The goal of this research is to improve the efficacy of treatment in patients with visceral leishmaniasis (VL). In VL, parasites target, deactivate and replicate within tissue macrophages. Replication does not cease nor are parasites killed unless macrophage-activating host immune mechanisms supervene or chemotherapy is given. A logical route to optimizing treatment, then, is combining activated host mechanisms with chemotherapy. This project's objective is to understand how host mechanisms act with chemotherapy to amplify and accelerate the initial response to drug and produce long-lasting post-treatment effects to prevent relapse. VL is an ideal candidate for immunochemotherapy and its testing, since in this infection: (a) there is no vaccine, making drug therapy the mainstay of clinical management, (b) available chemotherapy is not optimal, (c) experimental understanding of mechanisms which activate or deactivate resistance is solid and ready to be built upon, (d) candidate host mechanisms can be identified in an in vivo model, and (e) experimental adjustment of these mechanisms is both feasible and therapeutic in established visceral infection. Nonetheless, gaps exist in our pathogenetic understanding of specific host mechanisms to target in VL and in how to best formulate and apply immunochemotherapy. Our proposed work in a model of Leishmania donovani (Ld) infection will fill in these gaps, laying the groundwork for future interventions to employ with chemotherapy. To accomplish the Specific Aims, the Research Plan tests responses in vivo, effects in established infection and hypotheses in the relevant tissue focus where parasitized macrophages, influxing monocytes and T cells, and up- and downregulating immunoinflammatory mechanisms all intersect with drug.
Aim 1 : Determine how host Th1 mechanisms transform chemotherapy to leishmanicidal.
Aim 1 tests mechanisms which govern responses to drug within the assembled tissue granuloma: mononuclear cell recruitment by potentially therapeutic chemokines, GM-CSF-induced blood monocyte influx and granuloma remodeling, and effects which alter drug pharmacology in encircled, parasitized macrophages.
Aim 2 : Characterize and then disable both proximal and distal targets in a counter regulatory, deactivating mechanism which drives pathogenesis and limits chemotherapy.
Aim 2 tests the mechanism's distal effector products (IL-6, TGF-2, IL-27) which reside in an IL-10-based network of deactivating cytokines and then its more proximal initiation by TLR (TLR2) and MAPK (ERK1/2) signal transduction.
Aim 3 : Analyze how chemo- therapy activates host immune mechanisms.
Aim 3 examines the novel converse idea that drug therapy itself triggers identifiable, relevant and exploitable host defense mechanisms to ensure overall efficacy.
Aim 3 's plan tests direct effects on macrophage mechanisms at the time of drug therapy, and then focuses on the post-treatment period, when a chemotherapy-induced, IL-12- and iNOS/phox-independent mechanism emerges to orchestrate quiescence of persistent tissue infection and the long-term, relapse-free state.
This research improving treatment in patients with visceral leishmaniasis (kala-azar) is relevant to NIH's health mission for three reasons: (a) this infection is a most neglected parasitic disease with recognized significance in endemic regions, (b) without vaccine to prevent infection, the only practical avenue to advancing its clinical management is new treatment approaches, and (c) this experimental research in animals will show how to best harness host immune mechanisms to meaningfully enhance effectiveness of antileishmanial drug therapy. To develop and apply combination immunochemotherapy, our research objectives are to amplify and accelerate initial drug-induced parasite killing and strengthen long-lasting effects to prevent post-treatment relapse of residual visceral infection. This project's objectives and experimental strategies also hold the promise of improving treatment in other similar infections in which host defense depends on optimally activating T cell- dependent immune mechanisms.
|Murray, Henry W; Zhang, Yunhua; Zhang, Yan et al. (2013) Regulatory actions of Toll-like receptor 2 (TLR2) and TLR4 in Leishmania donovani infection in the liver. Infect Immun 81:2318-26|
|Murray, Henry W (2012) Leishmaniasis in the United States: treatment in 2012. Am J Trop Med Hyg 86:434-40|
|Murray, Henry W (2010) Treatment of visceral leishmaniasis in 2010: direction from Bihar State, India. Future Microbiol 5:1301-3|