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Type I and III interferons share similar antiviral properties, but there are some important distinctions. Hartmann and colleagues review the specialized functions of type III interferons, including their ability to mediate antiviral functions at barrier surfaces. Type III interferons (IFNs) or IFN-λs regulate a similar set of genes as type I IFNs, but whereas type I IFNs act globally, IFN-λs primarily target mucosal epithelial cells and protect them against the frequent viral attacks that are typical for barrier tissues. IFN-λs thereby help to maintain healthy mucosal surfaces through immune protection, without the significant immune-related pathogenic risk associated with type I IFN responses. Type III IFNs also target the human liver, with dual effects: they induce an antiviral state in hepatocytes, but specific IFN-λ4 action impairs the clearance of hepatitis C virus and could influence inflammatory responses. This constitutes a paradox that has yet to be resolved.

Host factors restricting the transmission of respiratory viruses are poorly characterized. We analyzed the contribution of type I and type III interferon (IFN) using a mouse model in which the virus is selectively administered to the upper airways, mimicking a natural respiratory virus infection. Mice lacking functional IFN-λ receptors (Ifnlr1−/−) no longer restricted virus dissemination from the upper airways to the lungs. Ifnlr1−/− mice shed significantly more infectious virus particles via the nostrils and transmitted the virus much more efficiently to naïve contacts compared with wild-type mice or mice lacking functional type I IFN receptors. Prophylactic treatment with IFN-α or IFN-λ inhibited initial virus replication in all parts of the respiratory tract, but only IFN-λ conferred long-lasting antiviral protection in the upper airways and blocked virus transmission. Thus, IFN-λ has a decisive and non-redundant function in the upper airways that greatly limits transmission of respiratory viruses to naïve contacts. Influenza (‘the flu’) and other respiratory viruses make millions of people ill every year, placing a large burden on the healthcare system and the economy. Unfortunately, few options for preventing or treating these infections currently exist. The flu virus spreads from infected individuals, enters a new host through the nose and establishes an infection in the upper airways. If the infection stays restricted to this region of the respiratory tract – which consists of the nasal cavity, sinuses, throat and larynx – it causes a rather mild disease. However, if it spreads to the lungs it can cause potentially life-threatening viral pneumonia. Epithelial cells line the upper respiratory tract, forming a physical border between the outside world and the human body. These cells are therefore the first to face the incoming virus. In response, the epithelial cells release messenger molecules termed interferons that warn nearby cells to increase their antiviral defenses. There are several subtypes of interferons, such as IFN-α, IFN-β and IFN-λ, but it was not known how each subtype helps to combat respiratory viruses. To investigate, Klinkhammer, Schnepf et al. exposed mice to flu viruses in a way that mimicked how an infection would naturally start in the upper airways in humans. Some of the mice were genetically engineered so that they could not respond to either IFN-α/β or IFN-λ. The virus spread most effectively from the nasal cavity to the lungs in mice whose IFN-λ system was defective. Infections in mice that lacked IFN-λ were also more likely to spread to other individuals. Furthermore, treating mice with IFN-λ, but not IFN-α, gave their upper respiratory tract long-lasting protection against flu infections and prevented the spread of the virus. IFN-λ therefore has a specific and significant role in protecting the upper airways against viruses, and could potentially be used as a drug to block the spread of infections between humans. Currently, IFN-λ is in clinical trials as a potential treatment for hepatitis D. To repurpose it for upper respiratory tract infections, its effectiveness against specific respiratory viruses will first have to be evaluated.

The presence of nucleic acids in the cytosol alerts the cell to viral infection or damaged self. The oligoadenylate synthase (OAS) proteins and cyclic GMP–AMP synthase (cGAS) are enzymes that detect this danger and promote antiviral immunity. Recent structural studies reveal that these enzymes have a common mechanism of action and probably the same evolutionary origin. Recent discoveries in the field of innate immunity have highlighted the existence of a family of nucleic acid-sensing proteins that have similar structural and functional properties. These include the well-known oligoadenylate synthase (OAS) family proteins and the recently identified OAS homologue cyclic GMP–AMP (cGAMP) synthase (cGAS). The OAS proteins and cGAS are template-independent nucleotidyltransferases that, once activated by double-stranded nucleic acids in the cytosol, produce unique classes of 2′–5′-linked second messenger molecules, which — through distinct mechanisms — have crucial antiviral functions. 2′–5′-linked oligoadenylates limit viral propagation through the activation of the enzyme RNase L, which degrades host and viral RNA, and 2′–5′-linked cGAMP activates downstream signalling pathways to induce de novo antiviral gene expression. In this Progress article, we describe the striking functional and structural similarities between OAS proteins and cGAS, and highlight their roles in antiviral immunity.

Interferon-λ (IFN-λ) acts on mucosal epithelial cells and thereby confers direct antiviral protection. In contrast, the role of IFN-λ in adaptive immunity is far less clear. Here, we report that mice deficient in IFN-λ signaling exhibited impaired CD8 + T cell and antibody responses after infection with a live-attenuated influenza virus. Virus-induced release of IFN-λ triggered the synthesis of thymic stromal lymphopoietin (TSLP) by M cells in the upper airways that, in turn, stimulated migratory dendritic cells and boosted antigen-dependent germinal center reactions in draining lymph nodes. The IFN-λ–TSLP axis also boosted production of the immunoglobulins IgG1 and IgA after intranasal immunization with influenza virus subunit vaccines and improved survival of mice after challenge with virulent influenza viruses. IFN-λ did not influence the efficacy of vaccines applied by subcutaneous or intraperitoneal routes, indicating that IFN-λ plays a vital role in potentiating adaptive immune responses that initiate at mucosal surfaces. The role of IFN-λ in adaptive immunity is not well characterized. Staeheli and colleagues show that in the lungs, IFN-λ elicits production of the cytokine TSLP from M cells and that this in turn is essential for effective adaptive immunity and control of infection with influenza virus.

Type I Interferons (IFN-Is) are a family of cytokines which play a major role in inhibiting viral infection. Resultantly, many viruses have evolved mechanisms in which to evade the IFN-I response. Here we tested the impact of expression of 27 different SARS-CoV-2 genes in relation to their effect on IFN production and activity using three independent experimental methods. We identified six gene products; NSP6, ORF6, ORF7b, NSP1, NSP5 and NSP15, which strongly (>10-fold) blocked MAVS-induced (but not TRIF-induced) IFNβ production. Expression of the first three of these SARS-CoV-2 genes specifically blocked MAVS-induced IFNβ-promoter activity, whereas all six genes induced a collapse in IFNβ mRNA levels, corresponding with suppressed IFNβ protein secretion. Five of these six genes furthermore suppressed MAVS-induced activation of IFNλs, however with no effect on IFNα or IFNγ production. In sharp contrast, SARS-CoV-2 infected cells remained extremely sensitive to anti-viral activity exerted by added IFN-Is. None of the SARS-CoV-2 genes were able to block IFN-I signaling, as demonstrated by robust activation of Interferon Stimulated Genes (ISGs) by added interferon. This, despite the reduced levels of STAT1 and phospho-STAT1, was likely caused by broad translation inhibition mediated by NSP1. Finally, we found that a truncated ORF7b variant that has arisen from a mutant SARS-CoV-2 strain harboring a 382-nucleotide deletion associating with mild disease (Δ382 strain identified in Singapore & Taiwan in 2020) lost its ability to suppress type I and type III IFN production. In summary, our findings support a multi-gene process in which SARS-CoV-2 blocks IFN-production, with ORF7b as a major player, presumably facilitating evasion of host detection during early infection. However, SARS-CoV-2 fails to suppress IFN-I signaling thus providing an opportunity to exploit IFN-Is as potential therapeutic antiviral drugs.

The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids. Here we use an affinity proteomics approach in evolutionary distant species (human, mouse and fly) to identify proteins that are conserved in their ability to associate with diverse viral nucleic acids. This approach shows a core of orthologous proteins targeting viral genetic material and species-specific interactions. Functional characterization of the influence of 181 candidates on replication of 6 distinct viruses in human cells and flies identifies 128 nucleic acid binding proteins with an impact on virus growth. We identify the family of TAO kinases (TAOK1, −2 and −3) as dsRNA-interacting antiviral proteins and show their requirement for type-I interferon induction. Depletion of TAO kinases in mammals or flies leads to an impaired response to virus infection characterized by a reduced induction of interferon stimulated genes in mammals and impaired expression of srg1 and diedel in flies. Overall, our study shows a larger set of proteins able to mediate the interaction between viral genetic material and host factors than anticipated so far, attesting to the ancestral roots of innate immunity and to the lineage-specific pressures exerted by viruses. Whether there are conserved nucleic acid (NA) binding proteins across species is not fully known. Using data from human, mouse and fly, the authors identify common binders, implicate TAOKs and show that these kinases bind NAs across species and promote virus defence in mammalian cells.

STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit. STING ER exit is the rate-limiting step in STING signaling, but the mechanism that drives this process is not understood. Paludan and colleagues identify CxORF56, called STEEP here, as a positive regulator of STING signaling.

Influenza A virus (IAV)‐induced severe disease is characterized by infected lung epithelia, robust inflammatory responses and acute lung injury. Since type I interferon (IFNαβ) and type III interferon (IFNλ) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFNλ treatment of IAV‐infected Mx1‐positive mice lowered viral load and protected from disease. IFNα treatment also restricted IAV replication but exacerbated disease. IFNα treatment increased pulmonary proinflammatory cytokine secretion, innate cell recruitment and epithelial cell death, unlike IFNλ‐treatment. IFNλ lacked the direct stimulatory activity of IFNα on immune cells. In epithelia, both IFNs induced antiviral genes but no inflammatory cytokines. Similarly, human airway epithelia responded to both IFNα and IFNλ by induction of antiviral genes but not of cytokines, while hPBMCs responded only to IFNα. The restriction of both IFNλ responsiveness and productive IAV replication to pulmonary epithelia allows IFNλ to limit IAV spread through antiviral gene induction in relevant cells without overstimulating the immune system and driving immunopathology. We propose IFNλ as a non‐inflammatory and hence superior treatment option for human IAV infection. Synopsis IFNα and IFNλ are both antiviral cytokines. IFNλ appears to confer better protection than IFNα in influenza experimentally infected organisms, as it helps control the virus in infected target cells in airway epithelia, and does not enhance inflammation in the lung. Both interferon alpha (IFNα) and lambda (IFNλ) protect from influenza virus infection when mice are treated prior to infection. When infected mice are treated therapeutically after onset of symptoms, IFNλ protects but IFNα aggravates disease. Both IFNα and IFNλ have antiviral effects, but IFNα also activates immune cells in the lung leading to immunopathology, while IFNλ does not. The response pattern to IFNα and IFNλ of human immune cells and lung epithelia is identical to that of mouse cells, strongly suggesting that the same effects would be found in humans. Graphical Abstract IFNα and IFNλ are both antiviral cytokines. IFNλ appears to confer better protection than IFNα in influenza experimentally infected organisms, as it helps control the virus in infected target cells in airway epithelia, and does not enhance inflammation in the lung.

Since its emergence in December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally and become a major public health burden. Despite its close phylogenetic relationship to SARS-CoV, SARS-CoV-2 exhibits increased human-to-human transmission dynamics, likely due to efficient early replication in the upper respiratory epithelium of infected individuals. Since different temperatures encountered in the human upper and lower respiratory tract (33°C and 37°C, respectively) have been shown to affect the replication kinetics of several respiratory viruses, as well as host innate immune response dynamics, we investigated the impact of temperature on SARS-CoV-2 and SARS-CoV infection using the primary human airway epithelial cell culture model. SARS-CoV-2, in contrast to SARS-CoV, replicated to higher titers when infections were performed at 33°C rather than 37°C. Although both viruses were highly sensitive to type I and type III interferon pretreatment, a detailed time-resolved transcriptome analysis revealed temperature-dependent interferon and pro-inflammatory responses induced by SARS-CoV-2 that were inversely proportional to its replication efficiency at 33°C or 37°C. These data provide crucial insight on pivotal virus–host interaction dynamics and are in line with characteristic clinical features of SARS-CoV-2 and SARS-CoV, as well as their respective transmission efficiencies.

Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV. Stimulator of interferon genes (STING) is known to be involved in defence against DNA viruses, but its role in the control of RNA viruses remains poorly explored. Here the authors show that STING participates in an innate immune response to RNA virus infection in a cGAS-independent manner.