The hallmark of the immune response seen in individuals with patent lymphatic filariasis is a profound inability to proliferate or produce cytokines associated with a Type 1 response (IL 2 and IFN-gamma;) in response to parasite antigen. This parasite specific anergy is mediated, in large part, by IL 10 with TGF-beta; 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 LF, a process driven by IL-10 itself. The mechanisms underlying the modulation of parasite-specific responses in LF continues to be a major research question. Using multiparameter flow cytometry, this antigen-specific modulation was shown to be associated with an expansion of IL-10 producing adaptive Treg and altered development of parasite-specific central and effector memory T cell populations. We have demonstrated that these Tregs influence both effector T cells and antigen presenting cells (APCs), but alter APC function indirectly through the effector T cells (Metenou et al, submitted). We have also shown that these nTregs in filarial infection are highly heterogeneous and activated but are programmed to be short lived. This may underlie their increase in number that is characteristic of infection with filarial parasites. Not only has patent 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. Most recently, we have shown that microfilariae inhibit the monocyte function through suppression of mTOR and through the induction of autophagy. 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, and HIV. As a first step in examining the interaction between Mtb and filarial infection and based on the epidemiology of filarial/Mtb coinfection, an in vitro system of co infection was established and used to demonstrate that pre-exposure of human DCs and macrophages to live filarial parasites induces immunoregulatory phenotypes that alters mycobacterial entry and replication (Chatterjee, unpublished). Concurrently, we developed an in vivo model in which we rendered mice microfilaremic and then infected them (by aerosol) with virulent Mtb. Our data very clearly suggests that microfilaremia induces alternative activation of macrophages in the lung but fails to alter the growth or clearance of Mtb; microarray data from the lungs of these mice suggest a generalized modulation of interferon-gamma and IFN-gamma; regulated pathways (Chatterjee, Talaat, unpublished). Human studies ex vivo focusing more on latent tuberculosis in filarial-infected and -uninfected individuals have demonstrated that filarial infection (and gastrointestinal nematodes as well) modulates mycobacterial-specific responses. We have now extended these studies by developing multiparameter flow cytometric approaches to identify Mtb-specific stem cell memory (SCM) CD4+ and CD8+ T cells and are exploring the relationship between chronic filarial antigen exposure and the alteration in Mtb-specific memory.
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