Protection against Staphylococcus aureus bacteremia-induced mortality depends on ILC2s and eosinophils

• Published in: JCI insight Vol. 4; no. 6
• Main Authors: Krishack, Paulette A., Louviere, Tyler J., Decker, Trevor S., Kuzel, Timothy G., Greenberg, Jared A., Camacho, Daniel F., Hrusch, Cara L., Sperling, Anne I., Verhoef, Philip A.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 21.03.2019
• Subjects: Infectious disease; Bacterial infections; Immunology; Th2 response; Asthma
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.124168

The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ Th cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we used a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2-initiating cytokine IL-33 activated pulmonary type 2 innate lymphoid cells (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity before lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33-mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a potentially novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.