A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome

Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains

Some leukocyte receptors come in groups of two or more where the partners share ligand(s) but transmit opposite signals. Some of the ligands, such as MHC class I, are fast evolving, raising the problem of how paired opposing receptors manage to change in step with respect to ligand binding properties and at the same time conserve opposite signaling functions. An example is the KLRC (NKG2) family, where opposing variants have been conserved in both rodents and primates. Phylogenetic analyses of the KLRC receptors within and between the two orders show that the opposing partners have been subject to post-speciation gene homogenization restricted mainly to the parts of the genes that encode the ligand binding domains. Concerted evolution similarly restricted is demonstrated also for the KLRI, KLRB (NKR-P1), KLRA (Ly49), and PIR receptor families. We propose the term merohomogenization for this phenomenon and discuss its significance for the evolution of immune receptors

Methicillin-resistant Staphylococcus aureus (MRSA) is increasing in Norway: a time series analysis of reported MRSA and methicillin-sensitive S. aureus cases, 1997-2010.

BACKGROUND: Accurate estimates of the incidence and prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections are needed to inform public health policies. In Norway, where both MRSA infection and carriage are notifiable conditions, the reported incidence of MRSA is slowly increasing. However, the proportion of MRSA in relation to all S. aureus isolates is unknown, making it difficult to determine if the rising incidence is real or an artifact of an increasing number of tests performed. AIM: To characterize recent trends in MRSA infections and obtain a more complete understanding of the MRSA level in Norway. METHODS: All reported cases of MRSA and methicillin-sensitive S. aureus (MSSA) from Oslo County (1997-2010) and Health Region East (2008-2008), representing approximately 11% and 36% of the Norwegian population, respectively, were analyzed using a stochastic time series analysis to characterize trends. RESULTS: In Oslo County, the proportion of methicillin-resistant cases increased from 0.73% to 3.78% during the study period and was well modeled by an exponential growth with a doubling constant of 5.7 years (95% CI 4.5-7.4 years). In Health Region East, the proportion of MRSA cases increased from 0.4% to 2.1% from 2002 to 2008, with a best-fitting linear increase of 0.26% (95% CI 0.21-0.30%) per year. In both cases, the choice of a linear or exponential model for the time trend produced only marginally different model fits. We found no significant changes due to revised national MRSA guidelines published in June 2009. Significant variations in the increasing time trend were observed in the five hospitals within the region. The yearly reported incidence of MSSA was relatively stable in both study areas although we found seasonal patterns with peaks in August. CONCLUSION: The level of MRSA is increasing in Norway, and the proportion of methicillin resistance in all S. aureus isolates are higher than the reported proportion of MRSA in invasive infections

The monthly proportion of MRSA cases in Oslo County: September 1997–2010.

<p>Thick black curve: based on exponential LSF; Blue curve: ; Black curve: based on linear LSF; Red curve: Linear LSF through June 2009; Green curve: Linear LSF after June 2009; Red dashed curve: 95% confidence bounds on exponential and linear LSF curve; ▪: Data, □: Stochastic simulation (run) .</p

The monthly number of MRSA cases in Health Region East: 2002–2008.

<p>▪: Data, ☆: Stochastic simulation based on the beta binomial distribution. Black curve: Exponential LSF; Black dashed curve: Linear LSF.</p

The standard deviation of the proportion of MRSA cases in Health Region East: 2002–2008.

<p>Blue curve: ; Green curve: ; Red curve: ; Black curve: _.</p

The standard deviation of the proportion of MRSA cases in Oslo County: September 1997–2010.

<p>Blue curve: ; Green curve: ; Red curve: ; Black curve: _.</p

Model fit of the proportion of methicillin-resistant <i>Staphylococcus aureus</i> for Oslo County and Health Region East to exponential time trend (A), linear time trend (B) and power law time trend (C) with sum of squared errors for three different fit functions and time t in months.

1<p>Dataset I.</p>2<p>Dataset II.</p

The number of monthly identified <i>Staphylococcus aureus</i> cases in Health Region East: 2002–2008.

<p>▪: Data; A curve showing the estimated mean number of cases is added.</p