Abstract
BackgroundInfluenza infects tens of millions of people every year in the USA. Other than notable risk groups, such as children and the elderly, it is difficult to predict what subpopulations are at higher risk of infection. Viral challenge studies, where healthy human volunteers are inoculated with live influenza virus, provide a unique opportunity to study infection susceptibility. Biomarkers predicting influenza susceptibility would be useful for identifying risk groups and designing vaccines.MethodsWe applied cell mixture deconvolution to estimate immune cell proportions from whole blood transcriptome data in four independent influenza challenge studies. We compared immune cell proportions in the blood between symptomatic shedders and asymptomatic nonshedders across three discovery cohorts prior to influenza inoculation and tested results in a held-out validation challenge cohort.ResultsNatural killer (NK) cells were significantly lower in symptomatic shedders at baseline in both discovery and validation cohorts. Hematopoietic stem and progenitor cells (HSPCs) were higher in symptomatic shedders at baseline in discovery cohorts. Although the HSPCs were higher in symptomatic shedders in the validation cohort, the increase was statistically nonsignificant. We observed that a gene associated with NK cells, KLRD1, which encodes CD94, was expressed at lower levels in symptomatic shedders at baseline in discovery and validation cohorts. KLRD1 expression in the blood at baseline negatively correlated with influenza infection symptom severity. KLRD1 expression 8 h post-infection in the nasal epithelium from a rhinovirus challenge study also negatively correlated with symptom severity.ConclusionsWe identified KLRD1-expressing NK cells as a potential biomarker for influenza susceptibility. Expression of KLRD1 was inversely correlated with symptom severity. Our results support a model where an early response by KLRD1-expressing NK cells may control influenza infection.
Highlights
Influenza infects tens of millions of people every year in the USA
Hematopoietic stem and progenitor cell (HSPC) proportions decrease in nasal epithelium over the course of rhinovirus challenge and correlate with increases in myeloid dendritic cell (mDC) and M1 macrophage proportions To study the presence of HSPCs at the site of infection, we examined HSPC proportions from nasal scrapings of human volunteers inoculated with human rhinovirus (HRV) (GSE11348) [22]
We found that KLRD1 expression correlated with expression of cytotoxic granule-associated genes, suggesting that higher KLRD1 expression may correlate with increased proportions of cytotoxic immune cells
Summary
Influenza infects tens of millions of people every year in the USA. Other than notable risk groups, such as children and the elderly, it is difficult to predict what subpopulations are at higher risk of infection. Viral challenge studies, where healthy human volunteers are inoculated with live influenza virus, provide a unique opportunity to study infection susceptibility. Influenza susceptibility is difficult to predict as responses to influenza exposure vary from no detectable infection to severe disease. Human influenza challenge studies provide a unique opportunity to study influenza susceptibility. In these studies, healthy individuals are inoculated with live influenza virus, and viral shedding titers and self-reported symptom scores are measured over the course of infection. Previous challenge studies have used transcriptional data to distinguish symptomatic shedders from asymptomatic nonshedders post-infection [2], detect infection prior to symptom onset [3], develop transcriptional signatures of symptom status [4, 5], and prototype individualized
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