The experimental oral infection of goats with MAH may be a valuable model for comparative TB research in several aspects:
The different courses of diseases allow the examination of certain TB entities, e.g.
granulomatous lesions seen in intestinal TB or granulomas seen in latent TB.
Especially, granulomas seen in the surviving goats resemble the heterogeneity of lesions reported in cattle and goats after infection with MTC members, as well as lesions in humans with pulmonary TB (VAN RHIJN et al. 2008; LENAERTS et al.
2015). The development of 3rd LT with well-organized granulomas has been reported in few studies only (ULRICHS et al. 2004; ULRICHS et al. 2005; ARANDAY-CORTES et al. 2013). Therefore, the presence of 3rd LT is a major advantage of this model to evaluate the relevance of this feature in the control of mycobacteria by the host immune response. Drug efficacy testing is another aspect for experimental TB models. The plethora of morphologically different granuloma stages could be of great interest for drug testing. Certain features like necrosis, mineralization, extensive fibrosis and vascularization of granulomas directly influence the pharmacodynamics and pharmacokinetics of administered drugs and might be evaluable by histopathology and modern live imaging in this goat model (BASARABA 2008;
BARRY et al. 2009).
The relative small size of goats allows much lower housing and feeding costs when compared with cattle (GONZALEZ-JUARRERO et al. 2013). In comparison to other livestock species, the goat model allows the utilization of modern live imaging systems, e.g. magnetic resonance imaging, computed tomography or positron emission tomography (DE VAL et al. 2011; LENAERTS et al. 2015). This feature could be of special value to monitor granuloma development in experimentally infected goats. The lack of a wide array of immunologic tools is usually considered as a constraint of large animal models (YOUNG 2009). However, the recent
obstacle as indicated recently by cytokine gene expression analysis in bovine pulmonary TB granulomas (PALMER et al. 2015).
Finally, another benefit of the experimental design was the classification of MAH as BSL 2 pathogen allowing an easier experimental performance than BSL 3 condition would have required. Since all MTC members are BSL 3 pathogens, special requirements for housing, occupational safety and tissue processing have to be considered (CHOSEWOOD u. WILSON 2011).
In conclusion, the obvious similarities of granulomas with those seen in bovine and human TB and the association of ectopic lymphoid tissue with organized granulomas highlights this model as appropriate for comparative TB and NTM research and the goat in particular as model species.
7 Summary
Jan Schinköthe:
Experimental oral infection of goats with Mycobacterium avium subsp.
hominissuis: Pathomorphological characterization of lesions in different courses of disease with special focus on cellular composition of granulomas
Goats were experimentally infected with Mycobacterium avium subsp. hominissuis (MAH) to determine the specificity of diagnostic antigens for Mycobacterium avium subsp. paratuberculosis. For this, each of 21 goats was inoculated orally 10-times, every 2-4 days with MAH receiving a total dose of 2.13 x 1010 cfu MAH. An unexpected onset of clinical signs progressing to severe disease was observed in 50
% of the goats at 2-3 mpi. The remaining goats had mild transient clinical signs and were healthy 13 mpi at the end of the trial. The first objective of this study was to characterize lesions in severely sick goats and in surviving goats at 13 mpi and to examine lesions for presence of MAH.
At necropsy, goats were examined for macroscopic lesions. Representative samples of lesions, intestinal tissues, lymphoid organs and large parenchyma were fixed in NBF and snap frozen. Histologic lesions were evaluated in HE stained FFPE sections. Detection of MAH in sampled tissues was performed by IHC and by bacterial cultivation.
Goats necropsied at 2-3 mpi had severe intestinal ulcerations with underlying granulomatous infiltrates in oGALT and large granulomas in ILN with variable quantities of MAH detected in tissue sections. Large amounts of MAH were cultivated from intestinal and ILN lesions and peripheral organs, indicating extra-intestinal spread of MAH. At 13 mpi, multiple small granulomas in oGALT and large granulomas in ILN were seen at necropsy. MAH was detected by IHC in few granulomas (3/9 goats) and cultured in low quantities in 6/9 goats at intestinal sites and ILN only. All goats excreted moderate to high amounts of MAH via feces until 2 mpi. Environmental contamination due to fecal shedding and low amounts of
mycobacteria in granulomas of otherwise healthy goats may represent a potential risk for human health.
Since large numbers of morphologically heterogeneous granulomas were found in goats at 2-3 mpi and 13 mpi, the second objective was to characterize their cellular composition and to compare them with granulomas seen in human and bovine tuberculosis. In consecutive frozen sections, CD4+, CD8+, γδ T lymphocytes, B lymphocytes, plasma cells, CD68+, CD25+, MHC-II+, proliferative and endothelial cells were labeled by IHC. Furthermore, collagen and AFB were stained by Azan, respectively, Kinyoun method.
Granulomas with extensive necrosis, little mineralization and variable numbers of AFB surrounded by many CD4+ T cells, but only few epitheloid macrophages were observed in severely sick goats at 2-3 mpi. They were interpreted as exuberant immune reaction. Organized granulomas with very few AFB were seen in clinically healthy goats at 13 mpi. The necrotic cores were surrounded by a zone of granulomatous infiltrate with many epitheloid macrophages and few lymphocytes.
This zone was initially wide and highly vascularized and became progressively smaller. It was enclosed by an increasing layer of connective tissue. All organized granulomas were surrounded by compartimentalized tertiary lymphoid tissue. The granulomas in experimental infection of goats with MAH reflect the heterogeneity of lesions seen in mycobacterial infections of humans and ruminants.
In conclusion, the experimental infection of goats with MAH resulted in different courses of disease, morphologically different granulomas with striking similarities to those seen in bovine and human TB, and the development of ectopic lymphoid tissue in organized granulomas. These features highlight this model as appropriate for comparative TB and NTM research and the goat in particular as model species.
8 Zusammenfassung
Jan Schinköthe:
Experimentelle orale Infektion von Ziegen mit Mycobacterium avium subsp.
hominissuis: Pathomorphologische Charakterisierung der Läsionen bei verschiedenen Krankheitsverläufen unter besonderer Berücksichtigung der zellulären Zusammensetzung der Granulome
Ziegen wurden experimentell mit Mycobacterium avium subsp. hominissuis (MAH) infiziert, um die Spezifität von diagnostischen Antigenen gegen Mycobacterium avium subsp. paratuberculosis zu testen. Hierfür wurde eine Gruppe von 21 Ziegen 10-mal, alle 2-4 Tage mit einer Gesamtdosis von 2,13 x 1010 KBE MAH oral inokuliert. Unerwartet traten bei 50% der Ziegen 2-3 Monate nach Erstinfektion (Mpi) schwere klinische Symptome auf und mehrere Tiere verendeten spontan oder mussten aus ethischen Gründen getötet werden. Die überlebenden Ziegen zeigten milde transiente klinische Symptome und waren bei der Sektion 13 Mpi klinisch gesund. Das erste Ziel dieser Studie war, die Läsionen sowohl bei den hochgradig Erkrankten als auch bei den überlebenden Ziegen zu charakterisieren und auf das Vorhandensein von MAH zu untersuchen.
Bei der Sektion wurden die makroskopischen Läsionen dokumentiert und repräsentative Proben von den Läsionen, intestinalen Geweben sowie lymphatischen und peripheren Organen entnommen und in Formalin fixiert bzw. kryokonserviert. Die histopathologische Analyse der Läsionen fand an HE-gefärbten Paraffinschnitten statt. Der Nachweis von MAH wurde mit Immunhistochemie (IHC) am Schnitt und mit bakterieller Kultivierung durchgeführt.
Ziegen zum Zeitpunkt 2-3 Mpi wiesen hochgradige intestinale Ulzerationen mit zugrunde liegenden granulomatösen Infiltraten in organisiertem Darm-assoziierten lymphatischen Gewebe (oGALT) und große Granulome in intestinalen Lymphknoten (ILN) auf. MAH konnte mit IHC in variabler Zahl intra- und extrazellulär nachgewiesen werden. Eine hohe Erregerlast wurde in intestinalen und ILN Läsionen sowie in
extraintestinale Verbreitung von MAH hin. 13 Mpi wurden bei allen untersuchten Ziegen mehrere kleine Granulome in oGALT und/oder große Granulome in ILN bei der Sektion gefunden. MAH ließ sich nur in wenigen Granulomen (3/9 Ziegen) durch IHC nachweisen bzw. aus 6/9 Ziegen in geringen Mengen kultivieren. Alle infizierten Ziegen schieden bis 2 Mpi moderate bis hohe Mengen an MAH über den Kot aus.
Die dabei eintretende Umgebungskontamination sowie das Vorhandensein von Mykobakterien in Granulomen von gesunden Ziegen könnte ein mögliches Risiko für die menschliche Gesundheit darstellen.
Da in den Ziegen 2-3 und 13 Mpi eine große Anzahl morphologisch heterogener Granulome gefunden wurde, war das zweite Ziel dieser Studie herauszufinden, wie die zelluläre Zusammensetzung der Granulome ist und diese mit denen bei der Tuberkulose der Rindes und des Menschen zu vergleichen. Dafür wurden in Konsekutivschnitten CD4+, CD8+, γδ-T-Lymphozyten, B-Lymphozyten, Plasmazellen, CD68+, CD25+, MHC-II+, proliferative Zellen und Endothelzellen mittels IHC markiert.
Kollagen und säurefeste Bakterien (AFB) wurden mit Azan- bzw. Kinyounfärbung dargestellt.
Granulome mit extensiven verkäsenden Nekrosen, die minimale Mineralisierungen und viele AFB enthielten, waren umgeben von vielen CD4+ T Lymphozyten mit wenigen epitheloiden Makrophagen und waren nur in ILN 2-3 Mpi vorhanden. Diese Befunde wurden als überschießende Immunantwort interpretiert. Organisierte Granulome mit sehr wenigen AFB wurden in klinisch gesunden Ziegen 13 Mpi gefunden. Die nekrotischen Zentren dieser Granulome waren umgeben von einer Zone aus granulomatösem Infiltrat mit vielen epitheloiden Makrophagen und wenigen Lymphozyten. Diese Zone war zu Beginn breit und gut vaskularisiert. Sie wurde fortschreitend schmaler und stattdessen entwickelte sich eine immer breiter werdende Schicht aus Bindegewebe. Alle organisierten Granulome waren zusätzlich von organisiertem tertiärem lymphatischem Gewebe umgeben. Die Heterogenität der Granulome bei MAH infizierten Ziegen zeigte eine große Ähnlichkeit mit Granulomen der Tuberkulose des Rindes und des Menschen.
Die verschiedenen Krankheitsverläufe mit Latenzphase, das Auftreten von morphologisch heterogenen Granulomen und die Entwicklung von tertiärem
lymphatischem Gewebe in organisierten Granulomen machen die experimentelle Infektion der Ziege mit MAH zu einem für die vergleichende Forschung an Infektionen mit tuberkulösen und nicht tuberkulösen Mykobakterien hervorragend geeigneten Modell.
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