Wednesday, March 25, 2020

Natural Killer to Kill or Transform?

Natural Killer cells emerge from distinct sources in embryonic development and each source of these earliest, innate immune cells confers different functions to the ascending cell lines. Fetal yolk sac, erythro-myeloid progenitor (EMP) derived NK cells, are uniquely biased for cytotoxic degranulation as opposed to inflammatory cytokine production, which are the dual hallmarks of all adult NK cells. But, parallel studies using human pluripotent stem cells (hPSCs) revealed that these progenitors can also give rise to NK cells that harbor a potent cytotoxic degranulation bias to kill.

In one of my previous articles, Natural Killer Shaping A Life I began to track processes supporting the unified origin of reproduction and immunity based on the theory of allorecognition.

Preceding implantation, the zygote divides to 16 cells that differentiate into an outer cell layer, trophoblast, and inner cell mass, embryoblast. The trophoblast becomes the fetal portion of the placenta, the embryoblast the embryo. Once differentiated into 30 cells a fluid-filled central blastocyst cavity forms. At about the 6th day of development, once it has reached nearly 100 cells the blastocyst mass begins its journey through the uterus to implant in the endometrium, which is where the embryo develops.

Yolk Sac
Implantation of the blastocyst is dependent, in part on a feto-maternal, immune handshake in which maternal NK cells of the Decidua (dNK), lining the Uterus are coerced by invading villus trophoblast cells to express cytokines that transform epithelial vascular cells in the placenta to release their binding enabling trophoblasts to replace them and  connect embryo to maternal blood supply  without rejection. This delicate phenomena is responsible for successful pregnancy. 

Following implantation, once cells of the inner embryoblast mass differentiate, only the cells of the yolk sac ultimately become the source of the NK cell of interest here. The other progenitor NK cell is sourced external to the yolk sac and that may also be basis of their functional differences.

The varied function of these dual sourced NK progenitors is transformation, as evidenced in trophoblast invasion, or killing damaged cells by cytolysis which the name "Natural Killer cell" describes. The dual source of the "killer" variety is thought to impart a WNT signaling influence over NK cell lineage. WNT-independent (WNTi-) and WNT-dependent (WNTd-) processes were found to distinguish the NK ontology. NK cells, biased toward degranulation and cell killing have been traced to the yolk sac, which remains isolated from rapidly differentiating external cells of the embryo until, over multiple weeks it gets fully absorbed.

dNK cells play an essential role in tissue and blood vessel transformation of the developing placenta. This has promoted an advanced body of thought that suggests certain tissue resident NK cells that possess some dNK characteristics may also be responsible for blood vessel transformation to accommodate new cancer or cancer stem cells that require new blood supply to develop into tumors. Therefore, cancer resident NK cells that, like dNK also express HLA-G or possess other trophoblast stem cell like characteristics may transform epithelial cells lining blood vessels in similar ways that connect fetal cells to the maternal blood supply without immune rejection.

To determine whether NK's varied ontology can shed any light on cancer cells coercing NK cells for tumor development and expansion, we identified the only three major gene expressions that are distinguished by their WNTi origin and which may inform about NK in adult mechanisms. Since our interest at Codondex is centered on p53 we correlated it with these genes:

1) NFIL3/E4bp4 transcription factor controls the commitment to NK lineage, directly regulates Eomes and ID2, which is responsible for P53 gain of function by suppressing ID2.

2) NCAM1/CD56 common NK gene is widely used to distinguish NK populations and strongly associated with p53 in multiple myeloma.

3) XBP1 a WNTi specific gene - regulates the p53/MDM2/P21 axis and is strongly present in yolk sac transcript analysis.  Unconventional splicing of XBP1 mRNA occurs in the unfolded protein response.

HLA-C is the only NK signaling molecule expressed by trophoblast cells that by a polymorphism can present variation for Adaptive immunity. Reduction of NK cytotoxicity was directly tied to the volume of Ets dependent expression from the site of the HLA-C polymorphism.  Further, Ets1, which is expressed in all NK ontologies, is necessary for a CBP/p53 transcription complex and transcription in UV-induced apoptosis in embryonic stem cells where the absence of p53 resulted in a high rate of embryonic malformations.

A possible scenario begins to emerge that near fully cytotoxic NK cells that bind HLA-KIR inhibiting and activating target cell receptors may be coerced to transcribe HLA-C, to express more inhibiting polymorphic or activating non-polymorphic transcripts, therefore greater or lesser Ets1 availability to coregulate XBP1 targets or CBP/p53 as the tipping point of degranulation and target cell killing.

Sunday, March 8, 2020

A lesson on virus, COVID-19 a.k.a Coronavirus

COVID-19 - Coronavirus
In the field of genetics I study 'transposable elements', which are tiny fragments of inactive, viral DNA that were historically inserted into and survive in the genes of cells of living organisms. It's thought that human DNA developed, in part as a result of around 8% inserted viral DNA that became fragmented and interspersed among other protein coding or regulatory DNA. Further, the function of the vast majority of our DNA is unknown, we know its there, but we don't know exactly what it is there for.

A virus like Corona is a functioning arrangement of proteins that protect not its DNA but the product of DNA, its RNA. This unique arrangement of proteins ensures the RNA's survival as code to make the proteins that protect it. The virus, its protective protein and DNA or RNA will die if exposed. So, survival is dependent on hitching a ride in an organism and freeloading in a cell where, once inserted, the virus DNA or RNA may attract that cells DNA/RNA-replication-proteins.

If the inserted sequences are attractive, they will dominate the activity of that cells replication-proteins. After being replicated many-many times over, the co-opted cell will produce the virus protein and assemble it into more viruses that will eventually kill the cell and move on to other cells where the process will repeat. The protein arrangement of a replicating virus, binds to a cell membrane before injecting its DNA or RNA into that cell. Ultimately the activity may invite immune system cells to identify, fight and kill infected cells before the virus can replicate further.

In some viral genes DNA that has become separate 'transposable elements' or fragments can lie dormant in cell genes for very long periods and their positions in the gene can change. Sometimes long sequences of a genes DNA break, when this occurs viral fragments located near proteins, attracted to recombine the break may also be assembled with other DNA that make the viral fragment more or less attractive to DNA-replication-proteins.

COVID-19 is a much more simple-recent addition. It injects not DNA, but the post DNA replication product known as RNA. This occurs after the proteins of COVID-19 connect to a human cell at least via receptor known as ACE2. If you are healthy and your immune system finely tuned, in more than 99% of cases the infected cell will be killed and virus dismantled.

COVID-19 RNA Replication and Protein Assembly
The most recent data suggests every infected person is successfully passing COVID-19 to 2.5 other people, many of whom do not express symptoms. It is quite likely COVID-19 will tail off with the rising temperatures in the northern hemisphere. In 2003 other Coronaviruses, SARS peaked in March and April and was done by May. MERS appeared in 2012, peaked in spring of 2014, and hasn't spread since then. Although Corona may already be more widespread, it is likely the panic presently being experienced around the world will subside and not re-arise in the winter of 2020/21. Since RNA viruses are less resilient that DNA viruses, I predict, Corona will disappear from our radar screens and like most "fake news" we will look back, scratch our heads and deeply consider how we should assess future events like this one.