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KLRD1-expressing natural killer cells predict influenza susceptibility
Genome Medicine
December 2018, 10:45 | Cite as
KLRD1-expressing natural killer cells predict influenza susceptibility
AuthorsAuthors and affiliations
Erika BongenFrancesco VallaniaPaul J. UtzPurvesh Khatri
Open Access
Research
First Online: 14 June 2018
Received: 28 February 2018
Accepted: 24 May 2018
109 Shares 1.8k Downloads
Part of the following topical collections:Genomics of Infection and Immunity
Abstract
Background
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. Biomarkers predicting influenza susceptibility would be useful for identifying risk groups and designing vaccines.
Methods
We 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.
Results
Natural 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.
Conclusions
We 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.
KeywordsInfluenza Natural killer cells Hematopoietic stem and progenitor cells KLRD1 CD94
Abbreviations
FDR
False discovery rate
GEO
Gene Expression Omnibus
HPC
Hematopoietic progenitor cell
HRV
Human rhinovirus
HSC
Hematopoietic stem cell
HSPC
Hematopoietic stem and progenitor cell
mDC
Myeloid dendritic cell
NCBI
National Center for Biotechnology Information
NK
Natural Killer
RSV
Respiratory syncytial virus
SEM
Standard error of mean
Electronic supplementary material
The online version of this article ( https://doi.org/10.1186/s13073-018-0554-1) contains supplementary material, which is available to authorized users.
Background
Influenza is a major public health problem that causes 9 to 35 million illnesses annually in the USA [1]. Children, older adults, pregnant women, and immunocompromised patients are at an increased risk of influenza infection. Within healthy young adults, influenza susceptibility is difficult to predict as responses to influenza exposure vary from no detectable infection to severe disease. A better understanding of the immune determinants of influenza susceptibility is necessary to identify novel high-risk populations and design better vaccines.
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. Infected individuals fall into four groups: symptomatic shedders, asymptomatic nonshedders, symptomatic nonshedders, and asymptomatic shedders. 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 predictors for infection [6]. However, to our knowledge, no cellular or transcriptional signatures that can predict infection susceptibility prior to inoculation have been reported.
Relatively little work has been done examining how preexisting immune cell populations affect influenza susceptibility. Wilkinson et al. demonstrated in an H3N2 influenza challenge study that higher baseline levels of influenza-specific CD4+ T cells in the blood were associated with reduced viral shedding and less severe symptoms [7]. Sridhar et al. followed healthy adults during two consecutive flu seasons and found that adults with higher baseline l (...truncated)