Immunoregulation /Immune Recognition In Filarial/Nonfilarial Parasitic Infection

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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 immune 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 Type1 response (IL2 and IFN) and Type-17 (IL-17) in response to parasite antigen. This parasitespecific anergy is mediated, in large part, by IL10 with TGF and CTLA-4 playing smaller regulatory roles Other members of the IL-10 superfamily (IL-19 and IL-24) have been now shown to be upregulated in patent lymphatic filariasis (LF), a process driven by IL-10 itself. Not only has filarial infection been shown to modulate T cell responses, but it has also been shown to result in profound monocyte dysfunction that can be reversed by effective treatment with anti-filarial chemotherapy. Subsequently we have shown that filarial infections induce an immunoregulatory population of monocytes that appear to be human parallels of alternatively activated macrophages. Using human monocytederived dendritic cells (DC) and human monocytes as well, we have explored the mechanisms by which parasite products alter the function of human APCs. Using global protein expression profiling comparisons between Mf-exposed or unexposed human mDCs, we have been able to show that parasite-derived products (from microfilariae) significantly downregulated the mammalian target of rapamycin (mTOR) and the eukaryotic initiation factor (eIF) 2, eIF4 and p70S6K .The inhibition of mTOR occurs within minutes of exposure and leads to autophagy as well. Because chronic filarial (and other helminth) infections may alter immune reactivity to other (non-parasite) antigens and because these alterations may have profound implications for the clinical outcome of these non-filarial infections, collaborative studies in India, Mali and Ecuador) have shown that the presence of active filarial infection and/or chronic intestinal helminth infection very clearly blunts the Type 1 (and Th17) response to non-filarial antigens in the context of co-infection. Over the past four years, we have focused on the influence of pre-existing helminth infections on Mycobacterium tuberculosis (Mtb) malaria, HIV and allergic diseases. In studies related to the helminth allergy interface (Hygiene hypothesis, we have demonstrated using a large cohort of patients with filarial infection with or without co-incident allergic sensitization and multiparameter (clinical, laboratory, flow cytometry, cytokine measurements) analyses that is early in infection there is actually a hyperreactive CD4+ state that diminished as the helminth infection becomes chronic Gazzinelli et al, J Immunol 2016 Finally, using a birth cohort study from Ecuador where thousands of children were followed longitudinally for the development of helminth infection, we examined the role of maternal helminth infection on responses to the EPI vaccines given in the first year of life. To our surprise maternal helminth infection failed to modulate the responses to 10 vaccines, and if anything was associated with higher titers of antibodies to the orally administered vaccine such as polio and rotavirus (Clark et al, J Infect Dis 2016)