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Principal Investigator: David Tyus
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $14,135
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Clostridioides difficile is a Gram-positive bacterium responsible for more hospital-acquired
infections than any other pathogen. C. difficile infection (CDI) manifests in a range of severity
from diarrheal illness to death, especially in advanced aged patients. Current therapy for CDI
largely relies on antibiotics and, while effective short term, greatly increases the risk for
recurrent infection. To address this issue, we look to identify immunomodulatory approaches
that spare the protective gut microbial communities. In this proposal I will interrogate the role of
IL-6 in CDI disease progression. In preliminary experiments, we found that neutralizing IL-6
worsened disease symptoms in our CDI murine model, suggesting a protective role for IL-6 in
CDI. Further, we found that transcription of a neurotransmitter receptor and positive regulator of
IL-6, the alpha 2 adrenergic receptor(a2ar), is decreased in severe CDI as compared to mild
CDI. Norepinephrine and epinephrine can bind a2ar in immune cells to increase their production
of IL-6. Released IL-6 can act through two signaling pathways: trans-signaling and classical
signaling. IL-6 trans-signaling typically causes pro-inflammatory effects while classical signaling
tends to have anti-inflammatory, regenerative effects. We hypothesize that IL-6 acts through
classical signaling to induce epithelial regeneration and, in turn, decrease disease severity in
CDI. To test this hypothesis, I will use a murine model of CDI. In Aim 1 I will investigate the role
of IL-6 and determine if classical or trans-signaling pathways dictate the effect of IL-6 by
monitoring disease severity and inflammatory profile in models deficient in IL-6 activity or
stimulated or deficient in trans-signaling. In Aim 2, I will identify the primary cellular source of
IL-6 during CDI and determine whether IL-6 production is regulated by catecholamines
norepinephrine and epinephrine in this context. Together, these data will allow us to consider
the signaling axes and cellular determinants that are potentially targetable in CDI. This work not
only has implications for CDI therapy but more broadly, it will allow us to understand the
contributing factors to the pleiotropic role of IL-6 in the gut.
Terms: <Address><Adrenaline><Adrenergic Agents><Adrenergic Drugs><Adrenergics><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antiinflammatory Effect><Attention><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><C diff><C difficile><C. diff><C. difficile><Catecholamines><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Chimera><Chimera organism><Clinical><Clostridioides difficile><Clostridium difficile><Communicable Diseases><Data><Death><Disease><Disease Progression><Disorder><Dysfunction><Elderly><Epinephrine><Epithelium><Fortification><Functional disorder><GI microbiota><Gastrointestinal microbiota><Gene Transcription><Genetic Transcription><Gram-Positive Bacteria><HPGF><Hematopoietic><Hepatocyte-Stimulating Factor><Hospital Infections><Hospital acquired infection><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune mediated therapy><Immune response><Immunes><Immunity><Immunologic Subtyping><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunophenotyping><Immunotherapy><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Interleukin-6><Intracellular Communication and Signaling><Levarterenol><Levonorepinephrine><MGI-2><Macrophage><Mediating><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Molecular Interaction><Monitor><Murine><Mus><Myeloid Differentiation-Inducing Protein><Mφ><Neurohumor Receptors><Neuromediator Receptors><Neuroregulator Receptors><Neurotransmitter Receptor><Noradrenaline><Norepinephrine><Nosocomial Infections><Outcome><Pathogenesis><Pathology><Patients><Persons><Physiopathology><Plasmacytoma Growth Factor><Production><Proteins><RNA Expression><Receptors, Adrenergic, alpha-2><Regulation><Research><Risk><Role><Sanitation><Severities><Severity of illness><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Source><Sympathins><Symptoms><Testing><Therapeutic><Therapeutic Epinephrine><Tissues><Transcription><Wild Type Mouse><Work><advanced age><alpha-adrenergic receptor><anti-inflammatory effect><biological signal transduction><chimeras><diarrheal disease><diarrheal illness><disease severity><enteral infection><enteric infection><enteric microbial community><enteric microbiota><enteric pathogen infection><enteropathogen infection><enteropathogenic infection><epithelium regeneration><experiment><experimental research><experimental study><experiments><gastrointestinal microbial flora><geriatric><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><hemopoietic><host response><immune modulation><immune regulation><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><immunologic reactivity control><immunomodulatory><immunophenotype><immunoregulation><immunoregulatory><immunoresponse><infected with enteropathogen><infection recurrence><innovate><innovation><innovative><institutional infection><interferon beta 2><intestinal flora><intestinal infection><intestinal microbiota><intestinal microflora><intestinal tract microflora><intestine infection><mortality><mouse model><murine model><neutralizing antibody><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathogen><pathophysiology><pharmacologic><recurrent infection><recurring infection><regenerate epithelium><regenerative><response><senior citizen><social role><therapeutic evaluation><therapeutic testing><wildtype mouse><α-adrenergic receptor>