Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome

Abstract

Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over- or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator- and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes.

Characterizing a focused landscape of familial acute respiratory distress syndrome

“…Our data also confirm the presence of shared pathways with group A and GP7 enriched gene subsets, including many implicated in lung pathogenesis such as airway pathology, acute phase response signaling, and hepatic fibrosis. These findings are in line with current information on ARDS from the available curated literature genes [26,[45][46][47][48][49][50].…”

“…A better understanding of these key temporal and topographic processes may contribute to advance diagnostic and prognostic biomarkers and effective therapies [7,[20][21][22]. Genome sequencing studies on ARDS have concentrated on identification of plasma biomarkers that may facilitate diagnosis of ARDS which could, in theory, improve clinical care, enhance our understanding of pathophysiology, and be used to enroll more homogeneous groups of patients in clinical trials of new therapies, increasing the likelihood of detecting a treatment effect [2,[23][24][25][26][27][28].…”

ETV7 limits antiviral gene expression and control of SARS-CoV-2 and influenza viruses

“…It is appreciated that negative regulators of the IFN response are required to prevent extreme and prolonged immune responses, which are associated with poor disease outcomes after infection (80)(81)(82). ETV7 potentially contributes to the cumulative activities of negative IFN regulators to limit IFN responses during pathogen clearance.…”

The Impact of the Interferon/TNF-Related Apoptosis-Inducing Ligand Signaling Axis on Disease Progression in Respiratory Viral Infection and Beyond

“…Interestingly, Beilharz et al (77) demonstrated that application of low doses of IFN-α reduces viral load, which to a certain degree led to attenuated disease progression, whereas high dose application of type I IFN contributed to morbidity (77). In line, high expression levels of ISGs have been shown to correlate to worse outcomes in ARDS patients (78). This observation corresponds to reports stating that the IFN threshold needed to induce antiviral ISGs-showing a beneficial effect in acute respiratory viral infection-is by at least 10-fold lower than the IFN dose necessary to trigger ISGs that show immunomodulatory, death-inducing, or anti-proliferative effects and thus can contribute to disease progression (79)(80)(81)(82).…”