Post-sepsis immunosuppression as an indication for Interferon therapy.
Link to the original paper in Nature Immunology
Patients in intensive care are well documented to suffer severe immunosuppression at the time of sepsis; these patients tend to have persistent immunosuppression leading to secondary infections. The pathobiology behind this is less well studied- a gap the Nature Immunology paper addressed. Their findings reveal a compelling narrative:
Stage 1. The First Assault (Hyperinflammation):
-Healthy volunteers received intravenous LPS (2 ng/kg), inducing acute hyperinflammation. This was confirmed by clinical symptoms (fever, tachycardia) and increased circulating cytokines (TNF, IL-10, IL-6) up to 8 hours post-LPS.
-Single-cell RNA sequencing (scRNA-seq) of blood and bone marrow leukocytes identified a distinct inflammatory CD163+SLC39A8+CALR+ monocyte-like subset ("infMono") at 4 hours post-LPS.
-InfMonos showed increased pro-monocyte gene expression (e.g., RETN, ALOXSAP) and reduced mature monocyte markers (MHC-II genes). This indicated new, immature monocytes emerging in bone marrow and peripheral blood.
-Non-negative matrix factorization (NMF) defined an infMono-specific gene program (inflammatory, heat shock, IFN response, immature pro-monocyte genes).
-A distinct IFN-I responsive gene program (e.g., MXI, IRF1, ISG15) was induced in T cells and NK cells, termed inflammatory T cells (Tinf cells).
Crucially, these infMono and Tinf cell gene programs were significantly enriched in early bacterial sepsis and severe COVID-19 patients, respectively, highlighting clinical relevance.
Stage 2. The Lull and Lingering Weakness (Immunosuppression):
-Seven days post-LPS, the late immunosuppressive phase featured diminished IFN-responsive gene expression in monocytes and impaired myelopoiesis. This significantly reduced immune reactions, encompassing cytokine generation, to a subsequent LPS challenge.
-Impaired monocyte maturation, particularly loss of intermediate (iMonos) and nonclassical (ncMonos) monocytes, mirrored late-phase sepsis and COVID-19 patients. Critically, IFN-I signaling was significantly impaired.
Stage 3. A Glimmer of Hope (Therapeutic Potential): IFN-beta (IFNß) treatment restored type-I IFN responses and proinflammatory cytokine production (TNF, IL-6) in previously immunosuppressed monocytes ex vivo. IFNß also induced classical monocyte maturation towards iMonos in vitro, suggesting a potential therapy for reversing immunosuppression.
So What? Interferon therapy may help reduce the duration of immunosuppression following sepsis or other severe inflammatory insults by restoring the 'cytokine homeostasis'.
https://lnkd.in/gx5cUdca