Intraabdominal Polymicrobial Sepsis Suppresses Interferon Responses in Immune Cells

Author(s):
Haotong Zhang; Da Tang; Jennifer Darby; Alyssa Gregory; Thomas Walko; Timothy Billiar

Background:

Interferon (IFN) responses in immune cells are suppressed after bacterial sepsis, burns, and trauma. There have been multiple clinical trials, but the IFN applications didn’t appear efficient in improving septic patients’ outcomes. While it has been assumed that this is due to impaired IFN release, recent transcriptomic studies from our group and others suggest that IFN signaling may be suppressed during sepsis.

Hypothesis:

We tested the hypothesis that bacterial sepsis leads to impaired IFN responsiveness in immune cells.

Methods:

C57/Bl6 mice were treated with LPS (iv 5mg/kg, n=4/group) or subjected to cecal ligation and puncture (CLP, n=4/group). Peripheral Blood Mononuclear Cells (PBMC) and Bone Marrow Mononuclear Cells (BMMC) were isolated at 6 or 30hr and subjected to single-cell RNAseq. Other cells were placed in culture and exposed to Type I or Type II IFN ex vivo for 18 hours. These cells were then isolated and subjected to transcriptomic analysis.

Results:

Consistent with previous reports, LPS treatment resulted in the up-regulated IFN-responsive genes based on RNAseq analysis. Leukocytes isolated from mice subjected to CLP exhibited suppressed IFN transcriptomic responses. Cultured BMMC from CLP-treated mice exhibited suppressed responses to IFNs compared to controls (p<0.05 vs. cell from control mice).

Conclusions:

The results of these experiments demonstrate that IFN responses are insult-specific and that IFN responses in immune cells are suppressed during CLP sepsis. Therefore, the mechanisms leading to alterations in IFN signaling during bacterial sepsis are likely to be multi-factorial and include changes in the responsiveness of immune cells to exogenous IFN.