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

Effectiveness and costs of a stepwise versus an all-in-one approach to diagnose mild bleeding disorders.

The diagnostic work-up of patients referred to the haematologist for bleeding evaluation is performed in a stepwise way: bleeding history and results of screening laboratory tests guide further diagnostic evaluation. This can be ineffective, time-consuming and burdensome for patients. To improve this strategy, the initial laboratory investigation can be extended. In a model-based approach, effectiveness and costs of a conventional stepwise versus a newly proposed all-in-one diagnostic approach for bleeding evaluation were evaluated and compared, using data from an observational patient cohort study, including adult patients referred for bleeding evaluation. In the all-in-one approach, specialized platelet function tests, coagulation factors, and fibrinolysis tests were included in the initial investigation. Final diagnosis, hospital resource use and costs and patient burden were compared. A total of 150 patients were included. Compared to the stepwise approach, in the all-in-one approach, 19 additional patients reached a diagnosis and patient burden was lower, but total costs per patient were higher [€359, 95% bootstrapped confidence interval (BCI) 283-518, p = 0.001]. For bleeding evaluation of patients referred to the haematologist, an all-in-one diagnostic approach has a higher diagnostic yield and reduces patient burden, at a higher cost. This raises the question what costs justify the diagnosis of a bleeding disorder and a less burdensome diagnostic strategy