Model for Shigella Infection.

痢疾杆菌感染的口服接种幼兔模型。

  • 影响因子:6.74700
  • DOI:10.1128/mBio.03105-19
  • 作者列表:"Kuehl CJ","D'Gama JD","Warr AR","Waldor MK
  • 发表时间:2020-01-21
Abstract

Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics.IMPORTANCEShigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.

摘要

志贺菌属在全球引起腹泻病。志贺氏菌病的典型特征是便血和结肠炎伴粘膜损伤,是全球腹泻死亡的主要细菌原因。病原体经口摄入后,通过依赖其 III 型分泌系统 (T3SS) 的机制侵入并在结肠上皮内复制。目前,缺乏以口腔感染为基础的研究细菌性痢疾发病机制的小动物模型。在这里,我们发现幼兔灌胃接种福氏志贺菌导致腹泻和结肠病理类似于在人类志贺菌病中发现的。福氏链球菌接种前禁食动物增加了疾病的频率。病原体定植于结肠,在结肠中观察到管腔和上皮内病灶。上皮内病灶可能通过福氏链球菌从细胞到细胞的扩散而产生。健壮的 S. 福氏肠道定植、结肠上皮的侵入和上皮脱落都需要 T3SS 和 IcsA, 在野生型感染的动物中,用原位 mRNA 标记检测到的促炎趋化因子白细胞介素 8 (IL-8) 在体外的细菌扩散和粘附所需的因子较高。Flexneri 与 icsA 或 T3SS 缺陷的突变株相比,提示上皮侵袭促进了这种趋化因子的表达。总的来说,我们的研究结果表明,幼兔口腔感染为研究志贺氏菌病的发病机制和测试新的治疗方法提供了一个有用的实验模型。重要沙氏菌是全球腹泻死亡的主要细菌原因。该病原体引起细菌性痢疾,一种以结肠粘膜损伤为特征的血性腹泻疾病,通常通过粪-口途径传播。缺乏依赖于口服感染途径的志贺氏菌病的小动物模型。在这里,我们发现幼兔口服接种福氏杆菌病导致了一种腹泻疾病和结肠病理,让人联想到人类志贺氏菌病。该模型中的腹泻、肠道定植和病理学依赖于 S.flexneri ⅲ 型分泌系统和 IcsA,经典的志贺菌毒力因子。因此,幼兔的口腔感染为研究细菌性痢疾的发病机制和开发试验新的治疗方法提供了一个可行的模型。

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影响因子:6.74700
发表时间:2020-01-21
来源期刊:mBio
DOI:10.1128/mBio.03105-19
作者列表:["Kuehl CJ","D'Gama JD","Warr AR","Waldor MK"]

METHODS:Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics.IMPORTANCEShigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.

影响因子:5.36
发表时间:2020-01-20
DOI:10.1007/s00259-020-04686-1
作者列表:["Willowson KP","Schembri GP","Bernard EJ","Chan DL","Bailey DL"]

METHODS:PURPOSE:To quantify the effects of absorbed radiation dose on healthy liver parenchyma following radioembolisation (RE) using [99mTc]TcMebrofenin to analyse both global and regional liver function. METHODS:Patients having RE to treat hepatic disease underwent a [99mTc]TcMebrofenin hepatobilliary scintigraphy (HBS) study at both baseline and 8 weeks following treatment. Changes in global liver uptake rate were compared with healthy liver absorbed dose measures derived from the post-treatment 90Y PET/CT, including average dose, minimum dose to 70% of the volume (D70) and volume receiving at least 50 Gy (V50). Changes in functional burden associated with treatment and spared liver volumes in patients receiving lobar RE were also assessed, as were changes experienced by regional volumes corresponding to various dose ranges. Standard liver function pathology tests (LFTs) (bilirubin, albumin, ALP, AST, ALT and GGT) were examined for changes between baseline and post-treatment. RESULTS:Thirty-five patients were included in the study, of which, 9 had lobar treatment. A significant linear correlation was found between both baseline global liver uptake rate (negative) and D70 with change in global liver uptake rate. Patients undergoing lobar treatments demonstrated a shift in functional burden, and a significant difference was seen between the mean dose corresponding to liver volumes that increased their functional burden (9 Gy) and those that decreased their functional burden (35 Gy). No baseline LFTs predicted a decrease in global liver function; however, D70 demonstrated a linear correlation with changes in bilirubin and GGT. CONCLUSIONS:Given the significant negative relationship between baseline and change in global liver uptake rate, baseline HBS studies should not be used alone to disqualify patients considered for RE. In terms of treatment planning and evaluation, D70 may be the most appropriate metric of dose, with values greater than 15 Gy indicative of a likely drop in global liver function. The evidence of increasing functional burden in spared liver volumes suggests that patients at risk of complications could benefit from a lobar approach to treatment.

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影响因子:3.32
发表时间:2020-01-09
DOI:10.1016/j.intimp.2019.106144
作者列表:["Fan M","Xiang G","Chen J","Gao J","Xue W","Wang Y","Li W","Zhou L","Jiao R","Shen Y","Xu Q"]

METHODS:NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for inflammatory bowel diseases. In this study, we found that Libertellenone M (Lib M), a secondary metabolite from the endophytic fungus Phomopsis sp. S12, has anti-inflammatory potential both in vitro and in vivo. Lib M selectively inhibited the expression of proinflammatory cytokine IL-1β and IL-18 in LPS-activated macrophages. The cleavage of pro-caspase 1 was remarkably reduced by Lib M in macrophages stimulated with three NLRP3 inflammasome activators. Administering Lib M attenuated dextran sulfate sodium-induced experimental acute colitis in mice and significantly reduced the production of these cytokines and cleaved caspase 1 in colon tissues. Apart from inhibition of NLRP3 inflammasome assembly, Lib M also suppressed NF-κB nuclear translocation in macrophages. Taken together, these findings suggest that Lib M-mediated inhibition of NLRP3 inflammasome activation could protect against colitis-like inflammatory diseases, and that this compound derived from a plant-associated fungus might inspire the exploration of novel immunosuppressive agents.

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