A Protective Neutralizing SARS-CoV-2 Ab
In this Top Read, Alsoussi et al. (p. 915) demonstrated that the mAb 2B04 protected mice from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immunization of mice with recombinant SARS-CoV-2 receptor-binding domain (RBD), followed by a boost using recombinant SARS-CoV-2 spike glycoprotein, resulted in serum that bound to SARS-CoV-2 recombinant proteins and neutralized viral infection. Plasmablasts (PBs) collected from the draining lymph nodes were cloned to generate 34 murine/human chimeric mAbs, representing 19 clonal lineages, all of which bound SARS-CoV-2 RBD. 2B04 weakly bound the RBD of both SARS-CoV and Middle East respiratory syndrome coronavirus but displayed the most potent neutralizing activity against SARS-CoV-2. Mice that transiently expressed human angiotensin-converting enzyme 2 in lung tissue via a nonreplicating adenoviral vector were infected with the SARS-CoV-2 strain 2019 n-CoV/USA_WA1/2020 to determine the protectivity of 2B04. Compared with the isotype-treated control, mice receiving 2B04 treatment prophylactically had significantly reduced weight loss, lower levels of viral RNA in the lung and spleen, and reduced inflammatory cell infiltrate in alveolar spaces following infection. These data identify a mAb that can both limit viral spread and mitigate symptoms during SARS-CoV-2 infection.
IFN-γ–Dependent Production of IL-18 Binding Protein
Interleukin-18 binding protein (IL-18BP) is a naturally occurring IL-18 decoy receptor that regulates free bioactive IL-18 levels in the serum. Elevated serum levels of IL-18 have been associated with macrophage activation syndrome (MAS). In this Top Read, Harel et al. (p. 1167) demonstrated that IL-18BP is induced in response to IFN-γ in both radioresistant and radiosensitive cells during CpG-induced MAS. IL-18BP knockout (KO) and wild-type (WT) mice were used to create bone marrow chimeras. Compared with either WT →WT chimeras, or chimeras with intact IL-18BP expression in either the radiosensitive or radioresistant cellular compartment, KO→KO chimeras exhibited severe clinical manifestations of MAS after repeated CpG injections. These data suggest that IL-18BP production from either radiosensitive or radioresistant cells is sufficient to mediate IL-18 serum levels. However, the contribution of each cellular compartment to IL-18BP mRNA and protein production varied according to anatomical location, with radiosensitive cells contributing a large portion of IL-18BP production in the spleen, whereas the lung relied on radioresistant cells for IL-18BP production. In WT animals, CpG stimulation increased levels of Il18bp mRNA in the liver and lung, but not the spleen. Increased I18bp mRNA was abrogated by neutralization of IFN-γ, suggesting that increased IL-18BP in response to CpG is mediated by IFN-γ. These data illustrate that IL-18BP is induced in response to IFN-γ in radiosensitive and radioresistant and that increased levels of IL-18BP decrease the effects of IL-18 in the CpG model of MAS.
ILC2 Interactions in Chronic Lung Disease
Although numerous studies have revealed that group 2 innate lymphoid cells (ILC2s) are a key component for host defense and inflammatory disease, defining the precise functional role of these cells has been hindered by a lack of models to specifically delete ILC2s. In this Top Read, Wu et al. (p. 1084) used Il7rawt/Cre-Rorafl/fl mice to achieve selective and effective deletion of ILC2s to assess their role during acute infection and progression to chronic inflammatory disease. Although ILC2s were activated during Sendai virus infection, they were not required for immune responses during the acute phase of infection. In contrast, activation of ILC2s was required for chronic production of IL-13 and for development of the asthma-like disease that peaks long after viral infection is cleared. Csfl-dependent myeloid–macrophage lineage cells were necessary for the development of chronic lung disease, serving as the major source of IL-13 production that, in turn, activated ILC2s. Thus, this study provides a revised scheme for understanding the pathogenesis and potential therapeutic targets for chronic disease after respiratory viral infection.
Human γδ T Cells Enhance Staphylococcal Immunity
Although studies in mice have shown that γδ T cells mediate immunity to Staphylococcus aureus in various tissue settings via secretion of cytokines, the role these cells may play in human responses to S. aureus remains unknown. In this Top Read, Cooper et al. (p. 1039) demonstrated that Vδ2+ cells derived from peripheral blood rapidly upregulated surface expression of CD69, CD86, and CCR7 and secreted high levels of IFN-γ when cocultured with S. aureus–infected monocyte-derived dendritic cells (DCs). This interaction was mediated by direct cell contact and secretion of IL-12 by infected DCs, which was further reinforced by a positive feedback loop wherein IFN-γ released by Vδ2+ cells upregulated IL-12 secretion by DCs. Furthermore, addition of γδ T cells increased activation of CD4+ T cells cocultured with S. aureus–infected DCs. Thus, this study reveals that γδ T cells are likely key players in the early host response to blood-borne S. aureus infection, where they may promote both innate and adaptive immune responses.
Fishy Anti-Inflammatory Cytokines
In this Top Read, Bottiglione et al. (p. 994) showed that both IL-4/13 and IL-10 paralogs suppress inflammation in zebrafish. Fish IL-4/13 paralogs encoded by two similar loci, il4/13a and il4/13b, were knocked out to create either single mutants, il4/13a−/− and il4/13b−/−, or a double mutant, il4/13a;b−/−. Compared with wild type (WT) fish, those with single knockout mutations in either il4/13a and il4/13b significantly upregulated mRNA of proinflammatory cytokines, suggesting that these genes may play a role in mitigating proinflammatory signals. Transcriptome analysis of adult il4/13a;b−/− double mutants revealed a shift toward type 1 immunity, as evidenced by increased expression of genes associated with Th1 differentiation, IFN-γ, TLR4 signaling, and macrophage activation, and decreased expression of genes associated with granulocyte and myeloid cell differentiation and fibroblast migration. Gill morphology was unaffected in both the single and double knockouts. The gills of zebrafish mutants lacking functional IL-10 (il10e46/e46) displayed significant morphological changes, suggesting a role for IL-10 in gill homeostasis. The authors used resiquimod (R848), which mimics viral single-stranded RNA, to further determine how IL-4/13a and IL-4/13b modulate an inflammatory response. The loss of il4/13a or il4/13b does not impair R848-induced inflammation. However, il4/13a;b−/− mutants had significantly higher levels of proinflammatory cytokine mRNA than WT, indicative of an enhanced type 1 response. R848 treatment resulted in a prolonged inflammatory response in il10e46/e46 mutants. Together, these data demonstrate anti-inflammatory roles for IL-4/13 and IL-10 and establish the role of IL-10 in gill homeostasis.
Gsk3α during Liver Ischemia Reperfusion Injury
In this Top Read, Ni et al. (p. 1147) sought to determine if N-terminal phosphorylation of glycogen synthase kinase 3 (Gsk3) α and β had any functional significance during ischemia reperfusion injury (IRI). Using Gsk N-terminal serine knock-in (KI) mutant mice, the authors showed that liver IRI was decreased in Gsk3αS21A mutants but increased in Gsk3βS9A mutant mice. Experiments using bone marrow chimeras revealed that Gsk3α mutation, but not Gsk3β mutation, protected mice from liver IRI, whereas both mutations exacerbated liver injuries. Mutant Gsk3α protected hepatocytes from TNF-α induced cell death by the activation of HIV-1 TAT-interactive protein 60 (TIP60)-mediated autophagy. Inhibition of either autophagy or TIP60 abolished the protection from inflammatory cell death and liver IRI afforded to Gsk3α mutants. Thus, this study reveals that Gsk N-terminal serine phosphorylation inhibits liver innate immune activation but suppresses hepatocyte autophagy in response to inflammation.
- Copyright © 2020 by The American Association of Immunologists, Inc.
