Metabolomic Analysis of Chemical Interactions between Burkholderia thailandensis and Host to Inform Alternative Treatments
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Aiosa, Nicole
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Abstract
Burkholderia pseudomallei, a soil-dwelling pathogen, is the etiological agent for the human disease melioidosis and classified as a Tier 1 Select Agent, posing a serious global threat. Due to the absence of an FDA-approved vaccine against melioidosis as well as the multi-drug resistance of B. pseudomallei, there continues to be high-fatalities from this infection in the tropics and sub-tropics. The lethality of B. pseudomallei is further amplified by its transmissibility through inhalation, ingestion, and skin abrasion as well as its diverse clinical presentations. Production of virulence factors and modification of host cell functions triggered by Burkholderia infection constitute important mechanisms in the pathogenesis of this respiratory infection, including evasion of host immune responses. Currently, the metabolic responses during host-pathogen interactions that could inform medical countermeasures are not well-understood, but recent advances in mass spectrometry methods are enabling the narrowing of this knowledge gap. Towards this end, we coupled untargeted metabolomic analyses of Burkholderia models of infection (Burkholderia thailandensis, a validated surrogate) in mammalian hosts with high-throughput screening methods of candidate probiotics in order to inform alternative treatment approaches to combat Burkholderia infection. Through dual metabolome profiling, we characterized the pathogen’s chemical arsenal employed during co-culture with mammalian cells where it produces proposed virulence factors such as burkholdacs, bactobolins, acybolins, acyl-homoserine lactones, and 4-hydroxy-3-methyl-2-alkylquinoline. Conversely, we robustly captured the chemical signature of the host’s immune response to the presence of this pathogen, revealing the activation of several immune lipid pathways including the release of prostaglandins, as well as major disruptions to the host’s primary metabolic pathways such as the tricarboxylic acid cycle upon exposure to Burkholderia. Our characterization of the host-pathogen chemical interactions enabled further investigation into candidate probiotic bacteria as a potential medical countermeasure for Burkholderia infection. Using whole-cell matrix-assisted laser desorption/ionization (MALDI) mass spectrometry to screen candidate bacteria against Burkholderia to further prioritize strains for in vivo protection assays, we identified a Bacillus velezensis CP8 strain that elicits natural product production by the model pathogen and results in growth inhibition. We also establish the potential application of a Brevibacillus borstelensis CP19 strain as an airway probiotic treatment against B. thailandensis infection models in vivo. Thus, we present the use of various mass spectrometry-based tools as an effective method for studying host-pathogen interactions and screening airway probiotic candidates as alternative treatment methods for antibiotic resistant respiratory pathogens like B. pseudomallei.
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2024-04-17
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Dissertation