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Rush desensitization (DS) is a widely used and effective clinical strategy for the rapid inhibition of IgE-mediated anaphylactic responses. However, the cellular targets and underlying mechanisms behind this process remain unclear. Recent studies have implicated mast cells (MCs) as the primary target cells for DS. Here, we developed a murine model of passive anaphylaxis with demonstrated MC involvement and an in vitro assay to evaluate the effect of DS on MCs. In contrast with previous reports, we determined that functional IgE remains on the cell surface of desensitized MCs following DS. Despite notable reductions in MC degranulation following DS, the high-affinity IgE receptor FcεRI was still capable of transducing signals in desensitized MCs. Additionally, we found that displacement of the actin cytoskeleton and its continued association with FcεRI impede the capacity of desensitized MCs to evoke the calcium response that is essential for MC degranulation. Together, these findings suggest that reduced degranulation responses in desensitized MCs arise from aberrant actin remodeling, providing insights that may lead to improvement of DS treatments for anaphylactic responses.

When draining lymph nodes become infected by Yersinia pestis (Y. pestis), a massive influx of phagocytic cells occurs, resulting in distended and necrotic structures known as buboes. The bubonic stage of the Y. pestis life cycle precedes septicemia, which is facilitated by trafficking of infected mononuclear phagocytes through these buboes. However, how Y. pestis convert these immunocytes recruited by host to contain the pathogen into vehicles for bacterial dispersal and the role of immune cell death in this context are unknown. We show that the lymphatic spread requires Yersinia outer protein J (YopJ), which triggers death of infected macrophages by downregulating a suppressor of receptor-interacting protein kinase 1-mediated (RIPK1-mediated) cell death programs. The YopJ-triggered cell death was identified as necroptotic, which released intracellular bacteria, allowing them to infect new neighboring cell targets. Dying macrophages also produced chemotactic sphingosine 1-phosphate, enhancing cell-to-cell contact, further promoting infection. This necroptosis-driven expansion of infected macrophages in buboes maximized the number of bacteria-bearing macrophages reaching secondary lymph nodes, leading to sepsis. In support, necrostatins confined bacteria within macrophages and protected mice from lethal infection. These findings define necrotization of buboes as a mechanism for bacterial spread and a potential target for therapeutic intervention.

Colonization with pathobiont microbes is a classical risk factor for invasive infection. However, the relative paucity of systemic infection despite ubiquitous pathobiont commensalism suggests colonization may also elicit protective host immunity. We show Candida albicans intestinal colonization of mice and humans drives systemic expansion of fungal-specific Th17 CD4+ T cells, and IL-17 responsiveness by circulating neutrophils, which synergistically protect against C. albicans invasive infection. Persistent C. albicans colonization is required, since protection is overturned by eradicating fungal colonization. Commensal C. albicans conferred protection extends to invasive infection by the extracellular bacterial pathogen, Staphylococcus aureus. However, positively calibrating systemic Th17 responses is not uniformly beneficial, as commensal C. albicans does not protect against intracellular influenza A virus infection, and exacerbates allergic airway inflammation susceptibility. Thus, systemic Th17 inflammation driven by CD4+ T cells responsive to commensal C. albicans tonic stimulation improves host defense against extracellular pathogens, but with harmful immunological consequences.

Summary Mucosal barriers are densely colonized by pathobiont microbes such as Candida albicans, capable of invasive disseminated infection. However, systemic infections occur infrequently in healthy individuals, suggesting that pathobiont commensalism may elicit host benefits. We show that intestinal colonization with C. albicans drives systemic expansion of fungal-specific Th17 CD4+ T cells and IL-17 responsiveness by circulating neutrophils, which synergistically protect against C. albicans invasive infection. Protection conferred by commensal C. albicans requires persistent fungal colonization and extends to other extracellular invasive pathogens such as Staphylococcus aureus. However, commensal C. albicans does not protect against intracellular influenza virus infection and exacerbates allergic airway inflammation susceptibility, indicating that positively calibrating systemic Th17 responses is not uniformly beneficial. Thus, systemic Th17 inflammation driven by CD4+ T cells responsive to tonic stimulation by commensal C. albicans improves host defense against extracellular pathogens, but with potentially harmful immunological consequences.

Commensal intestinal microbes are collectively beneficial in preventing local tissue injury and augmenting systemic antimicrobial immunity. However, given the near-exclusive focus on bacterial species in establishing these protective benefits, the contributions of other types of commensal microbes remain poorly defined. Here, we show that commensal fungi can functionally replace intestinal bacteria by conferring protection against injury to mucosal tissues and positively calibrating the responsiveness of circulating immune cells. Susceptibility to colitis and influenza A virus infection occurring upon commensal bacteria eradication is efficiently overturned by mono-colonization with either Candida albicans or Saccharomyces cerevisiae. The protective benefits of commensal fungi are mediated by mannans, a highly conserved component of fungal cell walls, since intestinal stimulation with this moiety alone overrides disease susceptibility in mice depleted of commensal bacteria. Thus, commensal enteric fungi safeguard local and systemic immunity by providing tonic microbial stimulation that can functionally replace intestinal bacteria.