Interferon control of the sterol metabolic network: bidirectional molecular circuitry mediating host protection

The sterol metabolic network is emerging center stage in inflammation and immunity. Historically, observational clinical studies show that hypocholesterolemia is a common side effect of interferon (IFN) treatment. More recently, comprehensive systems-wide investigations of the macrophage IFN response reveal a direct molecular link between cholesterol metabolism and infection. Upon infection, flux through the sterol metabolic network is acutely moderated by the IFN response at multiple regulatory levels. The precise mechanisms by which IFN regulates the mevalonate-sterol pathway—the spine of the network—are beginning to be unraveled. In this review, we discuss our current understanding of the multifactorial mechanisms by which IFN regulates the sterol pathway. We also consider bidirectional communications resulting in sterol metabolism regulation of immunity. Finally, we deliberate on how this fundamental interaction functions as an integral element of host protective responses to infection and harmful inflammation

Roseomics: a blank slate

Recent technological advances have led to an explosion in the system-wide profiling of biological processes in the study of herpesvirus biology, herein referred to as “-omics”. In many cases these approaches have revealed novel virus-induced changes to host cell biology that can be targeted with new antiviral therapeutics. Despite these successes, -omics approaches are not widely applied in the study of roseoloviruses. Here we describe examples of how -omics studies have shaped our understanding of herpesvirus biology, and discuss how these approaches might be used to identify host and viral factors that mediate roseolovirus pathogenesis

Sirtuins Are Evolutionarily Conserved Viral Restriction Factors

The seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD(+)-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that all seven sirtuins have broad-range antiviral properties. We demonstrate that small interfering RNA (siRNA)-mediated knockdown of individual sirtuins and drug-mediated inhibition of sirtuin enzymatic activity increase the production of virus progeny in infected human cells. This impact on virus growth is observed for both DNA and RNA viruses. Importantly, sirtuin-activating drugs inhibit the replication of diverse viruses, as we demonstrate for human cytomegalovirus, a slowly replicating DNA virus, and influenza A (H1N1) virus, an RNA virus that multiplies rapidly. Furthermore, sirtuin defense functions are evolutionarily conserved, since CobB, the sirtuin homologue in Escherichia coli, protects against bacteriophages. Altogether, our findings establish sirtuins as broad-spectrum and evolutionarily conserved components of the immune defense system, providing a framework for elucidating a new set of host cell defense mechanisms and developing sirtuin modulators with antiviral activity

The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics

Viruses have co-evolved with their hosts, acquiring strategies to subvert host cellular pathways for effective viral replication and spread. Human cytomegalovirus (HCMV), a widely-spread β-herpesvirus, is a major cause of birth defects and opportunistic infections in HIV-1/AIDS patients. HCMV displays an intricate system-wide modulation of the human cell proteome. An impressive array of virus–host protein interactions occurs throughout the infection. To investigate the virus life cycle, proteomics has recently become a significant component of virology studies. Here, we review the mass spectrometry-based proteomics approaches used in HCMV studies, as well as their contribution to understanding the HCMV life cycle and the virus-induced changes to host cells. The importance of the biological insights gained from these studies clearly demonstrate the impact that proteomics has had and can continue to have on understanding HCMV biology and identifying new therapeutic targets