Protection against Staphylococcus aureus bacteremia–induced mortality depends on ILC2s and eosinophils
Paulette A. Krishack, Tyler J. Louviere, Trevor S. Decker, Timothy G. Kuzel, Jared A. Greenberg, Daniel F. Camacho, Cara L. Hrusch, Anne I. Sperling, Philip A. Verhoef
Paulette A. Krishack, Tyler J. Louviere, Trevor S. Decker, Timothy G. Kuzel, Jared A. Greenberg, Daniel F. Camacho, Cara L. Hrusch, Anne I. Sperling, Philip A. Verhoef
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Research Article Immunology Infectious disease

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

Abstract

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.

Authors

Paulette A. Krishack, Tyler J. Louviere, Trevor S. Decker, Timothy G. Kuzel, Jared A. Greenberg, Daniel F. Camacho, Cara L. Hrusch, Anne I. Sperling, Philip A. Verhoef

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Figure 1

Patients who survive S. aureus bacteremia have higher levels of Th2 lymphocytes and lower levels of Th17 lymphocytes and neutrophils in the blood.

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Patients who survive S. aureus bacteremia have higher levels of Th2 lymp...
(A) On admission (t = 0), blood was collected for complete blood cell counts with differentials, allowing eosinophil and neutrophil analysis. *P < 0.05, Mann-Whitney test. For evaluation of Th lymphocyte subsets, PBMCs were isolated from patients diagnosed with S. aureus bacteremia at 2 time points: 2–4 days and 6–9 days after positive culture. Flow cytometry was used to quantify Th subsets, which are expressed as a percentage of total CD3+CD4+CD45RO+ non-Tregs, with (B) Th2s identified as CCR4+CCR6– and (C) Th17s identified as CCR6+, among survivors and nonsurvivors (matched on sequential organ failure assessment [SOFA] score and comorbidities) at 30 days after the initial S. aureus bloodstream culture. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. *P < 0.05, unpaired Student’s t test. Sample sizes were n = 19 for surviving patients and n = 8 nonsurvivors.