Viruses and the cellular RNA decay machinery.

The ability to control cellular and viral gene expression, either globally or selectively, is central to a successful viral infection, and it is also crucial for the host to respond and eradicate pathogens. In eukaryotes, regulation of message stability contributes significantly to the control of gene expression and plays a prominent role in the normal physiology of a cell as well as in its response to environmental and pathogenic stresses. Not surprisingly, emerging evidence indicates that there are significant interactions between the eukaryotic RNA turnover machinery and a wide variety of viruses. Interestingly, in many cases viruses have evolved mechanisms not only to evade eradication by these pathways, but also to manipulate them for enhanced viral replication and gene expression. Given our incomplete understanding of how many of these pathways are normally regulated, viruses should be powerful tools to help deconstruct the complex networks and events governing eukaryotic RNA stability

Caspase-Mediated Regulation and Cellular Heterogeneity of the cGAS/STING Pathway in Kaposi’s Sarcoma-Associated Herpesvirus Infection.

As a result of the ongoing virus-host arms race, viruses have evolved numerous immune subversion strategies, many of which are aimed at suppressing the production of type I interferons (IFNs). Apoptotic caspases have recently emerged as important regulators of type I IFN signaling both in noninfectious contexts and during viral infection. Despite being widely considered antiviral factors since they can trigger cell death, several apoptotic caspases promote viral replication by suppressing innate immune response. Indeed, we previously discovered that the AIDS-associated oncogenic gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV) exploits caspase activity to suppress the antiviral type I IFN response and promote viral replication. However, the mechanism of this novel viral immune evasion strategy is poorly understood, particularly with regard to how caspases antagonize IFN signaling during KSHV infection. Here, we show that caspase activity inhibits the DNA sensor cGAS during KSHV lytic replication to block type I IFN induction. Furthermore, we used single-cell RNA sequencing to reveal that the potent antiviral state conferred by caspase inhibition is mediated by an exceptionally small percentage of IFN-β-producing cells, thus uncovering further complexity of IFN regulation during viral infection. Collectively, these results provide insight into multiple levels of cellular type I IFN regulation that viruses co-opt for immune evasion. Unraveling these mechanisms can inform targeted therapeutic strategies for viral infections and reveal cellular mechanisms of regulating interferon signaling in the context of cancer and chronic inflammatory diseases.post-print1848 K

Coordinated Destruction of Cellular Messages in Translation Complexes by the Gammaherpesvirus Host Shutoff Factor and the Mammalian Exonuclease Xrn1

Several viruses encode factors that promote host mRNA degradation to silence gene expression. It is unclear, however, whether cellular mRNA turnover pathways are engaged to assist in this process. In Kaposi's sarcoma-associated herpesvirus this phenotype is enacted by the host shutoff factor SOX. Here we show that SOX-induced mRNA turnover is a two-step process, in which mRNAs are first cleaved internally by SOX itself then degraded by the cellular exonuclease Xrn1. SOX therefore bypasses the regulatory steps of deadenylation and decapping normally required for Xrn1 activation. SOX is likely recruited to translating mRNAs, as it cosediments with translation initiation complexes and depletes polysomes. Cleaved mRNA intermediates accumulate in the 40S fraction, indicating that recognition occurs at an early stage of translation. This is the first example of a viral protein commandeering cellular mRNA turnover pathways to destroy host mRNAs, and suggests that Xrn1 is poised to deplete messages undergoing translation in mammalian cells

The Somatic Reproductive Tissues of C. elegans Promote Longevity through Steroid Hormone Signaling

Removal of the germ cells of C. elegans extends lifespan in part because signals from the somatic reproductive tissues activate the nuclear hormone receptor DAF-12

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Virology under the microscope—a call for rational discourse

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology

Dopamine modulation of quiescence in dauer larvae, and other investigations on hibernation and lifespan in C. elegans

Studies in organisms from worms to humans have brought an increasing appreciation for a crucial role of the central nervous system in the regulation of many basic physiological processes including energy homeostasis, immune responses, development and aging. However, the mechanisms underlying such regulation are still incompletely understood. In C. elegans, two physiological processes that are notably modulated by the nervous system are the developmental decision to arrest in the hibernation-like dauer larval stage and the regulation of aging. In this thesis, we studied the interplay between endocrine systems controlling aging and dauer formation, such as insulin/IGF-1 signaling, and neuronal signaling, such as neurotransmitter and sensory signaling. We found that dopamine signaling may be specifically modulated by insulin/IGF-1 signaling to regulate the quiescence behavior of dauer, and it may also be involved in the process of exit from the dauer stage. Because there are physiological and molecular similarities between the dauer stage and seasonal hibernation in mammals, it is possible that dopamine signaling contributes to behavioral quiescence in hibernating mammals. In a separate study, we found that signals from the sensory system feed into the regulation of at least two different transcription factors, the FOXO homolog daf-16 and the steroid nuclear hormone receptor daf-12, both targets of endocrine pathways. In addition, we found that the sensory system is required for normal expression of immune response genes, and that sensory system mutants have increased susceptibility to a bacterial pathogen. These results indicate that sensory inputs can coordinately regulate several processes by affecting a number of important transcriptional responses. The insulin/IGF-1 pathway, the dopamine pathway and sensory inputs are crucial in the mammalian central nervous system for the regulation of many physiological as well as behavioral responses. Therefore these studies in a simpler, genetically tractable organism may offer valuable insights on how these systems may be coordinated in higher organisms

Viruses and the cellular RNA decay machinery.

The ability to control cellular and viral gene expression, either globally or selectively, is central to a successful viral infection, and it is also crucial for the host to respond and eradicate pathogens. In eukaryotes, regulation of message stability contributes significantly to the control of gene expression and plays a prominent role in the normal physiology of a cell as well as in its response to environmental and pathogenic stresses. Not surprisingly, emerging evidence indicates that there are significant interactions between the eukaryotic RNA turnover machinery and a wide variety of viruses. Interestingly, in many cases viruses have evolved mechanisms not only to evade eradication by these pathways, but also to manipulate them for enhanced viral replication and gene expression. Given our incomplete understanding of how many of these pathways are normally regulated, viruses should be powerful tools to help deconstruct the complex networks and events governing eukaryotic RNA stability

Genes acting downstream of sensory neurons to influence longevity, dauer formation and pathogen responses in C. elegans

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