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At least 181 records · Page 10Linked to original sources
PubMed1999

Inactivation of NF-kappaB by EBV BZLF-1-encoded ZEBRA protein in human T cells.

We have previously shown that the EBV ZEBRA protein (also denoted EB1, Z, or Zta) encoded by the BZLF open reading frame is expressed in primary human thymocytes and in human T lymphoblastoid cell lines infected by EBV. Expression of EBV-encoded gene products in T lymphocytes could contribute to viral pathogenesis during acute EBV infection as well as in individuals coinfected with EBV and HIV. HPB-ALL and Jurkat T lymphoblastoid cell lines transiently and stably expressing ZEBRA were characterized in this work. Expression of ZEBRA protein in human T lymphoblastoid cells was associated with decreased expression of an NF-kappaB reporter gene, altered expression of the NF-kappaB p50 protein subunit, and decreased DNA binding by components of NF-kappaB. These observations suggest that inactivation of NF-kappaB transcription by ZEBRA in EBV-infected T cells may be a novel mechanism of viral pathogenesis analogous in part to over-expression of the endogenous cytoplasmic inhibitor of NF-kappaB, IkappaBalpha.

DNA-Binding Proteins↗
PubMed2001

Products of US22 genes M140 and M141 confer efficient replication of murine cytomegalovirus in macrophages and spleen.

Efficient replication of murine cytomegalovirus (MCMV) in macrophages is a prerequisite for optimal growth and spread of the virus in its natural host. Simultaneous deletion of US22 gene family members M139, M140, and M141 results in impaired replication of MCMV in macrophages and mice. In this study, we characterized the proteins derived from these three genes and examined the impact of individual gene deletions on viral pathogenesis. The M139, M140, and M141 gene products were identified as early proteins that localize to both the nucleus and cytoplasm in infected cells. Gene M139 encodes two proteins, of 72 and 61 kDa, while M140 and M141 each encode a single protein of 56 (pM140) and 52 (pM141) kDa, respectively. No role for the M139 proteins in MCMV replication in macrophages or mice was determined in these studies. In contrast, deletion of either M140 or M141 resulted in impaired MCMV replication in macrophages and spleen tissue. Replication of the M140 deletion mutant was significantly more impaired than that of the virus lacking M141. Further analyses revealed that the absence of the pM140 adversely affected pM141 levels by rendering the latter protein unstable. Since the replication defect due to deletion of M140 was more profound than could be explained by the reduced half-life of pM141, pM140 must exert an additional, independent function in mediating efficient replication of MCMV in macrophages and spleen tissue. These data indicate that the US22 genes M140 and M141 function both cooperatively and independently to regulate MCMV replication in a cell type-specific manner and, thus, to influence viral pathogenesis.

3T3 Cells↗
PubMed2001

Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes.

The influenza A virus pandemic of 1918-1919 resulted in an estimated 20-40 million deaths worldwide. The hemagglutinin and neuraminidase sequences of the 1918 virus were previously determined. We here report the sequence of the A/Brevig Mission/1/18 (H1N1) virus nonstructural (NS) segment encoding two proteins, NS1 and nuclear export protein. Phylogenetically, these genes appear to be close to the common ancestor of subsequent human and classical swine strain NS genes. Recently, the influenza A virus NS1 protein was shown to be a type I IFN antagonist that plays an important role in viral pathogenesis. By using the recently developed technique of generating influenza A viruses entirely from cloned cDNAs, the hypothesis that the 1918 virus NS1 gene played a role in virulence was tested in a mouse model. In a BSL3+ laboratory, viruses were generated that possessed either the 1918 NS1 gene alone or the entire 1918 NS segment in a background of influenza A/WSN/33 (H1N1), a mouse-adapted virus derived from a human influenza strain first isolated in 1933. These 1918 NS viruses replicated well in tissue culture but were attenuated in mice as compared with the isogenic control viruses. This attenuation in mice may be related to the human origin of the 1918 NS1 gene. These results suggest that interaction of the NS1 protein with host-cell factors plays a significant role in viral pathogenesis.

Amino Acid Sequence↗
PubMedDate not supplied

The nonstructural NS5A protein of hepatitis C virus: an expanding, multifunctional role in enhancing hepatitis C virus pathogenesis.

The hepatitis C virus (HCV) NS5A gene product is a phosphorylated 56- to 58-kD nonstructural protein that displays a multitude of activities related to enhancement of viral pathogenesis. Although associated with other viral encoded proteins as part of the viral replicase complex positioned on the cytoplasmic side of the endoplasmic reticulum, a role for NS5A in viral replication has not been defined. Post-translational modifications of NS5A include phosphorylation and potential proteolytic processing to smaller molecular weight forms able to translocate to the nucleus. Both the identification of a putative interferon (IFN) sensitivity-determining region within NS5A, as well as the direct interaction with and inhibition of the IFN-induced double-stranded RNA-dependent protein kinase (PKR) by NS5A remain controversial. Truncated versions of NS5A can act as transcriptional activators, while other recently characterized interactions of NS5A with cellular proteins indicate its pleiotropic role in HCV-host interactions. NS5A itself has no direct effect on IFN-alpha signaling or activation, but other abundant interactions with members of the cellular signaling apparatus, transcription activation machinery and cell cycle-regulatory kinases have been described (e.g. growth factor receptor-bound protein 2, p53, p21/waf and cyclins). Many of these interactions block the apoptotic cellular response to persistent HCV infection. More recently, another altogether different mechanism attenuating the IFN-alpha response was reported based on induction of interleukin (IL)-8. IL-8, in model systems, potentiates viral replication and mutes the nonspecific intracellular IFN antiviral response. Evidence supporting a complex multimechanistic role of NS5A in promoting viral persistence, pathogenesis and, indirectly, viral-related hepatocarcinogenesis indicates its key role in HCV pathobiology.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Significance of the adenine nucleotide translocator in the pathogenesis of viral heart disease.

We found recently autoantibodies against the adenine nucleotide translocator (ANT), a carrier in the inner mitochondrial membrane, in sera of patients with myocarditis and dilated cardiomyopathy. To elucidate whether these antibodies are of pathophysiological importance, we investigated the function and expression of the adenine nucleotide translocator (ANT) in the heart muscle tissue of patients suffering from myocarditis and DCM. We found a markedly lowered transport capacity of the translocator accompanied by an elevation in total ANT protein content. The alteration in ANT protein amount is caused by an ANT isoform shift characterized by an increase in ANT 1 isoform protein associated with a decrease in ANT 2 isoform and an unchanged ANT 3 content. It could be shown that the isoform shift is not a progressive process during the disease period but an event in the early period of illness which becomes permanent. Simulating the effect of pathogenetic factors of autoimmunological diseases, we infected A/J mice with the enterovirus Coxsackie B3 and immunized guinea pigs with myocardial ANT protein. Both treatments led to autoimmunological responds and to a lowered myocardial transport capacity of ANT, to a disturbed energy metabolism and consequently to a depression of heart function.

Animals↗
PubMed1996

Pathomorphological Characteristics and Pathogenesis of Viral Hepatitis.

Viral hepatitis (VH) is an inflammatory reaction of the liver to hepatotropic viruses. Acute VH can be classified according to the virus and type of necrosis. Chronic hepatitis (CH) might be active, persistent or lobular based on previous classification. More recently the grade (necroinflammatory activity) and stage (fibrosis and architectural distorsion) of CH have been distinguished and scored. Apoptosis and necrosis probably coexist in VH and contribute to hepatocyte death. Several "death factors", such as transforming growth factor b, Apo1/Fas and tumor necrosis factor play a role in the execution of cell death. Injury of hepatocytes during viral infection can occur as a direct effect of the virus or as a result of the host immune response. Expression of different viral antigens can be detected during VH and might be visualized. Phenotyping of the portal inflammatory cell infiltrate in CH has shown a T-cell zone comprised of CD4+ helper T cells and CD8+ supressor/cytotoxic T cells at the periphery of the lobules. The pathogenetic mechanisms responsible for the final outcome of viral infection depend on viral factors (such as genotype, mutation etc.), virus-host interaction, expression of viral protein, several cytokines etc. which finally lead to the well known histological alterations of viral hepatitis.

Journal Article↗
PubMed2000

Molecular pathology and structural features of enteroviral replication. Toward understanding the pathogenesis of viral heart disease.

Enteroviruses of the Picornaviridae and primarily coxsackieviruses of group B (CVB) can be detected in humans and various experimental murine models of acute myocarditis and chronic heart muscle diseases indicating enterovirus persistence in the myocardium. Persistent myocardial infection is characterized by restricted viral replication and gene expression in myocytes capable of sustaining chronic inflammation. Viral cytotoxicity was found to be crucial for organ pathology both during acute and persistent infection. In-situ hybridization experiments at the cellular and subcellular level have demonstrated that virus replication is associated with severe structural changes of the cardiomyocyte cytoarchitecture at any stage of the disease. In tissue culture experiments and transgenic mice, it was shown that restricted replication and gene expression of the virus are capable of inducing myocytopathic effects. Investigations at the molecular level revealed that interference of coxsackievirus replication with the cellular metabolism is mediated by cleavage of host cell proteins by virus-encoded proteinases. Notably, there is also evidence that enteroviruses are able to activate specific cellular signal transduction pathways in the course of infection, thus promoting enteroviral replication. In summary, these data indicate that mutual influences of virus replication and subsequent modifications of the host cell metabolism are crucial for cardiac injury and dysfunction during acute and chronic disease.

Animals↗
PubMed2005

Pathogenesis of viral hemorrhagic fever.

Single-stranded RNA viruses from four different families cause a syndrome of fever and malaise, 'capillary leak' with loss of plasma volume, and coagulation defects which can lead to bleeding. Although direct cytopathic effects can contribute to disease severity, most features of illness are caused by innate immune responses, as the systemic spread of virus to macrophages and dendritic cells leads to the release of mediators that modify vascular function and have procoagulant activity. The synthesis of tissue factor by infected cells can also trigger coagulation. Failure of adaptive immunity through impaired dendritic cell function and lymphocyte apoptosis can have a crucial role in fatal infection.

Animals↗
PubMed2002

Clinical significance and pathogenesis of viral respiratory infections.

Viral respiratory tract infections, also known as colds, are the most common infection in humans. The majority of these infections are caused by rhinoviruses. Rhinovirus deposition in the nose or the eye initiates infection. The virus attaches to the host cell intercellular adhesion molecule-1 (ICAM-1) receptors in the back of the throat. Subsequent viral replication triggers the release of inflammatory mediators and activation of neurogenic pathways, which lead to symptoms. Symptoms occur within 10 to 16 hours after virus entry into the nose and peak on days 2 to 3 of infection. Symptom duration is typically 1 week, although 25% of cases last longer. Understanding the chronology of these events is important in the timing of treatment. Because of the rapidity of symptom onset, early treatment is the key to reducing viral replication and illness. Also, early treatment may reduce the risk of transmission.

Common Cold↗
PubMed1999

Involvement of Fas system-mediated apoptosis in pathogenesis of viral hepatitis.

Enhanced Fas system-mediated hepatocyte apoptosis is observed in hepatitis C virus (HCV)- and hepatitis B virus (HBV)-associated chronic liver diseases. In these forms of viral hepatitis, liver-infiltrating lymphocytes that recognize the viral antigen on hepatocytes become activated and express cytolytic Fas ligand (FasL) molecules. In contrast, hepatocytes exhibit enhanced Fas expression and become susceptible to FasL-mediated death. Augmentation of the Fas system has also been observed in other liver diseases and biliary disorders. Moreover, the Fas system is involved in removing aged hepatocytes. Thus, Fas-mediated apoptosis plays an important role in several liver diseases and in maintaining normal liver homeostasis.

Animals↗