Project 3: Defining adaptive immune interactions that shape Clostridioides difficile infection

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Principal Investigator: Michael C. Abt
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $348,154
Funding agency: National Institute of Allergy and Infectious Diseases

SUMMARY: PROJECT 3 - IMMUNOLOGY
The quality of the host immune response to Clostridioides difficile infection is one of the strongest predictors of
disease severity. Despite the protective capacity of the host immune response, the immune parameters that
promote immunity remain poorly understood. Approximately 25-35% of patients that recover from primary C.
difficile infection will experience a recurrence episode indicating the host often fails to develop natural immunity
following primary infection. Further, multiple vaccine trails have not met primary endpoint of reducing
occurrence of infection despite the vaccine candidates eliciting robust antibody responses against C. difficile
toxins, the primary virulence factors driving disease. A limited mechanistic understanding of why the
natural immune response to infection often does not promote immunity represents a critical roadblock
toward the goal of developing a vaccine that will elicit lasting protective immunity in high-risk
populations. This project will systematically evaluate the natural immune response to C. difficile infection
using both patient sample and a murine infection system. In aim 1 we will compare the capacity of the systemic
and intestinal mucosal antibodies elicited following infection to detect and bind to C difficile residing in the
intestinal lumen. Successful generation of an antibody response that targets C. difficile in the intestinal tract is
dependent on a coordinated C. difficile-specific CD4+ T and B cell response in the intestine and associated
draining lymph nodes and is the focus of studies proposed in aim 2. Last, in aim 3 we will investigate the in
vivo biogeography and transcriptome of C. difficile in the presence of adaptive immune pressure to identify
immune evasion mechanisms employed by C. difficile to promote persistence and transmission. The result of
all three aims will feedback into Project 1 (Vaccine Development) to inform mRNA vaccine studies by
providing a template how vaccine-induced immunity can be shaped to limit disease, prevent colonization, and
recurrence of C. difficile.
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Terms: <Acute><Age><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Blood Serum><C diff><C difficile><C. diff><C. difficile><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Surface Proteins><Cells><Characteristics><Childhood><Chronic Phase><Clinical><Clostridioides difficile><Clostridium difficile><Complement><Complement Proteins><DNA><Data><Defect><Deoxyribonucleic Acid><Disease><Disorder><Elderly><Engineering><Feces><Feedback><Filtration><Filtration Fractionation><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Transcription><Generations><Genetic Transcription><Goals><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Immune><Immune Evasion><Immune Precipitation><Immune Targeting><Immune memory><Immune response><Immune system><Immunes><Immunity><Immunocompetent><Immunodeficient Mouse><Immunologic Memory><Immunological Memory><Immunological response><Immunoprecipitation><Impairment><In Situ><In Vitro><Inducer Cells><Inducer T-Lymphocytes><Infection><Innate Immunity><Intestinal><Intestinal Mucosa><Intestines><Large Intestine><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Microscopy><Modern Man><Molecular Interaction><Mucosal Immunity><Mucous body substance><Mucus><Murine><Mus><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Pathogenicity Factors><Pathway interactions><Patients><Physiology><Population><Primary Infection><RNA Expression><RNA Seq><RNA sequencing><RNA vaccine><RNA-based vaccine><RNAseq><Rag1><Rag1 Mouse><Recurrence><Recurrent><Reporting><Resolution><Risk><Sampling><Serum><Severity of illness><Shapes><Sterility><System><T4 Cells><T4 Lymphocytes><Toxin><Transcription><Transmission><Vaccinated><Vaccine Clinical Trial><Vaccine Design><Vaccines><Virulence Factors><Visualization><adaptive immune response><adaptive immunity><adult youth><advanced age><age dependent><age related><aged><ages><anamnestic reaction><bowel><develop a vaccine><develop vaccines><development of a vaccine><disease severity><disparate effect><disparate impact><disparate result><draining lymph node><driving><elders><experience><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><flow cytophotometry><geriatric><global gene expression><global transcription profile><high dimensionality><high risk><high risk group><high risk individual><high risk people><high risk population><host response><immune competent><immune evasive><immune system response><immunoresponse><in vivo><inequitable effect><inequitable impact><inequitable outcome><infection recurrence><large bowel><late life><later life><mRNA><mRNA vaccine><mRNA-based vaccine><metagenome sequencing><metagenomic sequencing><microbial><model of animal><mucous><non vaccinated><not vaccinated><older adult><older person><outcome disparities><outcome inequality><outcome inequity><pathogen><pathway><patient population><pediatric><pressure><prevent><preventing><primary end point><primary endpoint><recurrent infection><recurring infection><regional lymph node><resolutions><response><secondary immune response><senior citizen><sterile><stool><success><transcriptome><transcriptome sequencing><transcriptomic sequencing><transmission process><unequal effect><unequal impact><unequal outcome><unvaccinated><vaccination study><vaccination trial><vaccine candidate><vaccine development><vaccine response><vaccine responsiveness><vaccine study><vaccine trial><vaccine-induced immunity><vaccine-induced protection><vaccine-induced response><young adult><young adulthood>