title: Aberrant cell cycle and apoptotic changes characterise severe influenza A infection--a meta-analysis of genomic signatures in circulating leukocytes.
abstract: Influenza A infection is a global disease that has been responsible for four pandemics over the last one hundred years. However, it remains poorly understood as to why some infected individuals succumb to life threatening complications whilst others recover and are relatively unaffected. Using gene-expression analysis of circulating leukocytes, here we show that the progression towards severe influenza A infection is characterised by an abnormal transcriptional reprogramming of cell cycle and apoptosis pathways. In severely infected humans, leukocyte gene-expression profiles display opposing cell cycle activities; an increased aberrant DNA replication in the G(1)/S phase yet delayed progression in the G(2)/M phase. In mild infection, cell cycle perturbations are fewer and are integrated with an efficient apoptotic program. Importantly, the loss of integration between cell cycle perturbations and apoptosis marks the transition from a mild viral illness to a severe, life threatening infection. Our findings suggest that circulating immune cells may play a significant role in the evolution of the host response. Further study may reveal alternative host response factors previously unrecognized in the current disease model of influenza.
authors.affiliation: Department of Intensive Care Medicine, Western Clinical School, Nepean Hospital, University of Sydney, New South Wales, Australia. gpar3109@uni.sydney.edu.au
authors.forename: Grant
authors.initials: G
authors.lastname: Parnell
authors.forename: Anthony
authors.initials: A
authors.lastname: McLean
authors.forename: David
authors.initials: D
authors.lastname: Booth
authors.forename: Stephen
authors.initials: S
authors.lastname: Huang
authors.forename: Marek
authors.initials: M
authors.lastname: Nalos
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tang
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D007251:Influenza, Human / Q000235:genetics* / Q000276:immunology / Q000473:pathology* / Q000821:virology; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D055815:Young Adult