Productivity of Cows in Relation to Breed Cross and Environment

The decade just passed will probably go down as the most challenging period in the history of beef cattle production in North America. Events which have contributed include the acceptance of performance recording programs, artificial insemination and its ever-broadening application in farm and range herds alike, national sire evaluation programs and the Exotic Boom. This latter event has probably had the greatest significance, for the importations of foreign cattle have necessitated a complete reappraisal of the traditional concepts of beef animals on this continent

Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis

Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFκB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu

Proteasomal protein degradation: adaptation of cellular proteolysis with impact on virus-and cytokine-mediated damage of heart tissue during myocarditis

Viral myocarditis is an inflammation of the heart muscle triggered by direct virus-induced cytolysis and immune response mechanisms with most severe consequences during early childhood. Acute and long-term manifestation of damaged heart tissue and disturbances of cardiac performance involve virus-triggered adverse activation of the immune response and both immunopathology, as well as, autoimmunity account for such immune-destructive processes. It is a matter of ongoing debate to what extent subclinical virus infection contributes to the debilitating sequela of the acute disease. In this review, we conceptualize the many functions of the proteasome in viral myocarditis and discuss the adaptation of this multi-catalytic protease complex together with its implications on the course of disease. Inhibition of proteasome function is already highly relevant as a strategy in treating various malignancies. However, cardiotoxicity and immune-related adverse effects have proven significant hurdles, representative of the target's wide-ranging functions. Thus, we further discuss the molecular details of proteasome-mediated activity of the immune response for virus-mediated inflammatory heart disease. We summarize how the spatiotemporal flexibility of the proteasome might be tackled for therapeutic purposes aiming to mitigate virus-mediated adverse activation of the immune response in the heart

Characterization of dendritic cells in the early stage of murine enterovirus myocarditis

CVB3 gilt als ein Hauptauslöser der akuten Virusmyokarditis. Die Krankheitsverläufe variieren von subklinischen Verläufen bis zur Entwicklung einer chronischen Myokarditis mit folgender Herzinsuffizienz. Die prädisponierenden Faktoren für Chronifizierung der Infektion sind weitgehend unbekannt. Experimentell wird zur Klärung dieser Frage ein Mausmodell genutzt, worin zwei immunkompetente Stämme die verschiedenen Krankheitsverläufe imitieren: nach der akuten Phase eliminieren resistente C57BL/6 Mäuse das Virus, während permissive A.BY/SnJ Tiere durch Viruspersistenz und chronische kardiale Inflammation auffallen. In dieser Arbeit wurde die Funktion der dendritischen Zellen, potenter Initiatoren der adaptiven Immunantwort, in der frühen Phase der in vivo CVB3-Infektion zwischen beiden Stämmen verglichen. Dabei zeigte sich auf DC von C57BL/6 eine regelhafte Expressionssteigerung der Maturierungsmarker CD80, CD86 und CD40 nach 36 h p.i. Die DC von A.BY/SnJ hingegen wiesen fast keine Expressionszunahme auf. Auch CCR7, ein wichtiger Migrationsmarker, konnte im Gegensatz zu C57BL/6 nicht induziert werden. Weiterhin war die defizitäre DC-Maturierung bei A.BY/SnJ anders als bei C57BL/6 nur von einer schwachen Induktion proinflammatorischer Zytokine begleitet. In DC von C57BL/6, nicht jedoch von A.BY/SnJ, wurde der Maturierungsvorgang durch eine verstärkte ISGylierung und einer simultanen Induktion des E2-Enzyms UBE2L6 begleitet. Tatsächlich zeigten sich A.BY/SnJ DC als weitgehend unfähig, durch Kreuzpräsentation von exogen zugeführtem Ovalbumin CD8+-T-Zellen transgener OT-I-Mäuse zu aktivieren, während dies den C57BL/6 DC gut möglich war. Weiterhin wurde das Auftreten von Aggregaten polyubiquitinylierter Proteine, sog. DALIS (dendritic cell aggresome-like structures), untersucht. DALIS stellen in DC und Makrophagen einen während der Reifungen auftretenden Speicher von poly-ubiquitinylierten DRiPs (defective ribosomal products) und damit eine potentielle Quelle für MHC-I restringierte Antigene dar. Während C57BL/6 diese Strukturen nach 48 h p.i. weitgehend eliminiert hatten, persistierten die DALIS bei A.BY/SnJ. Die Identifizierung des Virusproteins VP1 als Bestandteil der persistierenden DALIS in A.BY/SnJ DC suggeriert eine limitierte Antigenquelle für die virusspezifische CD8+-T-Zellantwort. Zusammenfassend stellen sich in permissiven A.BY/SnJ Mäusen, die im Verlauf eine chronische CVB3-Infektion zeigen, bereits bei der Initiierung der adaptiven Immunantwort diverse Defizite im Sinne einer DC- Dysfunktion dar. Ähnliche Defekte in Maturierung und Aktivierung finden sich analog bei anderen persistierenden Virusinfektionen, so dass hier der Zusammenhang zwischen fehlerhafter DC-Funktion und scheiternder CVB3-Clearance nahe liegt.Murine models of CVB3-induced myocarditis mimic divergent courses of human disease with host-specific outcomes ranging from complete recovery in resistant mice (C57BL/6) to chronic disease and dilated cardiomyopathy in the susceptible host (A.BY/SnJ). Dendritic cells are crucial in the initiation of the immune response. Upon exposure to antigens, several phenotypical changes are induced that eventually support T-cell activation. In particular the processing and presentation of MHC-I ligands to CD8+-T cells is largely dependent on the ubiquitin-proteasome system (UPS). The aim of this study was to elucidate the function of dendritic cells and especially the remodeling of the UPS in the early stage of infection as a potential contributing factor to the different outcomes in CVB3 myocarditis. In DC from C57BL/6 mice maturation and activation occurred in a well-coordinated manner, which was demonstrated by an increased expression of co-stimulatory molecules and the migration marker CCR7 as well as by an induction of numerous cytokines peaking at 36 h p.i with CVB3. In striking contrast, DC maturation / activation in A.BY/SnJ mice was tremendously impaired in in vivo CVB3 infection. Additionally, the ability to cross-present exogenous antigens was found to be severely restrained in this host, which was reflected by the inability to induce the activation and proliferation of antigen-specific cytotoxic T cells. Investigation of proteotoxic stress in CVB3 infection revealed accumulation of polyubiquitinylated proteins, which are referred to DALIS (dendritic cell aggresome-like inducible structures) in DC, in both C57BL/6 and A.BY/SnJ mice. DALIS are known as storage of DRiPs (defective ribosomal products) and therefore being discussed to function as a reservoir for MHC class I antigens before processing and presentation. Whereas C57BL/6 mice degraded these DALIS within the maturation process, these aggregates persisted in DC from A.BY/SnJ, thus potentially restricting the source of MHC-I ligands. Moreover, the CVB3 protein VP1 was trapped in persistend DALIS in A.BY/SnJ DC, indicating a limiting factor for CVB3 specific antigen supply. In conclusion, the here shown results revealed tremendous defects in dendritic cell function in A.BY/SnJ mice in CVB3 infection. Since DC maturation defects were observed in other persisting viral infections like HCV or HIV, restriction of appropriate DC maturation and antigen processing in A.BY/SnJ may be involved in the development of viral persistence and chronic myocarditis in susceptible hosts

Antigen-presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

Coxsackievirus B3 (CVB3)-infection is a frequent cause of acute myocarditis, which may result in chronic myocarditis and virus persistence. Investigation of the initial immune responses to CVB3 may shed light on the mechanisms that contribute to ongoing disease. DCs, as key professional APCs, were investigated in two MHC-matched hosts: while C57BL/6 mice are resistant to chronic CVB3-myocarditis, the A.BY/SnJ mouse strain exhibits susceptibility. DC maturation and activation were critically impaired in A.BY/SnJ mice, as reflected by the failure of DCs to induce co-stimulatory molecules and cytokine/chemokine responses. MHC class I-restricted antigen presentation via the cross-presentation pathway was also affected in DCs from A.BY/SnJ mice. DC maturation involves the accumulation of DC aggresome-like induced structures (DALISs) and the transient storage of defective ribosomal products (DRiPs). DCs from A.BY/SnJ mice showed permanent DALIS accumulation; the detection of poly-ubiquitinylated CVB3 proteins in these DALISs suggested a limitation in the MHC class I antigenic supply in this host. In conclusion, ongoing chronic disease in A.BY/SnJ mice due to a failure to clear the virus may be attributed to defects in DC maturation/activation and DC MHC class I antigen processing