The new chemokine CCL28 and its role during Salmonella infection

新趋化因子CCL28及其在沙门氏菌感染过程中的作用

• 批准号: 9553400
• 负责人: Manuela Raffatellu
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9553400
• 关键词: new; chemokine; CCL28; its; role

 DESCRIPTION (provided by applicant): Chemokines are small secreted proteins that induce chemotaxis in various cell types. This proposal focuses on CCL28, one of the most widely expressed mucosal chemokines. CCL28 is strongly expressed in the salivary gland and it therefore normally coats the digestive tract. It is also expressed by mucosal epithelial cells, exhibits antimicrobial activity, and its expression is induced in the mammary gland upon the onset of lactation. Its receptor is GPR2/CCR10, and a Ccr10-/- mouse cannot recruit IgA plasmablasts to the mammary gland. In the gut, CCL28 expression is induced in colonocytes in response to pro-inflammatory cytokines, suggesting that it could play an important role in colitis. CCL28 is therefore a Dual (homeostatic/inflammatory) chemokine. In this proposal, we have studied the phenotype of a Ccl28-/- mouse. Importantly, our preliminary data indicates that the Ccl28-/- mouse is extremely sensitive to infection with the enteric pathogen Salmonella enterica serotype Typhimurium. Salmonella enterica is a leading cause of morbidity and mortality worldwide. Serotype Typhimurium is one the most common isolates of Salmonella, causing inflammatory diarrhea in immunocompetent patients but also bacteremia in immunocompromised individuals. The main objective of our proposal is to study the mechanism through which CCL28 plays a role against infection with mucosal pathogens like S. Typhimurium. Our central hypothesis is that CCL28 plays a critical role in the protective response to S. Typhimurium infection, either through the recruitment of specific subsets of immune cells, or through direct antimicrobial activity. Our hypothesis is based on preliminary data indicating that a Ccl28-/- mouse shows dramatic mortality and increased bacterial load in lymphoid tissues following infection with S. Typhimurium. Accordingly, we will test our hypothesis through the following Specific Aims: In Specific Aim 1, we will confirm that CCL28 plays a protective role during S. Typhimurium infection, and will obtain more data on the conditions under which this susceptibility is observed. In Specific Aim 2, we will investigate the mechanism through which CCL28 exerts a protective effect during infection. We hypothesize that it can be due to a failure (in the Ccl28-/- mouse) to recruit certain leukocyte populations critical for controlling Salmonella infection, or alternatively, because the antimicrobial activityof Ccl28 is an important factor in natural resistance against Salmonella. To address these possibilities, we will analyze the leukocyte populations in the gut of Ccl28-/- mice compared to wild-type littermates. We will also study the potential susceptibility of a Ccr10-/- mouse to Salmonella infection. Successful implementation of this study will open a new field of research, namely, the role of CCL28 in the control of bacterial infections and host-pathogen interactions.

 描述（由申请人提供）：趋化因子是在各种细胞类型中诱导趋化性的小分泌蛋白。该提案的重点是CCL 28，最广泛表达的粘膜趋化因子之一。CCL 28在唾液腺中强烈表达，因此它通常覆盖消化道。它也由粘膜上皮细胞表达，表现出抗微生物活性，并且其表达在泌乳开始时在乳腺中被诱导。它的受体是GPR 2/CCR 10，Ccr 10-/-小鼠不能将伊加浆母细胞募集到乳腺。在肠道中，响应于促炎细胞因子，CCL 28表达在结肠细胞中被诱导，这表明它可能在结肠炎中发挥重要作用。 因此，CCL 28是一种双重（稳态/炎症）趋化因子。在这个提议中，我们研究了Ccl 28-/-小鼠的表型。重要的是，我们的初步数据表明Ccl 28-/-小鼠对肠道病原体肠道沙门氏菌血清型鼠伤寒的感染极其敏感。肠道沙门氏菌是世界范围内发病和死亡的主要原因。血清型鼠伤寒沙门氏菌是沙门氏菌最常见的分离株之一，引起免疫功能正常的患者的炎性腹泻，但也引起免疫功能低下的个体的菌血症。本研究的主要目的是研究CCL 28在抗粘膜病原体如沙门氏菌感染中的作用机制。鼠伤寒。我们的中心假设是CCL 28在对S.鼠伤寒杆菌感染，无论是通过招募特定亚群的免疫细胞，或通过直接的抗菌活性。我们的假设是基于初步数据，表明Ccl 28-/-小鼠在感染S.鼠伤寒因此，我们将通过以下具体目的来检验我们的假设：在具体目的1中，我们将证实CCL 28在S.鼠伤寒杆菌感染，并将获得更多的数据条件下，这种敏感性观察。在具体目标2中，我们将研究CCL 28在感染过程中发挥保护作用的机制。我们推测这可能是由于未能（在Ccl 28-/-小鼠中）募集对控制沙门氏菌感染至关重要的某些白细胞群体，或者因为Ccl 28的抗微生物活性是对沙门氏菌天然耐药性的重要因素。为了解决这些可能性，我们将分析Ccl 28-/-小鼠肠道中的白细胞群体与野生型同窝仔相比。我们还将研究Ccr 10-/-小鼠对沙门氏菌感染的潜在易感性。这项研究的成功实施将开辟一个新的研究领域，即CCL 28在控制细菌感染和宿主-病原体相互作用中的作用。