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Principal Investigator: PHILLIP SCOTT
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $557,812
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Cutaneous leishmaniasis is a major neglected tropical disease that is associated with clinical manifestations
ranging in severity from relatively benign lesions to chronic highly ulcerated lesions to metastatic disease.
Optimally, drug treatment would eliminate the parasites, but drugs developed to date fail to induce sterile
cure and are often woefully inefficient at controlling the disease. Our new data strongly suggests that
optimal control of cutaneous leishmaniasis requires a response that not only effectively eliminates the
parasite, but also reduces the potential for immunopathology. In a series of publications, we have outlined
the role of CD8 cytolytic T cells in driving inflammation by upregulating the inflammasome and inducing the
release of IL-1. Thus, our studies indicate that an immunopathologic pathway involving the inflammasome
and IL-1 production is a major driver of disease. We further found that blocking NLRP3 or IL-1 in
experimental models of severe cutaneous leishmaniasis ameliorates pathology mediated by CTLs without
blocking protective immune responses, suggesting that either would be excellent targets for host-directed
immunotherapy that could be used in conjunction with conventional anti-parasitic treatments. However,
significant gaps in our knowledge of this pathologic response remain. Here we will utilize a combination of in
vitro and in vivo approaches that will identify the cells undergoing inflammasome activation, determine the
proximal signals that activate NLRP3, and define the chemokines that maintain this chronic
immunopathologic response. To accomplish this in Aim 1 we will determine which cells contribute to NLRP3
dependent pathology during cutaneous leishmaniasis disease progression by defining when
inflammasomes are activated following infection, identifying the cells involved and determining which cells
are required for disease-promoting inflammasome activation. In Aim 2 we will identify the triggers of NLRP3
inflammasome activation in cutaneous leishmaniasis. Finally, we found that the chemokines CCL3 and
CCL4 are associated with treatment failure in patients, and therefore in Aim 3 we will determine if these
chemokines drive the chronicity of cutaneous leishmania lesions by promoting CD8 T cell or regulatory T
cell recruitment to leishmanial lesions. Our proposed experiments have clear translational significance since
they are founded upon substantial data obtained from leishmaniasis patients and are designed to identify
the essential cells and signals required for disease. Such information will allow for a more specific targeting
of immunopathology in leishmaniasis and identify additional targets for host-directed therapies in this
chronic infection. Finally, these studies will be of more general significance, as this pathologic pathway is
not unique to cutaneous leishmaniasis.
Terms: <ACT2><AT744.1><Act-2><Antiparasitic Agents><Antiparasitic Drugs><Antiparasitics><Automobile Driving><Benign><Binding><Bio-Informatics><Bioinformatics><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCL3><CCL3 gene><CCL4><CCL4 gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD183><CD195 Antigen><CD195 Antigen Gene><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CHEMR13><CHEMR13 Gene><CINC-2><CINC-2b><CKR-5><CKR-5 Gene><CKR-L2><CKR5><CKR5 Gene><CKR5 Receptors><CMKAR3><CMKBR5><CMKBR5 Gene><CXCL3><CXCL3 gene><CXCL9><CXCL9 gene><CXCR3><CXCR3 gene><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell-Mediated Lympholytic Cells><Cells><Chemokine (C-C Motif) Ligand 4><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C motif) Ligand 3><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Chemokine (C-X-C Motif) Receptor 3><Chemokine, CC Motif, Ligand 4><Chemotactic Cytokines><Chronic><Clinical><Cultured Cells><Cutaneous><Cutaneous Leishmaniasis><Cytolysis><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Disease><Disease Progression><Disorder><Drug Therapy><Drugs><Equilibrium><Experimental Models><Future><G Protein-Coupled Receptor 9><G0S19-1><GPR9><GRO3><GROg><Gene Transcription><Generations><Genetic Transcription><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><Homologous Chemotactic Cytokines><Host Factor><Host Factor Protein><Humig><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><Immune Activation 2><Immune mediated therapy><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><In Vitro><Individual><Infection><Inflammasome><Inflammation><Inflammatory><Integration Host Factors><Intercrines><Intracellular Communication and Signaling><Knowledge><LD78ALPHA><LYT3><Leishmania><Leishmaniasis><Lesion><Link><Lymphatic cell><Lymphocyte><Lymphocytic><Lysis><MIG Gene><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP-2B><MIP1A><MIP1B><MIP1B1><MIP2B><Macrophage Inflammatory Protein 1-Beta><Mediating><Medication><Mice><Mice Mammals><Mig Receptor><Mig-R><MigR><Modeling><Molecular><Molecular Interaction><Murine><Mus><Outcome><Parasites><Parasiticides><Pathologic><Pathology><Pathway interactions><Patients><Pattern><Pharmaceutical Preparations><Pharmacotherapy><Physiologic><Physiological><Play><Production><Publications><RNA Expression><Regulatory T-Lymphocyte><Reporter><Role><SCYA3><SCYA4><SCYB3><SCYB9><SIS cytokines><Scientific Publication><Series><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A3><Small Inducible Cytokine A4><Stem Cell Inhibitor><Sterility><T8 Cells><T8 Lymphocytes><Testing><Transcription><Treatment Failure><Treg><balance><balance function><biological signal transduction><cell type><chemoattractant cytokine><chemokine><chronic infection><crg-10><dermal leishmaniasis><design><designing><disease control><disorder control><driving><drug treatment><drug/agent><ex vivo imaging><experiment><experimental research><experimental study><experiments><host response><imaging approach><imaging based approach><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunopathology><immunoresponse><improved><in vitro Model><in vivo><insight><killer T cell><lymph cell><lymphocyte pore-forming protein><mouse model><murine model><necrocytosis><neglected tropical diseases><pathway><perforin><persistent infection><recruit><regulatory T-cells><response><social role><sterile><therapy failure>