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. 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. Filarial infections have a profound impact on the immune environment, influencing T cell subsets and antigen presenting cells. Using a pan-viral serological profiling platform, we studied the viral history of a large cohort of Loa loa-infected individuals, examining the IgG response to the human virome. Noteworthy differences were observed in viral immune repertoires between filarial-infected and uninfected individuals and between endemic (END) and expatriates (EXP), with altered binding specificity to certain viral epitopes. These findings suggest that chronic filarial infections significantly affect viral-specific immune responses through various mechanisms, potentially influencing viral-specific bystander memory and response to viral species (Human Herpesviridae, Rhinoviridae and Enteroviruses) . Moreover, END individuals in the cohort showed distinct virus-specific IgG peptide hits for the topmost seropositive viruses, indicating differences compared to EXP individuals. Our study highlights the complexity of viral immune memory in individuals with different infection profiles, with END subjects exhibiting a more extensive viral immune memory repertoire specific to HHV-6A, while EXP individuals demonstrated an enhanced capacity to mount immune responses against Enterovirus B and Rhinovirus A. The level of reactive antibody towards targeted viral antigens further supported these differences, emphasizing the importance of understanding the relationship and to identify potential opportunities for reducing the impact of parasite infections on viral memory responses.