KLRD1-expressing natural killer cells predict influenza susceptibility

Genome Medicine, Jun 2018

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.

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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)


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Erika Bongen, Francesco Vallania, Paul J. Utz, Purvesh Khatri. KLRD1-expressing natural killer cells predict influenza susceptibility, Genome Medicine, 2018, pp. 45, Volume 10, Issue 1, DOI: 10.1186/s13073-018-0554-1