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Principal Investigator: Samuel Eallonardo
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $21,501
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Pregnant women are more likely to be infected with the intracellular pathogen Listeria monocytogenes (Lm) than the general population, and the bacterium can be vertically transmitted leading to fetal infection and pregnancy loss. Despite its public/health/relevance, the determinants of maternofetal transmission remain undefined. Examination of clinical Lm isolates indicates that subpopulations of strains possess an enhanced ability for vertical transmission. One of these strains, 07PF0776, was first noted for its ability to target the heart, and this cardiotropism requires InlB, a bacterial surface protein known to be important for the invasion of mammalian cells. Experimental evidence indicates that InlB is similarly required for vertical transmission and that high InlB expression alone is sufficient to significantly enhance vertical transmission in an unrelated strain. The goal for this project is to elucidate the mechanisms by which InlB enhances the vertical transmission of hypervirulent Lm strains and of Lm generally. The project aims are designed to connect strain-specific genetic variations to altered bacterial behavior, host pathology, and immune responses. The current working hypothesis is that enhanced translation of inlB occurs in Lm hypervirulent subpopulations as the result of a trinucleotide substitution in the 5’ untranslated region (UTR) of the inlB transcript that promotes ribosome binding. It is also hypothesized that amino acid variations within InlB enhance InlB binding to the bacterial cell wall and thus increase InlB surface abundance. Aim 1 will determine how InlB levels are altered in 07PF0776 by looking at InlB synthesis, degradation, and cell wall affinity. This aim will also explore how the 5’ UTR contributes to increased protein expression. Aim 2 will determine how increased InlB expression promotes bacterial colonization of the placenta and fetus. Experiments will use pregnant mice as a model and compare strains with varying levels of InlB activity. Fluorescence microscopy combined with immuno-histochemistry will determine if InlB-high-expressing strains have enhanced invasion of specific placental cell types, or alternatively gain access through new portals of entry. RNAScope in situ hybridization and flow cytometry will establish how bacterial localization impacts the nature of the placental immune response. The ultimate goal of the above aims will be to establish the mechanisms by which strains of Lm cause severe fetal and neonatal disease. These studies may eventually allow for improved treatment of severe Lm infection and more effective strategies to protect pregnant women from Lm-induced pregnancy complications.
Terms: <21+ years old><5' Untranslated Regions><5'UTR><Abscess><Adult><Adult Human><Affinity><Amino Acids><Anti-HIV Positivity><Bacteria><Behavior><Binding><Blood><Blood Reticuloendothelial System><Cardiac><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Wall><Cells><Cells Placenta-Tissue><Clinical><Communicable Diseases><Data><Diagnosis><Disease><Disorder><Elderly><Environment><Exhibits><Fetal Death><Fetal Tissues><Fetus><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluorescence Light Microscopy><Fluorescence Microscopy><Frequencies><GI colonization><Gastroenteritis><General Population><General Public><Genetic><Genetic Diversity><Genetic Variation><Goals><HIV Positive><HIV Positivity><HIV Seroconversion><HIV Seropositivity><HIV antibody positive><HTLV-III Seroconversion><HTLV-III Seropositivity><Health><Health Benefit><Heart><Immune Cell Activation><Immune response><Immune signaling><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Immunosuppressed Host><In Situ Hybridization><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><InlB protein><Intracellular Communication and Signaling><Invaded><Knowledge><L monocytogenes><L. monocytogenes><Life Style><Lifestyle><Listeria Infections><Listeria monocytogenes><Listeriosis><Mammalian Cell><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mothers><Murine><Mus><Nature><Neonatal><Normal Placentoma><Nucleotides><Organ><Organism><Outcome><Outcome Study><Pathogenesis><Pathogenicity Factors><Pathology><Patients><Persons><Phenotype><Placenta><Placenta Embryonic Tissue><Placentome><Predisposition><Pregnancy Complications><Pregnancy loss><Pregnant Women><Production><Public Health><Receptor Signaling><Ribosomes><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Surface><Surface Proteins><Susceptibility><Transcript><Translations><Transmission><Tropism><Variant><Variation><Vertical Transmission><Virulence Factors><abortion><adulthood><advanced age><aminoacid><biological signal transduction><cell type><complications during pregnancy><cytokine><design><designing><expectant mother><expecting mother><experience><experiment><experimental research><experimental study><experiments><fetal><fetal infection><fetal loss><fetus death><fetus loss><fetus tissue><flow cytophotometry><food born pathogen><food borne pathogen><food-born><food-borne><foodborn><foodborn pathogen><foodborne><foodborne pathogen><gastrointestinal tract colonization><geriatric><gut colonization><host response><immune activation><immune system response><immunoresponse><immunosuppressed patient><improved><in situ Hybridization Genetics><in situ Hybridization Staining Method><infection risk><inlB gene product><insight><internalin B><intestinal colonization><intestinal epithelium><knowledgebase><living system><mRNA Leader Sequences><model organism><mortality><novel><pathogen><placenta infection><placental infection><posttranscriptional><pregnancy-related complications><pregnant><pregnant mothers><prevent><preventing><protein expression><protein function><receptor binding><receptor bound><senior citizen><tool><translation><transmission process>