<p>Allergic asthma is a disease involving airway inflammation, commonly linked to allergen exposure. Computed tomography (CT) is used to quantitatively assess changes in density, hence inflammation, in the lung. CT imaging provides the ability to non-invasively and longitudinally study disease progression and evaluate treatment efficacy. The objective of this study was to determine the sensitivity of CT to detect the anti-inflammatory effects of budesonide (BUD) by measuring airway tissue density in a rat model of allergic airway disease.</p> <p>Female<strong> </strong>Brown Norway rats were exposed intratracheally to house dust mite (HDM) extract (250 µg in 100µL saline) or saline control every other day for a total of five administrations (inflammatory phase). ABUD dose and temporal response study was performed usingBUD 0, 10, 100, and 300 µg/kg administered concurrently with HDM for three and six treatments (treatment phase). CT scanning was performed at baseline, post inflammatory phase, and after three and six BUD treatments. From the CT, density was measured in a defined volume of interest surrounding the major airways. Bronchoalveolar lavage (BAL) and histological samples were collected at the same time points.</p> <p>After the inflammatory phase, a significant increase in peribronchial density was found in the HDM group compared to controls. This corresponded to a significant increase in inflammation by histology andBALtotal cell count (TCC), specifically eosinophils. Within the treatment phase after three treatments,BUD100 and 300 µg/kg led to a significant shift in lung density compared to HDM exposure alone, to a state similar to baseline. All BUD treated groups expressed a significant reduction in peribronchial density after six treatments. However, histology andBALTCC only showed a significant decrease in inflammation after six treatments for all three BUD doses.</p> <p>CT densitometry is a sensitive, non-invasive method of evaluating the anti-inflammatory effects of budesonide and can be used for future screening of therapies in allergic lung models. Airway segmentation of CT permits the localized assessment of peribronchial inflammation, while other outcome measurements, such as BAL cytology, provide whole lung assessment which may not accurately reflect important regional changes.</p> / Master of Science (MSc)

Equine arteritis virus (EAV) has a global impact on the equine industry being the causative agent of equine viral arteritis (EVA), a reproductive, respiratory, and systemic disease of equids. A distinctive feature of EAV infection is that it establishes long-term persistent infection in the reproductive tract of stallions and is continuously shed in the semen (carrier state). Recent studies showed that long-term persistence is associated with a specific allele of the CXCL16 gene (CXCL16S). However, the cellular and molecular mechanisms underlying the establishment and maintenance of persistent infection are yet to be determined. The studies were undertaken herein unequivocally demonstrated that the ampulla is the main EAV tissue reservoir rather than immunologically privileged tissues (i.e., testes) and that EAV has specific tropism for stromal cells and CD8+ T and CD21+ B lymphocytes but not glandular epithelium in the reproductive tract. Furthermore, persistent EAV infection is associated with a significant humoral, mucosal antibody and inflammatory response at the site of persistence, characterized by induction of high levels of neutralizing antibodies (IgG1), mucosal anti-EAV-specific IgA, IgG1, IgG3/5, and IgG4/7 with variable neutralizing efficacy; and moderate, multifocal lymphoplasmacytic ampullitis, with significant infiltration of T lymphocytes (mainly CD8+ and low numbers of FOXP3+ lymphocytes), CD21+ B lymphocytes, diverse Ig-secreting plasma cells, and Iba-1+ and CD83+ tissue macrophages/dendritic cells. Moreover, EAV long-term persistent infection is associated with a CD8+ T lymphocyte transcriptional profile with upregulation of T-cell exhaustion-related transcripts and homing chemokines/chemokine receptors (CXCL9-11/CXCR3 and CXCL16/CXCR6), orchestrated by a specific subset of transcription factors (EOMES, PRDM1, BATF, NFATC2, STAT1, IRF1, TBX21), which are associated with the presence of the susceptibility allele (CXCL16S). Finally, these studies have determined that long-term EAV persistence is associated with the downregulation of a specific seminal exosome-associated miRNA (eca-mir-128) along with an enhanced expression of CXCL16 in the reproductive tract, a putative target of eca-mir-128. These findings provide evidence that this miRNA plays a crucial role in the regulation of the CXCL16/CXCR6 axis in the reproductive tract of persistently infected stallions, a chemokine axis strongly implicated in EAV persistence. The findings presented herein suggest that complex host-pathogen interactions shape the outcome of EAV infection in the stallion and that EAV employs complex immune evasion mechanisms favoring persistence in the reproductive tract. Further studies to identify specific mechanisms mediating the modulation of the CXCL16/CXCR6 axis and viral immune evasion in the reproductive tract of the EAV long-term carrier stallion are warranted.

Ventricular dysfunction and dilated cardiomyopathy (DCM) develop among untreated HIV-infected people at much higher rates than among HIV-negative individuals, resulting in significant contributions to morbidity and mortality. Mechanisms underlying development of HIV-associated cardiomyopathy (HIVCM) are as yet poorly understood. The well-characterized simian immunodeficiency virus (SIV) model of HIV infection provides a unique context for HIVCM pathogenesis studies in that SIV-infected rhesus monkeys develop myocardial lesions and contractile dysfunction similar to those described in HIV-infected people, suggesting a shared disease mechanism. Lymphocytic myocarditis is a commonly reported finding in AIDS patients at autopsy and constitutes one of several conditions known to predispose to development of DCM, irrespective of HIV-infection status. As lymphocytic myocarditis also occurs with high frequency among SIV-infected rhesus monkeys, a retrospective analysis of rhesus monkey cardiac tissue collected at necropsy was performed to examine viral and cellular correlates of lymphocytic inflammation within myocardial tissue. One subpopulation of macrophages, which has been reported by other groups to be associated with an anti-inflammatory phenotype, was found to correlate inversely with lymphocytic infiltration and positively with numbers of virus infected cells, suggesting effects of an anti-inflammatory cytokine production profile. In contrast, the detrimental effects of inflammatory cytokines on myocardial structure and function are well-recognized and HIV infection in general is characterized by chronic immune activation and inflammatory cytokine dysregulation. To further investigate a role for myocardial cytokine production in development of HIVCM, a prospective study was conducted in which SIV-infected rhesus monkeys and uninfected controls were treated with recurrent administration of inactivated Mycobacterium aviumcomplex bacteria (MAC). SIV-infected, MAC-treated animals rapidly developed significant ventricular systolic dysfunction and chamber dilatation not seen in control groups, suggesting an exaggerated myocardial sensitivity to exogenous antigenic stimulation. Concurrent treatment with the TNFα antagonist etanercept completely abrogated development of these changes, strongly implicating a causative role for TNFα in evolution of the contractile dysfunction and chamber remodeling. Findings reported from the current studies suggest that characteristics of local myocardial macrophage populations and the myocardial tissue cytokine milieu may play more important roles than lymphocytic infiltration, cardiomyocyte damage, or viral proteins in the pathogenesis of HIVCM.

Coral diseases were first noted in the 1960s and 1970s and have had major impacts globally on coral reef community structures. In the Caribbean, a major outbreak of white band disease has been considered responsible for the drastic decline of Caribbean Acroporids since the 1970s. In addition to white band disease, another more recently described condition known as rapid tissue loss (RTL) has had major impacts on Acropora cervicornis populations, specifically offshore Broward County Southeast Florida. While these diseases have contributed to the population decline, determining their etiologies has been elusive. Coral diseases have been characterized by shifts in their microbial counterparts within many levels of the coral host. While some coral diseases have had specific pathogens identified, research has not been able to determine pathogens for most. Evidence points toward bacterial causes for many diseases, but due to the complexity of the coral holobiont and the interaction with the environment, elucidating the causes has proven difficult. Many studies have examined the microbiomes of specific diseases and determined some potential pathogens or at least taxa playing important roles in the disease, although none have looked at RTL. Recognizing the local affect of RTL on A. cervicornis, this study set out to gain a baseline understanding of the healthy and RTL affected microbiome of A. cervicornis. 16S rRNA gene sequencing was used to examine the microbiome of completely healthy colonies, healthy regions of diseased colonies, and the disease margin of diseased colonies. Analysis of four microbial diversity metrics revealed marked increases in diversity with respect to declining health states. Additionally, community dissimilarity analysis and analysis of differentially abundant taxa exhibited distinct microbial community structures due to coral health. Several highly abundant (Rickettsiales, Rhodobacteraceae) and a few low abundance (Bdellovibrionales) taxa were identified as primary drivers of the differences. Additionally, Piscirickettsiaceae, a known fish pathogen, was consistently associated with RTL and warrants further investigation. All of the taxa identified with in RTL have been associated with other Acroporid and non-Acroporid diseases throughout the Caribbean and the rest of the world. The consistent IV association of similar taxa for coral diseases around the world, including those found in this study, supports the recent ideas of non-specific primary pathogens. While most disease studies, coral and otherwise, aim to determine a single pathogen for a single disease, this study and others suggest there could be a multitude of organisms responsible for the disease. Therefore understanding the interactions of the coral holobiont and the environment is important to understanding coral disease. While this study reveals significant changes in the bacterial community associated with RTL as well as some potential pathogens, the relationships appear complex and perhaps at a functional level rather than merely taxonomic. Furthermore, this study did not examine viruses, fungi, or protists, which could be possible pathogens. Therefore, to further develop an understanding of RTL and many other coral diseases it will be necessary to consider additional none-bacterial members of the holobiont as well as the bacterial functions and taxa coupled with the roles of environmental factors.

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Ziel der vorliegenden Arbeit war es, Screening–Methoden zu prüfen, um auf einfache, kostensparende Weise und mit ausreichender statistischer Sicherheit festzustellen, ob der Erreger der Paratuberkulose (Mycobacterium avium ssp. paratuberculosis) in einer Herde vorhanden ist oder nicht. Dazu wurden zwei auf dem kulturellen Erregernachweis beruhende Verfahren, die Untersuchung individueller Kotproben auf der Basis von Stichproben und die Untersuchung von Umgebungskotproben, einem serologischen Untersuchungsansatz, dem Nachweis von MAP–Antikörpern nach Aufkonzentrierung in gepoolten Einzelmilchproben, gegenübergestellt. Als Referenzmethode diente die kulturelle Einzeltieruntersuchung aller über 24 Monate alten Tiere des jeweiligen Bestandes. In 20 Thüringer Milchviehherden mit bekannter Einzeltierprävalenz wurden 5063 Einzeltierkotproben, 200 Umgebungskotproben und 262 aufkonzentrierte Milchpools aus 4337 laktierenden Rindern untersucht. Zusätzlich wurde eine systematische retrospektive Stichprobenkalkulation (nStichprobe = 1458 Einzeltierkotproben) vorgenommen. Die Kultivierung der Einzeltierkotproben und der Umgebungskotproben erfolgte über 12 Wochen auf HEYM–Nährmedium mit anschließender Speziesidentifizierung durch PCR und Ziehl–Neelsen–Färbung. Die Umgebungskotproben wurden zu zwei Untersuchungszeitpunkten (Frühjahr und Sommer) an jeweils fünf Lokalisationen eines Betriebes entnommen: Abkalbebereich, Melkbereich einschließlich Vorwartehof, Laufbereich, Haupttriebweg, Übergang zum Kälberbereich. Die Untersuchung der Milchpools erfolgte nach vorheriger Aufkonzentrierung mittels zweier verschiedener ELISAs. Im Frühjahr entnommene Umgebungskotproben aus 16 MAP–positiven Betrieben detektierten das Vorhandensein des Erregers in neun Betrieben (56,3 %). Betriebe mit einer Einzeltierprävalenz von über 4,5 % wurden in neun von zehn Fällen (90 %) sicher erkannt. Im Sommer entnommene Umgebungskotproben fielen durch eine sehr starke Kontamination auf. Von den 16 MAP–positiven Beständen wurden 15 Herden (93,7 %) mittels Stichprobenuntersuchung als Bestand mit Paratuberkulosevorkommen identifiziert, wobei lediglich ein Bestand mit einer Einzeltierprävalenz von 0,49 % nicht detektiert wurde. Die serologische Untersuchung der Milchpools lieferte keine verwendbaren Ergebnisse. Mit Hilfe der Untersuchung von Umgebungskotproben lassen sich Herden mit einer durch kulturelle Untersuchung ermittelten Einzeltierprävalenz von 4,5 % und darüber mit hinreichender Sicherheit auffinden. Bei der Bewertung dieses Schwellenwertes ist zu beachten, dass bei Verwendung von nur einem Kulturröhrchen je Kotprobe von einer Sensitivität der Methode von 60 % im Vergleich zur Verwendung von drei Kulturröhrchen auszugehen ist. Für eine Überwachung unverdächtiger Herden ist die Sensitivität dieses Untersuchungsansatzes jedoch zu gering. Die individuelle kulturelle Untersuchung einer Stichprobe zeigte eine ausreichend hohe Sensitivität, um bei der Überwachung größerer unverdächtiger Herden eingesetzt werden zu können. Ein Einsatz serologischer Milchuntersuchung ist zur Bewertung von Beständen zur Ermittlung des MAP–Infektionsstatus gegenwärtig nicht zu empfehlen. Für die Überwachung größerer, als Paratuberkulose–unverdächtig anerkannter Bestände ist somit ein wechselnder Einsatz von Einzeltierkotproben aller Rinder über 24 Monaten und einer aussagekräftigen systematischer Stichprobenuntersuchung möglich und trägt damit zur Erleichterung der derzeit noch zeit– und kostenintensiven Paratuberkulose–Diagnostik bei.

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