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

Complexity Analysis of the Viking Labeled Release Experiments

The only extraterrestrial life detection experiments ever conducted were the three which were components of the 1976 Viking Mission to Mars. Of these, only the Labeled Release experiment obtained a clearly positive response. In this experiment 14C radiolabeled nutrient was added to the Mars soil samples. Active soils exhibited rapid, substantial gas release. The gas was probably CO2 and, possibly, other radiocarbon-containing gases. We have applied complexity analysis to the Viking LR data. Measures of mathematical complexity permit deep analysis of data structure along continua including signal vs. noise, entropy vs.negentropy, periodicity vs. aperiodicity, order vs. disorder etc. We have employed seven complexity variables, all derived from LR data, to show that Viking LR active responses can be distinguished from controls via cluster analysis and other multivariate techniques. Furthermore, Martian LR active response data cluster with known biological time series while the control data cluster with purely physical measures. We conclude that the complexity pattern seen in active experiments strongly suggests biology while the different pattern in the control responses is more likely to be non-biological. Control responses that exhibit relatively low initial order rapidly devolve into near-random noise, while the active experiments exhibit higher initial order which decays only slowly. This suggests a robust biological response. These analyses support the interpretation that the Viking LR experiment did detect extant microbial life on Mars