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

JCI Insight. 2019 Mar 21;4(6):e124168. 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.

Keywords: Asthma; Bacterial infections; Immunology; Infectious disease; Th2 response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1d / genetics
  • Asthma / immunology
  • Bacteremia / mortality
  • Bacteremia / prevention & control*
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Eosinophils / immunology*
  • Eosinophils / metabolism*
  • Humans
  • Hypersensitivity
  • Immunity, Innate*
  • Interleukin-13
  • Interleukin-33 / immunology
  • Interleukin-5
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / immunology
  • Promyelocytic Leukemia Zinc Finger Protein / genetics
  • Pulmonary Edema / immunology
  • Pulmonary Edema / pathology
  • Staphylococcal Infections / immunology*
  • Staphylococcus aureus / immunology*
  • Th17 Cells / immunology
  • Th2 Cells / immunology


  • Antigens, CD1d
  • CD1d antigen, mouse
  • Cytokines
  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-13
  • Interleukin-33
  • Interleukin-5
  • Promyelocytic Leukemia Zinc Finger Protein
  • Zbtb16 protein, mouse