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Brucellosis is a chronic, recurring disease caused by the bacterium Brucella abortus, along with other species of the genus Brucella, and is one of the most common bacterial zoonosis worldwide. The bacteria preferentially infect and reside within host macrophages, causing an undulant fever, joint pain, and other flu-like symptoms, in addition to more severe problems like hepatosplenomegaly and endocarditis. Brucella infection is most often acquired via inhalation through the respiratory route, or via consumption of unpasteurized dairy products. Although ingestion is a major route of infection, the transcriptional response of B. abortus during oral infection remains poorly characterized. In this project, RNA sequencing was used to discover genes with the greatest transcriptional changes in B. abortus subjected to deoxycholate, a host bile acid encountered by bacteria during oral infection. Gene deletion strains of B. abortus were then created and tested for susceptibility to pH and bile acid stress, along with their ability to invade and replicate within macrophages. If the genes of interest are important for the oral infection process, B. abortus strains lacking these genes will likely be more susceptible to pH and deoxycholate stress and may exhibit attenuation in the macrophage infection model. Determination of genes important for the oral infection process would further elucidate the molecular mechanisms by which B. abortus invades the host, and could help lead to future treatments and novel therapeutics. / Master of Science / Brucellosis, caused by the bacterium Brucella abortus, is a zoonotic disease, meaning that humans can acquire the illness from animals. Once infected, sufferers of brucellosis experience a chronic, recurring fever that repeatedly rises and falls. Additionally, the disease can cause enlargement of the spleen and liver, and can sometimes cause inflammation of the valves within the heart. Although B. abortus can infect a host through many routes of entry (inhalation, accidental injection, etc), patients are often infected through the consumption of contaminated, unpasteurized dairy products. The genes utilized by B. abortus during oral infection have not been well characterized, so it is not well known what mechanisms B. abortus uses to survive the pH and bile acid stresses it faces in the host stomach and intestines. This research examines which genes are increasingly or decreasingly utilized by B. abortus when it is subjected to deoxycholate—a bile acid stress used to simulate the host small intestine. Genes that exhibited the largest change in expression upon deoxycholate exposure were then chosen for further study: new strains of B. abortus lacking these genes of interest were created to determine if the gene deletion decreased the bacteria's ability to survive acid and deoxycholate stress, along with its ability to infect host macrophages, a type of white blood cell. If deletion of these genes weakens the ability of B. abortus to survive and infect, then these genes likely have a role during the oral infection process. By further elucidating which genes are used by B. abortus to survive host defenses and infect via the oral route, one could then create new medicines that are more effective at inhibiting the mechanisms needed by B. abortus for successful infection and persistence within the host.

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