Defining mechanisms of fungal-bacterial interactions during infection
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Principal Investigator: Stephen K Dolan Organization: CLEMSON UNIVERSITY Fiscal Year: 2024 Award: $150,000 Funding agency: National Institute of Allergy and Infectious Diseases Project Summary Aspergillus fumigatus (Af) is the most common and life-threatening airborne opportunistic fungal pathogen. Investigations into Af pathogenesis have focused primarily on mono-species infections. The impact of co- infecting microbes on Af physiology during infection remains an understudied but critically important research area. Using cystic fibrosis (CF) infection as a model, my recent work has focused on characterizing Af physiology in the presence and absence of the coinfecting bacterial pathogen, Pseudomonas aeruginosa (Pa), using multi- omics approaches combined with reverse genetics. I have uncovered two major mechanisms of Af and Pa interkingdom communication, mediated through the toxic, microbial secondary metabolites gliotoxin (produced by Af) and hydrogen cyanide (produced by Pa). The proposed project builds logically on this work and aims to uncover the mechanistic basis underlying the physiological shifts which occur in both organisms upon coculture in synthetic CF sputum media. This work will also test if clinical isolates of Af and Pa maintain these secondary metabolite response networks after chronic human infection and test to what extent polymicrobial interactions impact Af physiology during human infection using advanced sequencing technologies. The overall goal of this application is two-fold: 1) to define the specific molecular basis for interactions that occur between Af and Pa (Specific Aim 1); and 2) to expand on these findings to determine the impact of microbial interactions and the host environment on Af physiology during human CF infection (Specific Aim 2). This work is likely to yield important discoveries that will aid in our understanding of both fungal physiology and the underlying mechanisms of interkingdom microbial interactions within chronic polymicrobial infections. Terms: <A fumigatus><A. fumigatus><Acceleration><Airway infections><Area><Aspergillus fumigatus><Behavior><CF infection><CF lung disease><CF patients><CF sputum><Characteristics><Chronic><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Communication><Cystic Fibrosis><Cystic Fibrosis sputum><Data><Development><Disease><Disease Outcome><Disorder><Drug Metabolic Detoxication><Drug Metabolic Detoxification><Environment><Exhibits><Exposure to><Foundations><Fungus Diseases><Future><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Gliotoxin><Goals><Growth><Heterogeneity><Human><Hydrocyanic Acid><Hydrogen Cyanide><Immune response><Immune system><Immunological response><In Situ><Infection><Investigation><Investigators><Laboratories><Life><Lung><Lung Respiratory System><Mediating><Mediator><Metabolic><Metabolic Drug Detoxications><Metabolic Pathway><Metabolism of Toxic Agents><Microbe><Microbial Bioactive Compound><Microbial Biofilms><Microbial Secondary Metabolite><Microbial natural product><Microbial-Derived Compound><Modeling><Modern Man><Molecular><Mucous body substance><Mucoviscidosis><Mucus><Mutation><Mycoses><Nutrient><Nutritional><Nutritional Requirements><Organism><P aeruginosa><P. aeruginosa><Pathogenesis><Pattern><Persons><Physiologic><Physiological><Physiology><Predisposition><Production><Proliferating><Property><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Pulmonary Body System><Pulmonary Cystic Fibrosis><Pulmonary Organ System><Reaction><Research><Research Personnel><Researchers><Respiratory Infections><Respiratory System><Respiratory Tract Infections><Respiratory Tracts><Respiratory tract structure><Severity of illness><Stress><Susceptibility><Technology><Testing><Therapeutic Fungicides><Tissue Growth><Toxin><Translating><Virulence><Viscosity><Work><anti-fungal><anti-fungal agents><anti-fungal drug><anti-microbial agent><anti-microbial drug><bacteria pathogen><bacterial pathogen><biofilm><chronic infection><comparative><computer based prediction><confocal imaging><cystic fibrosis infection><cystic fibrosis lung><cystic fibrosis lung disease><cystic fibrosis patients><design><designing><detoxification><developmental><disease severity><fungal infection><fungal pathogen><fungi pathogen><fungus infection><genetic approach><genetic strategy><genome mutation><host response><immune system response><immunoresponse><improved><in vitro Model><individuals with CF><individuals with cystic fibrosis><infection in CF><infection in cystic fibrosis><infection risk><innovate><innovation><innovative><living system><lung function><microbial interaction><microorganism><microorganism interaction><mortality><mucous><multiomics><multiple omics><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nutrient requirement><nutritious><ontogeny><opportunistic pathogen><panomics><pathogen><pathogenic bacteria><pathogenic fungus><patients with CF><patients with cystic fibrosis><persistent infection><predictive modeling><programs><pulmonary><pulmonary function><response><reverse genetics><secondary metabolite><transcriptomics>