Role of Position 627 of PB2 and the Multibasic Cleavage Site of the Hemagglutinin in the Virulence of H5N1 Avian Influenza Virus in Chickens and Ducks

Highly pathogenic H5N1 avian influenza viruses have caused major disease outbreaks in domestic and free-living birds with transmission to humans resulting in 59% mortality amongst 564 cases. The mutation of the amino acid at position 627 of the viral polymerase basic-2 protein (PB2) from glutamic acid (E) in avian isolates to lysine (K) in human isolates is frequently found, but it is not known if this change affects the fitness and pathogenicity of the virus in birds. We show here that horizontal transmission of A/Vietnam/1203/2004 H5N1 (VN/1203) virus in chickens and ducks was not affected by the change of K to E at PB2-627. All chickens died between 21 to 48 hours post infection (pi), while 70% of the ducks survived infection. Virus replication was detected in chickens within 12 hours pi and reached peak titers in spleen, lung and brain between 18 to 24 hours for both viruses. Viral antigen in chickens was predominantly in the endothelium, while in ducks it was present in multiple cell types, including neurons, myocardium, skeletal muscle and connective tissues. Virus replicated to a high titer in chicken thrombocytes and caused upregulation of TLR3 and several cell adhesion molecules, which may explain the rapid virus dissemination and location of viral antigen in endothelium. Virus replication in ducks reached peak values between 2 and 4 days pi in spleen, lung and brain tissues and in contrast to infection in chickens, thrombocytes were not involved. In addition, infection of chickens with low pathogenic VN/1203 caused neuropathology, with E at position PB2-627 causing significantly higher infection rates than K, indicating that it enhances virulence in chickens

Unfolded protein response in cancer: the Physician's perspective

The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). Cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress and other metabolic dysregulation that cause ER stress and activation of the UPR. Depending on the duration and degree of ER stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic pathways, or death signals by inducing cell death programs. Sustained induction or repression of UPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In this review, we discuss the basic mechanisms of UPR and highlight the importance of UPR in cancer biology. We also update the UPR-targeted cancer therapeutics currently in clinical trials

A systematical analysis of the signal transduction pathways induced by the Latent Membrane Protein 1 (LMP1) of Epstein-Barr virus.

To systematically investigate mechanisms of signal transduction by the EBV oncogene LMP1, the time-dependent regulation of cellular signaling pathways by inducible LMP1 variants was studied in mouse embryonic fibroblasts lacking expression of signaling molecules. This led to insights into the importance of cellular TRAF6 and TRADD for LMP1 signaling, and specifically uncovered indirect activation of STAT3 mediated by the LMP1-dependent secretion of the inflammatory cytokine LIF. The relevance of the presented results for carcinogenesis was addressed in NPC cells and EBV-transformed B cells

The Latent Membrane Protein 1 (LMP1).

Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell-cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1's molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus-host interaction and a potential therapeutic target