Over the past few years, several groups have identified new genes that are transcriptionally induced downstream of type I interferon (IFN) signalling and that inhibit infection by individual or ...multiple families of viruses. Among these IFN-stimulated genes with antiviral activity are two genetically and functionally distinct families--the IFN-induced protein with tetratricopeptide repeats (IFIT) family and the IFN-induced transmembrane protein (IFITM) family. This Review focuses on recent advances in identifying the unique mechanisms of action of IFIT and IFITM proteins, which explain their broad-spectrum activity against the replication, spread and pathogenesis of a range of human viruses.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections ...are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.
Type I interferons (IFNs) (IFN-α, IFN-β) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional ...programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease.
Lazear, Schoggins, and Diamond review the shared and distinct features of type I and III interferons, from molecular mechanisms through physiological responses. In this context, they discuss the current state of interferon-based therapeutic approaches in the clinic and highlight gaps in understanding of the biology of these cytokines.
Zika virus (ZIKV) had remained a relatively obscure flavivirus until a recent series of outbreaks accompanied by unexpectedly severe clinical complications brought this virus into the spotlight as ...causing an infection of global public health concern. In this review, we discuss the history and epidemiology of ZIKV infection, recent outbreaks in Oceania and the emergence of ZIKV in the Western Hemisphere, newly ascribed complications of ZIKV infection, including Guillain-Barré syndrome and microcephaly, potential interactions between ZIKV and dengue virus, and the prospects for the development of antiviral agents and vaccines.
Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some ...of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis.
Flaviviruses are vector-borne RNA viruses that can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases including hepatitis, vascular shock syndrome, ...encephalitis, acute flaccid paralysis, congenital abnormalities and fetal death. This epidemiological pattern has occurred numerous times during the last 70 years, including epidemics of dengue virus and West Nile virus, and the most recent explosive epidemic of Zika virus in the Americas. Flaviviruses are now globally distributed and infect up to 400 million people annually. Of significant concern, outbreaks of other less well-characterized flaviviruses have been reported in humans and animals in different regions of the world. The potential for these viruses to sustain epidemic transmission among humans is poorly understood. In this Review, we discuss the basic biology of flaviviruses, their infectious cycles, the diseases they cause and underlying host immune responses to infection. We describe flaviviruses that represent an established ongoing threat to global health and those that have recently emerged in new populations to cause significant disease. We also provide examples of lesser-known flaviviruses that circulate in restricted areas of the world but have the potential to emerge more broadly in human populations. Finally, we discuss how an understanding of the epidemiology, biology, structure and immunity of flaviviruses can inform the rapid development of countermeasures to treat or prevent human infections as they emerge.
Dengue virus (DENV) is a mosquito-transmitted RNA virus that infects an estimated 390 million humans each year. Here, we review recent advances in our understanding of the biology of DENV and ...describe knowledge gaps that have impacted the development of effective vaccines and therapeutics.
Dengue virus infects nearly 400 million humans each year. Recent insights into the disease have driven the development of vaccines and therapeutics.
Following the emergence of a novel coronavirus in Wuhan, China instituted shutdown measures starting in late January and continuing into February 2020 to arrest the spread of disease. This resulted ...in a sharp economic contraction unparalleled in recent Chinese history. Satellite retrievals show that nitrogen dioxide pollution declined by an unprecedented amount (~50% regionally) from its expected unperturbed value, but regional‐scale column aerosol loadings and cloud microphysical properties were not detectably affected. The disparate impact is tied to differential economic impacts of the shutdown, in which transportation, a disproportionate source of nitrogen oxide emissions, underwent drastic declines (~90% reductions in passenger traffic), whereas industry and power generation, responsible for >90% of particulate emissions, were relatively less affected (~20% reductions in electricity and thermal power generation). A combination of anomalously warm and humid meteorological conditions and complex chemical interactions further decreased nitrogen dioxide concentrations but likely enhanced secondary aerosol formation.
Plain Language Summary
To slow the spread of COVID‐19, China implemented strict policies limiting travel and public gatherings in February 2020, resulting in a pronounced economic decline. Satellite measurements show that levels of nitrogen oxides, gases that are a major component of air pollution, were substantially lower than what we would normally expect for February. Surprisingly, however, we did not observe any similar changes in airborne particles (another major component of air pollution) or in the size of cloud droplets (which is partly determined by the abundance of airborne particles). This is important because airborne particles, in addition to harming human health, affect the climate by changing how much sunlight is absorbed on Earth versus reflected back into space. The transportation sector of the economy was hit particularly hard by the coronavirus shutdown, but heavy industries and power plants were relatively less affected. Transportation is a major source of nitrogen oxides but not of airborne particles or their chemical precursors, which are mostly emitted by industry and power plants. The shutdown's much larger effect on transportation than on industry or power plants, along with changes in weather and chemical interactions, help explain the differences we see in the different types of air pollution.
Key Points
Rapid economic collapse in February 2020 due to the COVID‐19 pandemic and partial recovery in March 2020 are unique in recent Chinese history
Regional decline in NO2 pollution is unprecedented in the satellite record, but no change in aerosol or cloud properties is detected
Different economic impacts by sector, meteorology, and complex chemical interactions help explain differences in NOx and aerosol response
When type III interferon (IFN-λ; also known as interleukin-28 IL-28 and IL-29) was discovered in 2003, its antiviral function was expected to be analogous to that of type I IFNs (IFN-α and IFN-β) via ...the induction of IFN-stimulated genes (ISGs). Although IFN-λ stimulates expression of antiviral ISGs preferentially in cells of epithelial origin, recent studies have defined additional antiviral mechanisms in other cell types and tissues. Viral infection models using mice lacking IFN-λ signaling and SNP associations with human disease have expanded our understanding of the contribution of IFN-λ to the antiviral response at anatomic barriers and the immune response beyond these barriers. In this review, we highlight recent insights into IFN-λ functions, including its ability to restrict virus spread into the brain and to clear chronic viral infections in the gastrointestinal tract. We also discuss how IFN-λ modulates innate and adaptive immunity, autoimmunity, and tumor progression and its possible therapeutic applications in human disease.
Interferon-λ induces antiviral gene programs in restricted cell types, including epithelial cells. Diamond and colleagues discuss recent insights into the induction of interferon-λ, its role in barrier immunity, and its connections to human disease.
Zika virus (ZIKV) is a mosquito-transmitted flavivirus that has emerged as a global health threat because of its potential to generate explosive epidemics and ability to cause congenital disease in ...the context of infection during pregnancy. Whereas much is known about the biology of related flaviviruses, the unique features of ZIKV pathogenesis, including infection of the fetus, persistence in immune-privileged sites and sexual transmission, have presented new challenges. The rapid development of cell culture and animal models has facilitated a new appreciation of ZIKV biology. This knowledge has created opportunities for the development of countermeasures, including multiple ZIKV vaccine candidates, which are advancing through clinical trials. Here we describe the recent advances that have led to a new understanding of the causes and consequences of the ZIKV epidemic.
PDF
