Interrogating innate immunity to helminth parasites

描述(由申请人提供)：目前全球土壤传播蠕虫感染的流行率估计为20亿人，估计有10亿人感染鞭毛虫。蠕虫感染可导致严重的营养不良、生长迟缓和长期残疾。此外，疫区活体种群的感染给当地社区带来了巨大的经济负担。鉴于蠕虫感染的全球流行以及工业化国家的变态反应性疾病的流行，更好地了解控制TH2细胞因子介导的免疫和炎症的途径至关重要。CD4+TH2细胞产生IL-4、IL-5、IL-9和IL-13，其发育依赖于IL-4R、STAT6和GATA3。此外，在TH2细胞因子反应的背景下激活的B细胞主要进行类别转换，以产生抗原特异性的IgG1和IgE。组织中2型细胞因子驱动的炎症导致杯状细胞增生、粘液产生、平滑肌收缩增加和粒细胞群的涌入。尽管我们对控制TH2细胞分化和调控的途径有了很大的了解，但启动蠕虫或过敏原特异性TH2细胞反应的分子和细胞途径仍然缺乏明确的定义。我以前的工作表明，TSLP促进表型和功能不同的、IL-3独立的嗜碱性粒细胞群体的群体扩张，并且TSLP诱导的嗜碱性细胞足以部分恢复正常易感TSLPR缺陷小鼠的CD4+TH2细胞反应和保护性免疫。此外，我的新的初步研究首次表明，TSLP诱导的嗜碱性细胞与DC合作促进CD4+TH2细胞的反应，并且TSLP诱导的嗜碱性细胞可以直接改变DC群体的激活状态。总之，这些数据提出了一种假设，即TSLP诱导的嗜碱性粒细胞通过影响DC群体的激活状态促进TH2细胞因子介导的炎症和对鞭毛虫的保护性免疫。根据我的新数据，两个具体目标将解决以下问题：(I)TSLP诱导的嗜碱性细胞是否促进对旋毛虫的保护性免疫？(Ii)TSLP诱导的嗜碱性粒细胞是否以促进TH2细胞因子反应和保护性免疫的方式调节DC群体？总而言之，这些研究将询问TSLP促进对鞭虫的保护性免疫的先天免疫机制。我预计，明确TSLP和嗜碱性粒细胞促进保护性免疫的机制将指导未来预防和治疗土源性蠕虫感染的临床努力。

DESCRIPTION (provided by applicant): The global prevalence of soil transmitted helminth infections is currently estimated at two billion individuals infected worldwide, with an estimated one billion people infected with Trichuris. Helminth infections can lead to significant malnutritio, growth retardation and long-term disability. In addition, infections of live stock populations in endemic areas exert enormous economic burdens on the local communities. Given the global prevalence of helminth infections coupled with the pandemic of allergic diseases in industrialized countries, it is critical to gain a better understanding of the pathways that contro TH2 cytokine-mediated immunity and inflammation. CD4+ TH2 cells produce IL-4, IL-5, IL-9 and IL-13, and their development is dependent on IL-4R, STAT6 and GATA3. In addition, B cells activated in the context of a TH2 cytokine response primarily class switch to produce antigen-specific IgG1 and IgE. Type 2 cytokine-driven inflammation in tissues results in goblet cell hyperplasia, mucus production, increased smooth muscle contractility, and the influx of granulocyte populations. Despite significant developments in our understanding of the pathways that control the differentiation and regulation of TH2 cells, the molecular and cellular pathways that initiate helminth- or allergen-specific TH2 cell responses remain poorly defined. My previous work demonstrates that TSLP promotes the population expansion of a phenotypically and functionally distinct, IL-3-independent basophil population and that TSLP-elicited basophils are sufficient to partially restore CD4+ TH2 cell responses and protective immunity to Trichuris in normally susceptible TSLPR-deficient mice. In addition, my new preliminary studies indicate, for the first time, that TSLP-elicited basophils cooperate with DCs to promote CD4+ TH2 cell responses and that TSLP-elicited basophils can directly alter the activation state of DC populations. Collectively, these data provoke the hypothesis that TSLP-elicited basophils promote TH2 cytokine-mediated inflammation and protective immunity to Trichuris by influencing the activation status of DC populations. Based on my new data, two specific aims will address the following questions: (i) Do TSLP-elicited basophils promote protective immunity to Trichuris? (ii) Do TSLP-elicited basophils regulate DC populations in a manner that promotes TH2 cytokine responses and protective immunity to Trichuris? Collectively, these studies will interrogate the innate immune mechanisms through which TSLP promotes protective immunity to Trichuris. I anticipate that defining the mechanisms through which TSLP and basophils promote protective immunity will direct future clinical efforts to prevent and treat soil transmitted helminth infectins.