|[stem-ebola] Human NK Phenotype May Impact Ebola Lethality|
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
Back to the top