Immunoregulation /Immune Recognition In Filarial/Nonfilarial Parasitic Infection

National Institute Of Allergy And Infectious Diseases

Investigators

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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. This parasite-specific anergy is mediated, in large part, by IL-10 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 filarial infection and in strongyloidiasis (a process driven by IL-10 itself and IL-37). Moreover, it appears that chronic helminth infection severely modulates the major gc cytokines (IL-2/IL7/IL15/IL21) that in turn alters the frequency of memory T cell subsets. Almost all of these processes can be reversed by definitive anthelmintic therapy. 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. Subsequently we have shown that filarial infections induce an immunoregulatory population of monocytes that appear to be human parallels of alternatively activated macrophages. We have explored the mechanisms by which parasite products alter the function of human APCs (both monocytes and DC). Using global protein expression profiling comparisons between microfilariae (mf)-exposed or mfunexposed human DCs, we have been able to show that parasite-derived products from mf significantly downregulated mTOR and the downstream molecules eIF2, eIF4 and p70S6K. The inhibition of mTOR occurs within minutes of parasite exposure and leads to autophagy and the induction of IDO. To explore more fully how the parasites drive this mTOR inhibition, 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. 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 and Mali 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 years, we have focused on the influence of pre-existing helminth infections on Mycobacterium tuberculosis (Mtb), malaria, and metabolic disorders. Using an in vitro system of co-infection we showed that exposure to live filarial parasites induces immunoregulatory DC and monocyte phenotypes that alters mycobacterial entry and replication, a process that is dependent on the IL-10/TPL2 axis in these cells. Human studies ex vivo focusing more on latent and active tuberculosis in filarial- or Strongyloides-infected and -uninfected individuals have demonstrated that these helminth infections: 1)modulate Mtb-induced chemokine responses and thereby cell trafficking; 2) monocyte activation and function; and 3) tissue remodeling. This modulation appears to enable a more permissive state for Mtb growth and lead to worse outcomes. In collaboration with the Sacks lab, we were able to demonstrate a critical interaction between M2-like dermal macrophages (or M2-like macrophages in the peritoneum) with eosinophil recruitment to the site of the pathogen (either Leishmania or Ascaris) through eotaxin-2 (CCL24).