Document text
Principal Investigator: Prajwal Gurung
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $504,819
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Pathogen recognition receptors and their associated adaptors are essential for the prompt detection of
pathogens and the subsequent initiation of effective host responses and restoration of homeostasis. Over the
last decade, Nod-like receptors (NLRs) have been on the forefront of innate immune research, and several
groundbreaking studies have been published, to which my research has contributed. Leishmania spp. are
parasites with global health importance, yet the role of NLRs and their adaptors during Leishmania spp.
infection has been an understudied area.
Receptor interacting protein kinase 2 (RIPK2) is an essential adaptor downstream of cytoplasmic sensors
NLRC1 and NLRC2, and play an important role in a wide variety of clinical settings including bacterial, viral and
fungal infections, as well as non-infectious inflammatory diseases such as multiple sclerosis, inflammatory
bowel disease and metabolic diseases. However, the role of RIPK2 during cutaneous leishmaniasis remain
unknown. In this grant, we propose to investigate the precise cellular and molecular mechanisms involving
RIPK2 during Leishmania major (L. major)-induced cutaneous disease. Our preliminary work has already
elucidated several exciting features of the role of RIPK2 during L. major infection. We found that RIPK2-
deficient mice are highly susceptible to L. major infection. Unexpectedly, mice deficient in NLRC2 or both
NLRC1/NLRC2 are dispensable in L. major infection suggesting a novel sensor that function upstream of
RIPK2. Moreover, RIPK2 interacted with CARD9 to provide protection against L. major. Based on these
preliminary data, we propose that a novel Dectin-1/RIPK2/CARD9 signaling axis modulates anti-leishmanial
immunity.
Successful completion of this project will yield a better understanding of RIPK2 biology in general, unveil a
novel pathway involving RIPK2 in signal transduction, and potentially identify therapeutic targets to ameliorate
Leishmania spp.-associated pathology.
1
Terms: <Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Affect><Area><Autoregulation><B-Cell CLL/Lymphoma 10><B-Cell Leukemia/Lymphoma 10><BCL10><BCL10 gene><Bacterial Infections><Basic Research><Basic Science><Biochemical><Biology><Causality><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cells><Clinical><Communicable Diseases><Complex><Cutaneous Disorder><Cutaneous Leishmaniasis><Cytoplasm><Data><Dermatoses><Development><Disease><Disorder><Disseminated Sclerosis><Etiology><Event><Family><Fungus Diseases><Genetic><Goals><Grant><Homeostasis><Host resistance><Human><Immune><Immune response><Immunes><Immunity><Immunological response><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammasome><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Innate Immune Response><Intracellular Communication and Signaling><Kinases><Knowledge><Leishmania><Leishmania (Leishmania) major><Leishmania major><Leishmania tropica major><Leishmaniasis><Link><MALT1><Mediating><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Target><Mucosa- associated lymphoid tissue lymphoma translocation protein-1><Multiple Sclerosis><Murine><Mus><Mycoses><Outcome><Parasites><Pathogen detection><Pathogenesis><Pathology><Pathway interactions><Persons><Phosphotransferase Gene><Phosphotransferases><Physiological Homeostasis><Play><Predisposition><Protein Kinase Interaction><Publishing><Receptor Activation><Receptor Protein><Receptor-Interacting Protein><Research><Resistance><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin Diseases><Skin Diseases and Manifestations><Surface><Susceptibility><Therapeutic Fungicides><Thesaurismosis><Transphosphorylases><Viral Diseases><Virus Diseases><Work><adapter protein><adaptive immune response><anti-fungal><anti-fungal agents><anti-fungal drug><bacteria infection><bacterial disease><biological signal transduction><causation><combat><cutaneous disease><dectin 1><dermal disease><dermal disorder><dermal leishmaniasis><developmental><disease causation><effective therapy><effective treatment><fungal infection><fungus infection><global health><host response><immune system response><immunoresponse><inflammatory disease of the intestine><inflammatory disorder of the intestine><insular sclerosis><intestinal autoinflammation><metabolism disorder><mouse model><mucosa-associated lymphoid tissue 1><murine model><necrocytosis><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><obligate intracellular parasite><pathogen><pathway><receptor><resistant><response><restoration><sensor><skin disorder><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><treatment strategy><viral infection><virus infection><virus-induced disease>