Immunoregulation /Immune Recognition In Filarial/Nonfilarial Parasitic Infection

National Institute Of Allergy And Infectious Diseases

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Abstract

The overriding goal of this project is to provide an understanding of how the immunologic responses to filarial and related parasites are controlled. The major aspects of this project involve the parasite-specific responses in lymphatic filariasis (LF), loiasis, onchocerciasis and most recently strongyloidiasis in terms of regulation, pathogenesis protective immunity, and the genetic underpinnings of these host responses. The major objectives are to identify the mechanisms by which the modulation/regulation of immune responsiveness works in filarial and related parasitic infections; 2) to identify factors involved in the pathogenesis of disease in filarial infections; 3) to identify the role of host and parasite factors underlying the differential responsiveness to parasite antigens and the subsequent clinical and immunologic outcome; and 4) to understand the immunologic correlates of immunity in human filarial infection. The hallmark of the T cell response seen in individuals with patent systemic helminth infections (e.g. the filariae or S. stercoralis) is a profound inability to proliferate or produce cytokines associated with a Type-1 response (IL-2 and IFN-) and Type-17 (IL-17) in response to parasite antigen.Interleukin (IL)-10 is the primary cytokine driving the modulation of the host response in filarial infections. We performed binding assays with Brugia malayi antigen extracts and human IL-10R1. Bm5539 was the top-binding hit. We identified a short sequence, termed truncated Bm5339, that has structural similarities to the human IL-10 functional dimer. Sequence comparisons revealed that other filarial parasites possess Bm5539 orthologues. Using recombinant Bm5539 in a modified Luciferase Immunoprecipitation System assay, we confirmed that both the truncated and full-length forms of the protein can bind to human IL-10R1. Truncated Bm5539 could inhibit human IL-10-driven phosphorylation of STAT3, thereby demonstrating that Bm5539 acts as an IL-10 antagonist, most likely through competitive binding to the receptor. We provide a structural basis for these observations using computational modeling and simulations. Not only have chronic helminth infections been shown to modulate T cell responses, but it has also been shown to result in profound monocyte (and dendritic cell DC) dysfunction that can be reversed by effective anthelmintic treatment. We have explored the mechanisms by which parasite products alter the function of human APCs (both monocytes and DC). To explore more fully how the parasites drive APC dysfunction, we have identified the cargo (miRNA/proteins) contained within the extracellular vesicles (EVs) of mf, then demonstrated that they are internalized rapidly by APCs, and finally demonstrated their ability to downregulate the phosphorylation of mTOR. Moreover, using RNAseq in DCs exposed to EVs or EV depleted parasite E/S productions, we have demonstrated that EVs, by themselves, are largely repsonsible for driving APC dysfunction. Type-2 associated responses are the hallmarks of both allergic diseases and helminth infections. To characterize the heterogeneity and function of Th2 cells that are mostly responsible for these responses. Using multiparameter flow cytometry we identified 3 expanded CD4+ T cell subsets found in filarial -infected subjects. Two of these subsets were responsible for the majority of IL-4, IL-5, or IL-13 produced. Single cell multiomic RNA profiling of these 3 sorted subsets, demonstrated that 2 of these had features of pathogenic Th2 effector (PeTh2) cells, but were highly plastic. This distinct molecular and functional program of Th2 effector cell subsets sheds new light on the Th2 cell plasticity and their contribution to immune regulation in helminth infection and allergic disorders.