Neutrophils are the first immune cell population recruited to sites of infection, including viral infections, and exhibit both protective and pathologic functions. In antibacterial and antifungal immunity, the role of neutrophils is well defined. However, in antiviral immunity, much less is known. Conventional wisdom suggests that neutrophils enhance antiviral defenses, yet evidence for that is limited. Interaction with other immune cell populations, virus internalization and killing, the release of cytokines, chemokines, and antimicrobial components are all mechanisms by which neutrophils can contribute to pathogen clearance. NET formation, extensively studied during bacterial infection, can further mediate antiviral defense by trapping and inactivating virus. In the present review, we discuss the current understanding of the complex role of neutrophil immunity in viral infections and disease pathogenesis and the potential mechanisms identified to date. We pinpoint the importance of a finely tuned neutrophilic response for achieving effective immune protection while avoiding detrimental tissue damage that can form the basis for the development of novel therapeutics.

IL‐28 (IFN‐λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL‐28 cytokine family members were found to be profoundly down‐regulated in allergic asthma. We now reveal a novel role of IL‐28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild‐type mice with recombinant or adenovirally expressed IL‐28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN‐γ. Moreover, abrogation of endogenous IL‐28 cytokine function in IL‐28Rα^−/− mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL‐28A immunoregulatory activity was its capacity to modulate lung CD11c⁺ dendritic cell (DC) function to down‐regulate OX40L, up‐regulate IL‐12p70 and promote Th1 differentiation. Consistently, IL‐28A‐mediated protection was absent in IFN‐γ^−/− mice or after IL‐12 neutralization and could be adoptively transferred by IL‐28A‐treated CD11c⁺ cells. These data demonstrate a critical role of IL‐28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c⁺ DC function in experimental allergic asthma. →See accompanying Closeup by Michael R Edwards and Sebastian L Johnston http://dx.doi.org/10.1002/emmm.201100143

The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.