KLRD1 : A Biomarker For Predicting Influenza Susceptibility?

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When we talk about  about `high risk’ influenza patients, it is generally where their age and/or co-morbidities (COPD, Asthma, pregnancy, etc. ) can lead to a greater chance of infection and/or complications. 

But there may be other factors at work as well.

In the past we've looked at some fascinating research on the role of host genetics and certain biomarkers that might determine whether certain people are more (or less) susceptible to severe influenza infection than others.

In 2008, in the Journal of Infectious Diseases, we saw a study that suggested there might be a heritable susceptibility to death from the influenza virus:

Evidence for a heritable predisposition to death due to influenza.

Albright FS, Orlando P, Pavia AT, Jackson GG, Cannon Albright LA.

While interesting, that study didn’t provide us with a smoking gene.

In 2009 (see The Best Defense) we inched a bit closer, with research from Harvard Medical School and the Howard Hughes Medical Institute, that identified the IFITM3 protein as capable of inhibiting the replication of influenza, and other viruses, such as West Nile and Dengue. 

We revisited the IFITM3 story again in early 2012, in Luck Of The Draw, when we looked at research from the Wellcome Trust Sanger Institute, that found that people who carried a particular variant of the IFITM3 gene - (SNP rs12252-C) - were more likely to be hospitalized with severe influenza

In 2013, a study by Professor Peter Doherty (see PNAS: Genetic Marker & Cytokine Levels Linked To Severity Of Human H7N9 Infection) linked IFITM3 CC gene variant (aka C/C Genotype)  to hypercytokinemia (aka a `Cytokine Storm’), and severe outcomes in H7N9 infections.

This genetic marker– while comparatively rare in Caucasians - is far more common in Han Chinese, and may (partially) account for some of the particularly high mortality rates we’ve seen with novel influenza’s in Asia. 

And in 2015, in A Genetic Predisposition To Severe Flu Infection, we looked at a study published in Science Express that identified yet another (rare) genetic marker -  a mutation of the IRF7 gene -  linked to a lack of interferon production which can lead to a more severe influenza infection.

And just last year, in New IFITM3 Genetic Marker May Help Identify High Risk Flu Patients, researchers from St. Jude Children's Research Hospital  found patients who carried a particular inherited variation in the  IFITM3 gene were `more than twice as likely to develop severe, life-threatening flu symptoms as those who carried the protective version of the gene'.

As you can see, there are multiple avenues of inquiry into host susceptibility to influenza infection, and while progress continues to be made, the final answer is unlikely simple or even limited to one gene.

To this growing list we can add a new study, published today in Genome Medicine by researchers at Stanford University, that identifies a gene called KLRD1 as a potential biomarker for influenza susceptibility.

First a snippet from the press release, and then a link to the open-access study.

Stanford scientists discover biomarker for flu susceptibility

Scientists at Stanford are believed to be the first to have discovered a biomarker that can predict who will be most susceptible to influenza.

Jun 13 2018

Researchers at the Stanford University School of Medicine have found a way to predict whether someone exposed to the flu virus is likely to become ill.

Purvesh Khatri, PhD, associate professor of medicine and of biomedical data science, and his team used a computational approach to pinpoint a blood-based genetic biomarker to determine an individual’s susceptibility to the disease.

“We’ve been after this for about four years,” Khatri said. “To our knowledge, it’s the first biomarker that shows susceptibility to influenza, across multiple strains.”

The biomarker is a gene called KLRD1, and it essentially acts as a proxy for the presence of a special type of immune cell that may be a key to stamping out nascent flu infection. Put simply: the more of this cell type found in a person’s blood, the lower their flu susceptibility. The research even hints at new avenues for pursuing a broadly applicable flu vaccine.

A paper describing the work will be published online June 14 in Genome Medicine. Khatri is the senior author. Graduate student Erika Bongen is the lead author.

(Continue . . . )

The actual study is lengthy, at times technical, and far too complex to summarize here.  The abstract provides the gist, but you'll probably want to follow the link to read it in its entirety.

When you return I'll have a short postscript.

KLRD1-expressing natural killer cells predict influenza susceptibility

Erika BongenView ORCID ID profile,  Francesco Vallania, Paul J. Utz and Purvesh KhatriEmail author
Genome Medicine201810:45

https://doi.org/10.1186/s13073-018-0554-1

© The Author(s). 2018

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.

(Continue . . . )

Like all research, this study was subject to a number of limitations (see below), and so the findings - while impressive -  may not be quite as clear cut as the lede of the press release would suggest. 

As the conclusion of the abstract states, they identified `KLRD1-expressing NK cells as a potential biomarker for influenza susceptibility.'

Press releases, after all, do tend to emphasize the positives.  From the DISCUSSION section of the study. 

        (Snippet)

Our study was limited due to our dependence on publicly available challenge study data. Arguably, the number of samples in the challenge studies used here were low. A post hoc statistical power analysis indicated we had sufficient power to detect NK cell and HSPC immune cell proportion differences [38]. We only included symptomatic shedders and asymptomatic nonshedders in our analysis. It is unclear whether our results are applicable to symptomatic nonshedders and asymptomatic shedders. Participants across all challenge studies were healthy young adults. Our results may not be applicable to children or the elderly and need to be investigated in these groups. Furthermore, we only had access to transcriptomic data. Additional studies should confirm whether symptomatic shedders have lower proportions of NK cells at baseline and whether high expression of KLRD1 in the blood directly correlates with greater numbers of CD94+ NK cells via flow cytometry.

While I suspect we are still a long way from knowing all of the gene variants and  biomarkers linked to influenza susceptibility, researchers continue to expand their watch list, and more importantly, their understanding of how they work.