Editors' ChoiceSepsis

Out of the frying pan into the fire: IFN-γ in post-sepsis immunosuppression

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Science Translational Medicine  25 Mar 2020:
Vol. 12, Issue 536, eabb2776
DOI: 10.1126/scitranslmed.abb2776

Abstract

Secretion of IFN-γ in sepsis contributes to post-sepsis immunosuppression and secondary candidemia.

Following acute sepsis, patients enter a period of immunosuppression and increased susceptibility to secondary infections. Candidemia—detection of Candida species in the blood—is a common and devastating sequela, with a mortality rate exceeding 50%. Although many immune cell populations including a subset of T cells termed invariant natural killer T (iNKT) cells contribute to immune dysregulation in sepsis, the fundamental mechanism of post-sepsis immunosuppression remains unknown. Reduced capacity of T cells to produce interferon-γ (IFN-γ), which plays an important role in antimicrobial immunity, has led to its consideration as an immunostimulatory agent in the setting of primary sepsis and, more recently, spawned multiple trials investigating its use to treat post-sepsis immunosuppression.

Kim et al. upend this premise. In their recent work, they demonstrate that, rather than exerting a protective effect, IFN-γ is a key mediator of post-sepsis immunosuppression. This investigation was motivated by the authors’ surprising discovery that higher levels of IFN-γ in early sepsis were associated with greater risk of secondary Candida infection. Kim et al. utilized multiple mouse models of sepsis to reveal that during sepsis, activated iNKT cells stimulate secretion of IFN-γ by natural killer cells in a mechanism mediated by mTOR (mechanistic target of rapamycin), a master regulator of growth and metabolism. This increase in IFN-γ results in impairment of macrophage phagocytic function, which is critical for clearance of infection. Importantly, inhibition of mTORC1 by the drug rapamycin during sepsis decreases IFN-γ secretion by NK cells, normalizes phagocytic function of macrophages, and improves survival of secondary candidemia.

The work of Kim and colleagues defines novel and unexpected immunosuppressive effects of IFN-γ and mTOR signaling in septic patients. The findings also identify a potential therapeutic role for rapamycin in post-sepsis immunosuppression, although the effect may not be equally as robust for all pathogens. Rapamycin seems an unlikely candidate: First developed in 1975 as an antifungal, it was subsequently discovered to have potent immunosuppressive properties and became a mainstay of antirejection therapy in organ transplant patients. Now, rapamycin may have a chance to return to its antimicrobial roots, combating secondary infections in survivors of sepsis.

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