Project Grant R01AI185041

NEURO-IMMUNE MECHANISMS AGAINST SKIN-PENETRATING HELMINTHS - NEURO-IMMUNE MECHANISMS AGAINST SKIN-PENETRATING HELMINTHS SUMMARY DIVERSE HELMINTH SPECIES ESTABLISH HOST INFECTION THROUGH DIRECT SKIN PENETRATION, BUT THE MECHANISMS OF CUTANEOUS IMMUNITY ARE POORLY UNDERSTOOD. CURIOUSLY, PERCUTANEOUS INFECTION OF OVER 250 MILLION PEOPLE WITH THE WATER-BORNE BLOOD FLUKE SCHISTOSOMA MANSONI OFTEN GOES UNNOTICED AND MOST OF THESE INDIVIDUALS EXPERIENCE FREQUENT RE-INFECTION DUE TO POOR IMMUNE RESPONSES TO SKIN-PENETRATING LARVAE. WHETHER A MECHANISTIC LINK EXISTS BETWEEN IMPAIRED PROTECTIVE IMMUNITY AND FAILURE OF SKIN AFFERENT NEURONS TO RELEASE IMMUNOSTIMULATORY FACTORS IS A MAJOR GAP IN OUR CURRENT UNDERSTANDING OF HOST IMMUNITY. MOREOVER, THE ROLE OF THE ALARMIN CYTOKINE INTERLEUKIN 33 (IL-33) IN DRIVING HOST RESISTANCE OR SUSCEPTIBILITY TO SKIN PENETRATION BY HELMINTH LARVAE HAS NOT BEEN TESTED. OUR DATA REVEAL THAT PRE-EMPTIVE ACTIVATION OF MOUSE SKIN-AFFERENTS DRIVES INNATE RESISTANCE TO PARASITE INVASION ACCOMPANIED BY THE RECRUITMENT OF INTERLEUKIN (IL)-17-PRODUCING CD4 AND GD T CELL SUBSETS, AND INFLAMMATORY MONOCYTES. SURPRISINGLY, SKIN NEURON ACTIVATION ALSO RAPIDLY DEPLETES IL-33 IN TISSUE MACROPHAGES AND TYPE 2 CONVENTIONAL DENDRITIC CELLS (CDC2), BUT NOT SKIN FIBROBLASTS. INDEED, MICE WITH A GENETIC DELETION OF IL-33 ONLY IN CD11C+ MYELOID ANTIGEN PRESENTING CELLS (APC) PHENOCOPY HOST IMMUNE RESPONSES IN WILD-TYPE MICE WITH ACTIVATED SKIN-SENSORY NEURONS. THIS PROJECT SEEKS TO IDENTIFY THE SPECIFIC NEURON SUBSETS AND THE SOLUBLE MEDIATORS THEY RELEASE THAT DRIVE HOST RESISTANCE AND DISCERN WHETHER SUCH PROTECTION REQUIRES LOSS OF MYELOID-SPECIFIC IL-33. ONE OF THE KEY IMMUNOREGULATORY NEUROPEPTIDES RELEASED BY SKIN AFFERENTS IS CALCITONIN GENE-RELATED PEPTIDE (CGRP) AND OUR DATA SHOW THAT CGRP ADMINISTRATION RESULTS IN MYELOID APC- INTRINSIC LOSS OF IL-33 THROUGH UNKNOWN MECHANISM(S). THEREFORE, OUR CENTRAL HYPOTHESIS THAT ITCH-RESPONSIVE SKIN NEURONS INITIATE HOST RESISTANCE TO SKIN PENETRATING HELMINTHS VIA CGRP-MEDIATED REDUCTION OF MYELOID-SPECIFIC IL-33, WHICH INITIATES PRODUCTION OF IL-17-PROMOTING CYTOKINES FROM SKIN MACROPHAGE AND CDC SUBSETS. THE TWO SPECIFIC AIMS OF THIS PROPOSAL ARE TO: (1) IDENTIFY THE NEURON SUBSETS NECESSARY AND SUFFICIENT FOR SKIN RESISTANCE TO HELMINTH INFECTION AND (2) DETERMINE HOW CGRP CAUSES DECREASE IN MYELOID- SPECIFIC IL-33 AND HOST RESISTANCE TO PARASITE INVASION. SUCCESSFUL COMPLETION OF THIS PROJECT DESIGNED TO UNDERSTAND HOW SENSORY NEURON-APC INTERACTIONS CONTROL HOST PROTECTION AND IL-33 EXPRESSION STANDS TO PROVIDE KEY INSIGHT(S) FOR DEVELOPING PREVENTATIVE MEASURES AGAINST HELMINTH SKIN PENETRATION IN HUMANS, WHICH DO NOT CURRENTLY EXIST.