The new chemokine CCL28 and its role during Salmonella infection

 描述(由申请人提供)：趋化因子是一种小的分泌蛋白，可诱导各种细胞类型的趋化作用。这项建议集中在CCL28，一种表达最广泛的粘膜趋化因子。CCL28在唾液腺中强烈表达，因此通常被覆盖在消化道。它也由粘膜上皮细胞表达，具有抗菌活性，在哺乳开始时在乳腺中诱导表达。它的受体是GPR2/CCR10，Ccr10-/-小鼠不能将IgA浆母细胞招募到乳腺。在肠道中，CCL28在促炎细胞因子的诱导下在结肠细胞中表达，这表明它在结肠炎中可能发挥重要作用。 因此，CCL28是一种双重(稳态/炎症)趋化因子。在这个建议中，我们研究了CCL28-/-小鼠的表型。重要的是，我们的初步数据表明，CCL28-/-小鼠对肠道病原体肠道沙门氏菌血清型鼠伤寒沙门氏菌的感染非常敏感。肠炎沙门氏菌是世界范围内发病率和死亡率的主要原因。血清型鼠伤寒沙门氏菌是最常见的沙门氏菌之一，可引起免疫功能正常患者的炎症性腹泻，但也可引起免疫功能低下患者的菌血症。我们建议的主要目的是研究CCL28对诸如鼠伤寒沙门氏菌等粘膜病原体的感染起作用的机制。我们的中心假设是CCL28在对鼠伤寒沙门氏菌感染的保护性反应中发挥关键作用，无论是通过招募特定的免疫细胞亚群，还是通过直接的抗菌活性。我们的假设是基于初步数据显示，CCL28-/-小鼠在感染鼠伤寒沙门氏菌后，表现出显著的死亡率和淋巴组织中细菌负荷的增加。因此，我们将通过以下特定目标来验证我们的假设：在特定目标1中，我们将确认CCL28在鼠伤寒沙门氏菌感染过程中发挥保护作用，并将获得更多关于观察到这种敏感性的条件的数据。在特定的目标2中，我们将研究CCL28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(在CCL28-/-小鼠中)未能招募到对控制沙门氏菌感染至关重要的某些白细胞群体，或者是因为CCL28的抗菌活性是对沙门氏菌自然耐药的一个重要因素。为了解决这些可能性，我们将分析CCL28-/-小鼠肠道中的白细胞数量，并与野生型小鼠进行比较。我们还将研究Ccr10-/-小鼠对沙门氏菌感染的潜在敏感性。这项研究的成功实施将开辟一个新的研究领域，即CCL28在控制细菌感染和宿主-病原体相互作用中的作用。

 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.