Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity

The mechanical career of Councillor Orffyreus, confidence man

In the early 18th century, J. E. E. Bessler, known as Orffyreus, constructed several wheels that he claimed could keep turning forever, powered only by gravity. He never revealed the details of his invention, but he conducted demonstrations (with the machine's inner workings covered) that persuaded competent observers that he might have discovered the secret of perpetual motion. Among Bessler's defenders were Gottfried Leibniz, Johann Bernoulli, Professor Willem 's Gravesande of Leiden University (who wrote to Isaac Newton on the subject), and Prince Karl, ruler of the German state of Hesse-Kassel. We review Bessler's work, placing it within the context of the intellectual debates of the time about mechanical conservation laws and the (im)possibility of perpetual motion. We also mention Bessler's long career as a confidence man, the details of which were discussed in popular 19th-century German publications, but have remained unfamiliar to authors in other languages.UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Físic