Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza

Abstract

Transcriptional profiles and host response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole blood mRNA signatures, local and systemic immune mediator concentrations in 131 adults hospitalised with influenza from which extensive clinical and investigational data were obtained by the MOSAIC consortium. Signatures reflecting interferon-related antiviral pathways were common up to day 4 of symptoms in cases not requiring mechanical ventilatory support; in those needing mechanical ventilation an inflammatory, activated neutrophil and cell stress/death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but could enhance its development, while attenuating the early ‘viral’ signature. Our findings emphasise the importance of timing and severity in the interpretation of host responses to acute viral infection, and identify specific patterns of immune activation that may enable the development of novel diagnostic and therapeutic tools for severe influenza.

Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

“…Similar to influenza, severe cases of COVID-19 are associated with massive alveolar damage and progressive respiratory failure (54), and SARS-CoV-2 has been shown to induce expression type I and III IFNs in primary human AEC cultures (55). In addition, histopathological Attempts to gain a better understanding of human influenza pathogenesis have largely been restricted to whole blood expression analysis (61)(62)(63), and therefore exclude localised immune and epithelial repair responses in lung tissues (64). However, macaques infected with the highly virulent 1918 H1N1 strain, revealed an elevated ISG signature late during infection bronchial tissue (65).…”

Microarray Gene Expression Dataset Re-Analysis Reveals Variability in Influenza Infection and Vaccination

“…Although there are similarities in both figures, some key differences in expression are observed in genes connected with high fever (IL-1 and IL-6). Studies have shown elevated levels of IL-1β and IL-6 following infection with influenza A (45, 46).…”

“…Additionally, we compared our biologically significant gene list for influenza infection (978 genes) to Dunning et al,who identified whole blood RNA signatures in hospitalized adults with influenza. Their findings indicated that genes involved in interferon-related pathways were activated at the start of the infection and by day 4 had started to decrease with a shift in inflammatory and neutrophil related pathways (46). Our findings also indicate enrichment for neutrophil related pathways in the case of influenza infection.…”

COVID‐19: Lessons from SARS and MERS

“…It may also be possible to enhance the protective host immune response to infection, or inhibit immunopathogenesis (which is thought to contribute to disease severity for some respiratory pathogens). In particular, 'cytokine storms' are thought to be major contributors to the severity of many lower respiratory tract infections, such as influenza [20] and SARS [21]. Host-targeted therapies might therefore be aimed at either enhancement of innate immune clearance of SARS-CoV-2 or inhibition of inflammatory damage to the airway and the development of secondary bacterial pneumonias.…”