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

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

Produtividade acumulada como critério de seleção em fêmeas da raça nelore Accumulated productivity as selection criteria in nellore breed females

O presente trabalho teve por objetivo determinar os componentes de variância e estimar a herdabilidade da produtividade acumulada (PAC) de 15.070 fêmeas, criadas em diferentes rebanhos participantes do Programa de Melhoramento Genético da Raça Nelore. A PAC é um índice que considera a produção total de bezerros desmamados em kg, o tempo total de produção de bezerros e o início de parição. As análises estatísticas foram realizadas por meio do programa SAS (Statistical Analysis System) e os componentes de variância pelo método de máxima verossimilhança restrita utilizando o software MTDFREML. A média da PAC foi de 130kg de bezerros desmamados por vaca ao ano, e os efeitos do pai da vaca, rebanho e ano de nascimento da vaca foram significativos (P<0,0001) na variação dessa característica. O coeficiente de herdabilidade da PAC foi estimado em 0,15, indicando a existência de variabilidade genética suficiente para sua inclusão nos programas de melhoramento, o que resultaria na obtenção de fêmeas mais produtivas nos rebanhos.<br>This work had for objective to determine the variance components and to estimate the heritability of the accumulated productivity (ACP) of 15,070 females, reared in different participant herds of the Nellore Breeding Program. ACP is an index that considers the total production of calves weaned in kg, the total time of production of calves and the calving beginning. The statistical analyses were accomplished through the SAS program (Statistical Analysis System) and the variance components for the restricted maximum likelihood method using the software MTDFREML. The average of ACP was of 130kg of calves weaned by cow to the year, and the sire of cow effects, herd and year of the birth cow significatly (P<0.0001) affected in the variation of this characteristic. The coefficient of heritability of ACP was estimated in 0.15, indicating the existence of enough genetic variability for its inclusion in the improvement programs, what would result in the obtaining of more productive females in the herds