Pathway mapping of leukocyte transcriptome in influenza patients reveals distinct pathogenic mechanisms associated with progression to severe infection

Yoann Zerbib,Anthony Mclean,Adrienne F A Meyers,Yoav Keynan,Klaus Schughart,Benjamin M Tang,T Blake Ball,Maryam Shojaei,Marek Nalos,Amarnath Pisipati,Aseem Kumar,Anand Kumar,John Ho,Emily K Jenkins

doi:10.1186/s12920-020-0672-7

Abstract

BackgroundInfluenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death. The host-response pathways associated with the progression to severe influenza disease are not well understood.MethodsTo gain insight into the disease mechanisms associated with progression to severe infection, we analyzed the leukocyte transcriptome in severe and moderate influenza patients and healthy control subjects. Pathway analysis on differentially expressed genes was performed using a topology-based pathway analysis tool that takes into account the interaction between multiple cellular pathways. The pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza.Results107 patients (44 severe and 63 moderate influenza patients) and 52 healthy control subjects were included in the study. Severe influenza was associated with upregulation in several neutrophil-related pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (NET) formation. The degree of upregulation in neutrophil-related pathways were significantly higher in severely infected patients compared to moderately infected patients. Severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation such as CD4+ T-cell co-stimulation, CD8+ T cell and Natural Killer (NK) cells effector functions. Apoptosis pathways were also downregulated in severe influenza patients compare to moderate and healthy controls.ConclusionsThese findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection.

Highlights

Influenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death
Two physicians independently assigned the patients to groups, based on the following criteria (1) whether mechanical ventilation was used, (2) that influenza virus was confirmed on PCR of airway samples, (3), that the clinical features are consistent with influenza illness
Clinical data One hundred seven patients were recruited with laboratory-confirmed influenza infection (either nasopharyngeal swab or bronchoalveolar lavage (BAL))

Summary

Introduction

Influenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death. The host-response pathways associated with the progression to severe influenza disease are not well understood. Circulating leukocytes have been identified as the main host factors linked to infection severity, as revealed by transcriptomics studies [11,12,13]. Transcriptomics studies capture global gene-expression changes expressed by circulating leukocytes and findings from these studies showed that influenza host response displayed distinctively changes across the full range of mild, moderate and severe infection [12,13,14,15,16]. Transcriptomics studies provide gene-level analysis; they offer limited insight into the underlying biological pathways affected by influenza infection. A pathway-level analysis approach will be more informative since it provides a considerably greater amount of biologically relevant information and will allow a better understanding of the pathogenic mechanisms linked to disease progression

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