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Re: [stem-ebola] Human NK Phenotype May Impact Ebola Lethality

Wow, thank you Vincent. I added the citations to our references page.
Best Regards,

IBM Almaden Research Center, 650 Harry Rd.
San Jose, CA 95120-6099
email: jhkauf@xxxxxxxxxx
phone: (408) 927-2477  (tie 457-2477)

From: vruslan@xxxxxxxxxxxxxx
To: stem-ebola@xxxxxxxxxxx,
Date: 10/03/2014 06:36 PM
Subject: [stem-ebola] Human NK Phenotype May Impact Ebola Lethality
Sent by: stem-ebola-bounces@xxxxxxxxxxx

Just to get some ideas out there...

Today, I dug up an interesting paper on how human genetic profile may
influence Ebola disease pathogenesis.

As many of us are aware, Ebola preferentially infects monocytes
(macrophages, etc) early in infection, and rarely infects lymphocytes
(T-cells, B-cells, NK cells).  Unfortunately, Ebola tissue tropism does
not account for the poorly understood effect of 'bystander apoptosis' --
depletion of lymphocytes -- which probably has something to do with
cytokines, chemokines, and lymphocyte gene _expression_...

In any case, the paper referenced below found that human genetic profile
for Natural Killer Cells (NK Cells) may influence Ebola disease
pathogenesis.   In particular, the presence of KIR2DS1 and KIR2DS3 (NK
Cell Immunoglobulin-like receptors) were associated with higher Ebola

Conversely, the absence of both KIR2DS1 and KIR2DS3 were associated with
apparent intrinsic resistance to Ebola Virus Disease (much lower CFR).  
To me anyway, this suggests a critical role of the intrinsic profile of
the human innate immune response... in particular, the involvement of NK
Cells.  NK Cells might be important because of their unique ability to
recognize virus-infected cells ("non-self") in the complete absence of
MHC protein flags or antibodies.

Here are four interesting ideas that might be inferred from this

1. There may be a genetic sub-set of the human population with intrinsic
resistance to EVD ("hyper-resistant phenotype").

2. There may be a genetic sub-set of the human population with intrinsic
susceptibility to EVD.

3. EVD _sub-clinical infections in humans may be higher than previously
appreciated_ (due to KIR2DS1-/KIR2DS3- population sub-groups that
sero-convert but do not report EVD illness -- where IgG cross-reactivity
is not a suitable explanation).   (see Fig 1, IgG+ column).

4. NK Cells may be involved in the EVD effect of 'bystander apoptosis'.

Here are some quotes from this fascinating paper and a reference to

"A higher proportion of non-survivors possessed the activating KIR2DS1,
whereas two non-survivors lacked the inhibitory KIR2DL1. Interestingly,
KIR2DS1 and KIR2DS3 genes were also significantly more frequent in
fatalities (46.8% and 53.3%, respectively) than in survivors (4.6% and
9.5%, respectively; Table 1), thus indicating a potential effect of
these activating KIRs in fatal outcome."

"[...] Contacts were characterized by KIR distribution that differed
from controls, survivors, and fatalities, defining a fourth category,
implying that this population results from either (1) simple exposure to
the virus (abortive infection), meaning that the KIR repertoire here
includes repertoires of both survivors and fatalities, or (2) ZEBOV
infection, then the KIR repertoire in this population contributes to an
asymptomatic, “hyperresistant” phenotype."

"An activating KIR profile was associated with fatal outcome. This
deleterious effect seems linked to KIR2DS1 and KIR2DS3 genes that were
by far more present amongst non-survivors."

"[These genes] may influence _expression_, ligand binding, cytolysis, and
cytokine secretion, as described for other KIRs (Yawata et al. 2006)."

"It is generally thought that in the context of ZEBOV infection, it is
the over-activation of the immune response that is responsible for the
rapid depletion in NK cells and lymphocytes. Our results support this
hypothesis, suggesting that the activity of KIR2DS1 and KIR2DS3, in
conjunction with the appropriate ligands, may favor the activation
status of the host's NK cells and participate in the physiopathological
process by excessively destroying infected cells."

Association of KIR2DS1 and KIR2DS3 with fatal outcome in Ebola virus
infection  (Wauquier et al, 2010).
Immunogenetics. 2010 Dec;62(11-12):767-71. doi:
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