Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production-effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.

A monoclonal antibody to Siglec-8 suppresses non-allergic airway inflammation and inhibits IgE-independent mast cell activation.

In addition to their well characterized role in mediating IgE-dependent allergic diseases, aberrant accumulation and activation of mast cells (MCs) is associated with many non-allergic inflammatory diseases, whereby their activation is likely triggered by non-IgE stimuli (e.g., IL-33). Siglec-8 is an inhibitory receptor expressed on MCs and eosinophils that has been shown to inhibit IgE-mediated MC responses and reduce allergic inflammation upon ligation with a monoclonal antibody (mAb). Herein, we evaluated the effects of an anti-Siglec-8 mAb (anti-S8) in non-allergic disease models of experimental cigarette-smoke-induced chronic obstructive pulmonary disease and bleomycin-induced lung injury in Siglec-8 transgenic mice. Therapeutic treatment with anti-S8 inhibited MC activation and reduced recruitment of immune cells, airway inflammation, and lung fibrosis. Similarly, using a model of MC-dependent, IL-33-induced inflammation, anti-S8 treatment suppressed neutrophil influx, and cytokine production through MC inhibition. Transcriptomic profiling of MCs further demonstrated anti-S8-mediated downregulation of MC signaling pathways induced by IL-33, including TNF signaling via NF-κB. Collectively, these findings demonstrate that ligating Siglec-8 with an antibody reduces non-allergic inflammation and inhibits IgE-independent MC activation, supporting the evaluation of an anti-Siglec-8 mAb as a therapeutic approach in both allergic and non-allergic inflammatory diseases in which MCs play a role.

Zygotic Genome Activation Triggers Chromosome Damage and Checkpoint Signaling in C. elegans Primordial Germ Cells.

Recent findings have identified highly transcribed genes as a source of genome instability; however, the degree to which large-scale shifts in transcriptional activity cause DNA damage was not known. One example of a large-scale shift in transcriptional activity occurs during development, when maternal regulators are destroyed and zygotic genome activation (ZGA) occurs. Here, we show that ZGA triggers widespread chromosome damage in the primordial germ cells of the nematode C. elegans. We show that ZGA-induced DNA damage activates a checkpoint response, the damage is repaired by factors required for inter-sister homologous recombination, and topoisomerase II plays a role in generating the damage. These findings identify ZGA as a source of intrinsic genome instability in the germline and suggest that genome destabilization may be a general consequence of extreme shifts in cellular transcriptional load.

Trouble in transitioning: activation of zygotic transcription can lead to DNA breakage and genome instability.

Recent work from our laboratory has identified zygotic genome activation as a source of intrinsic DNA damage during germline development in C. elegans. More specifically, we have found that the primordial germ cells Z2 and Z3 experience DNA damage and damage checkpoint activation shortly after RNA polymerase II is activated by a nutrient-dependent signal in L1 stage animals. In this Commentary we review these data, put them into context with other examples of programmed DNA double-strand breaks (DSBs) during gene activation, and speculate as to how a DSB would facilitate signal-dependent activation of gene expression.