Interrogating innate immunity to helminth parasites

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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.