Establishment of Chronic Typhoid Infection in a Mouse Carriage Model Involves a Type 2 Immune Shift and T and B Cell Recruitment to the Gallbladder
Establishment of Chronic Typhoid Infection in a Mouse Carriage Model Involves a Type 2 Immune Shift and T and B Cell Recruitment to the Gallbladder
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DOI：
10.1128/mbio.02262-19
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发表时间：
2019-09-01
期刊：
影响因子：
6.4
通讯作者：
Gunn, John S.
中科院分区：
文献类型：
--
作者：
Gonzalez, Juan F.;Kurtz, Jonathan;Gunn, John S.
伤寒主要由伤寒沙门氏菌引起，是一种威胁生命的全身性疾病，在世界范围内造成严重的发病率和死亡率。3%到5%的伤寒沙门氏菌感染者由于细菌在胆囊中的滞留而成为慢性携带者。我们已经证明沙门氏菌在胆结石上形成生物膜来建立胆囊带。然而，从病原体和宿主的角度对胆囊慢性携带者的深入分子理解还不够明确。为了研究沙门氏菌感染后胆囊壁的动态变化，我们在小鼠的早期(7天)和慢性(21天)时间点进行了转录图谱分析。转录组测序(RNA-Seq)显示，从感染后7天的Th1促炎反应(Dpi)转变为21dpi的抗炎Th2反应，特征是免疫球蛋白和Th2主转录调节因子GATA3水平增加。此外，生物信息学分析预测了特征Th2标志物的上游调节，包括白细胞介素4(IL-4)和Stat6。免疫组织化学和荧光激活细胞分类器(FACS)分析证实，胆结石小鼠的淋巴细胞，包括T和B细胞，在21dpi时显著增加。有趣的是，沙门氏菌特异的CD4T细胞水平在21dpi的胆结石小鼠的胆囊中高出10倍。我们推测，生物被膜状态允许沙门氏菌抵抗Th1炎症反应的最初攻击，而尚未确定的事件影响宿主免疫向更宽容的2型反应的切换，从而导致慢性感染的建立。重要的是，慢性伤寒携带者的存在已经在公众视野中超过100年，部分原因是围绕伤寒玛丽的宣传。此外，几十年来，人们一直知道，胆结石是顽固的主要部位，最近，胆结石起到了关键作用。尽管如此，人们对允许伤寒沙门氏菌在胆囊中持续存在的生理条件知之甚少。在这项研究中，我们分析了慢性携带者模型小鼠的胆囊区转录图谱。我们发现从早期的促炎免疫反应转变为后来的抗炎反应，这可以解释允许沙门氏菌持续存在的僵局。有趣的是，我们发现患有胆结石的小鼠体内沙门氏菌特异性T细胞的数量增加了10倍。这项工作使我们更接近于了解慢性携带者的机制基础，目标是根除这种疾病。
Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening systemic disease responsible for significant morbidity and mortality worldwide. Three to 5% of individuals infected with S. Typhi become chronic carriers due to bacterial persistence in the gallbladder. We have demonstrated that Salmonella forms biofilms on gallstones to establish gallbladder carriage. However, an in-depth molecular understanding of chronic carriage in the gallbladder, from the perspective of both the pathogen and host, is poorly defined. To examine the dynamics of the gallbladder in response to Salmonella infection, we performed transcriptional profiling in the mouse gallbladder at early (7 days) and chronic (21 days) time points. Transcriptome sequencing (RNA-Seq) revealed a shift from a Th1 proinflammatory response at 7 days postinfection (dpi) toward an anti-inflammatory Th2 response by 21 dpi, characterized by increased levels of immunoglobulins and the Th2 master transcriptional regulator, GATA3. Additionally, bioinformatic analysis predicted the upstream regulation of characteristic Th2 markers, including interleukin-4 (IL-4) and Stat6. Immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis confirmed a significant increase in lymphocytes, including T and B cells, at 21 dpi in mice with gallstones. Interestingly, the levels of Salmonella-specific CD4 T cells were 10-fold higher in the gallbladder of mice with gallstones at 21 dpi. We speculate that the biofilm state allows Salmonella to resist the initial onslaught of the Th1 inflammatory response, while yet undefined events influence a switch in the host immunity toward a more permissive type 2 response, enabling the establishment of chronic infection.IMPORTANCE The existence of chronic typhoid carriers has been in the public eye for over 100 years in part because of the publicity around Typhoid Mary. Additionally, it has been known for decades that the gallbladder is the main site of persistence and recently that gallstones play a key role. Despite this, very little is known about the physiological conditions that allow Salmonella enterica serovar Typhi to persist in the gallbladder. In this study, we analyze the transcriptional profile of the gallbladder in a mouse model of chronic carriage. We found a shift from an early proinflammatory immune response toward a later anti-inflammatory response, which could explain the stalemate that allows Salmonella persistence. Interestingly, we found a 10-fold increase in the number of Salmonella-specific T cells in mice with gallstones. This work moves us closer to understanding the mechanistic basis of chronic carriage, with a goal toward eradication of the disease.