Thesis (M.S.)--University of Wisconsin--Madison, 1949. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 30-33).

Thesis (Ingeniero Zootecnista)--Escuela Superior Politecnica de Chimborazo. Facultad de Ciencias Pecuarias. Escuela de Ingeniera Zootecnica. / Abstract in Spanish and English.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1992. / Vita. Abstract. Includes bibliographical references (leaves 33-36). Also available via the Internet.

Thesis (M.S.)--University of Wisconsin--Madison, 1966. / eContent provider-neutral record in process. Description based on print version record. Bibliography: l. 77-84.

Proefschrift Maastricht. / Met lit. opg. en een samenvatting in het Nederlands.

For many years bovine brucellosis was a zoonosis endemic in large parts of the world. While it is still endemic in some parts, such as the Middle East or India, several countries such as Australia and Canada have successfully eradicated brucellosis in cattle by applying vaccines, improving the hygienic standards in cattle breeding, and slaughtering or quarantining infected animals. The large economical impact of bovine brucellosis and its virulence for humans, coming in direct contact to fluid discharges from infected animals, makes the eradication of bovine brucellosis important to achieve. To achieve this goal several vaccines have been developed in the past decades. Today the two most commonly used vaccines are Brucella abortus vaccine strain 19 and strain RB51. Both vaccines have been shown to be effective, but the mechanisms of immune responses following vaccination with either of the vaccines are not understood yet. In this thesis we analyze the immunological data obtained through vaccination with the two strains using mathematical modeling. We first design a measure that allows us to separate the subjects into good and bad responders. Then we investigate differences in the immune responses following vaccination with strain 19 or strain RB51 and boosting with strain RB51. We develop a mathematical model of immune responses that accounts for formation of antagonistic pro and anti-inflammatory and memory cells. We show that different characteristics of pro-inflammatory cell development and activity have an impact on the number of memory cells obtained after vaccination. / Master of Science

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.

The roles of genes responsible for the survival and persistence of Brucella in the host and the relationship between these genes and the disease were investigated via signature-tagged transposon mutagenesis. As much as 8% of the Brucella genome is important for survival of this organism in the host. This is an unusually high number and may help to explain the chronic or persistent nature of Brucella infections. Mutants attenuated in the mouse model were divided into two groups. The early mutants failed to establish infection or colonize the host. The late mutants colonized the host but failed to maintain infection. The vaccine potential of two mutants (virB10 and gcvH) that were unable to sustain infection was compared to that of a vaccine strain, S19. Survival of strain S19 in vivo was up to 12 weeks while virB10 and gcvH mutants were cleared from spleen at 8, and 24 weeks post-inoculation, respectively. Mice were vaccinated with individual mutants and then challenged with virulent S2308 at 8, 16, and 24 weeks postvaccination. As a result, protective immunity correlated with persistence of the mutant strain [gcvH>virB10]. These results suggest that survival is one of several factors that may influence protective immunity making it difficult to compare strains. For example, examination of host immune response revealed a similar pattern of host immune function (TH1 over TH2) in all mice except those vaccinated with virB10 mutant. Since gcvH mutant provided the best immunity, experiments were designed to explore its contribution of persistence to protection. In an effort to reduce non-specific activation induced by prolonged survival of gcvH mutant, protection was monitored after different periods of vaccination exposure followed with doxycycline treatment. In these studies, persistence of gcvH mutant enhanced protection against challenge. Overall, defined mutations in genes affecting survival may render mutants as vaccine candidates capable of stimulating protective immunity equal to or better than fortuitously isolated attenuated strains. Future studies should focus on characterization of these and other genes responsible for the persistence of Brucella to improve the safety and efficacy of live vaccines.

Proefschrift Universiteit van Amsterdam. / Met index, lit. opg. - Met samenvatting in het Nederlands.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.