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

[vruslan@xxxxxxxxxxxxxx]

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 
lethality.

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 
paper...

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 
it...

"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."

source:
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: 
10.1007/s00251-010-0480-x
http://www.ncbi.nlm.nih.gov/pubmed/20878400
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978320/