p53 in the SARS-CoV2 Storm

Coronavrius induced cytokine storm

A massive simulation and analysis using the supercomputer at Oakridge led scientists to more accurately identify the general idea that a Covid19 induced "cytokine storm" is responsible for disease progression. After detailed genetic analysis they specifically predicted that Bradykinin (BK) initiated the storm. If correct, this would help improve treatment directions for admitted patients. 

BK receptors are coded by BDKRB1 and BDKRB2 (BK2) gene's that operate in a kallikrein-kinin system (KKS), like the Renin Angiotensin System (RAS) as another potent regulator of blood pressure. BK is a part of the vasopressor system that induces hypotension and vasodilation, it is degraded by ACE and enhanced by angiotensin1-9, which is produced by ACE2 the receptor that SARS-COV2 binds. BK has been implicated as being active in the metabolic response to stress.

Similar to angiotensin peptides, BK is produced from an inactive pre-protein kininogen through activation by serine protease kallikrein (KKL). KLK1-KLK15 are mostly represented as a cluster of serine proteases on chromosome 19, with different tissue distributions. 

KLK's 1-15 further evidence a convergence on chromosome 19, associated closely with a large number of genes involved in blood pressure. KLK's are located at 19q13.41, an active transposon region with a 2x background deletion rate clustered near Zinc Fingers and KIR's (Killer cell like receptors). Chr19 is also associated with MHC precursors around which innate immunity and Natural Killer (NK) cell signaling developed. A link was confirmed in mice uterine NK cells that regulated local tissue blood pressure by at least Angiotensin Type 1 Receptor (AT1R) partly in response to mechanical stretch of vasoconstriction and vasodilation induced by uterine NK's internal RAS. 

A study of BK2 confirmed a conserved p53 binding site (rat, mouse and human) and p53-mediated activation of the BK2 promoter was augmented by transcriptional co-activators, CBP/p300. The results demonstrated BK2 promoter as a target of the p53-mediated activation and suggested a new physiological role for p53 in the regulation of G protein-coupled receptor (GPCR) gene expression. 

A follow up study, by the same group explained that Angiotensin II (AngII), the product of Angiotensin-Renin-Angiotensin1-Ace stimulates the phosphorylation of p53 (on serine 15) and CREB (on serine 133), and that AngII signaling converges on the p53-CRE enhancer to stimulate BK2 gene transcription.  

The convergence revealed that AT1R signaling activated CREB phosphorylation and in vivo assembly of p-CREB on the BK2 promoter in conjunction with histone hyperacetylation. It confirmed that AngII stimulates BK2 gene transcription in IMCD3 cells via AT1R. Thus, under conditions of augmented AngII and AT1R signaling, BK expression will be enhanced, thereby maintaining a balance of these two powerful counter-regulatory systems representing a novel form of cross-talk between GPCR's that link RAS and KKS, crucially here via p53.

This combined research indicates that activation of BK2 on endothelial cells, which is mediated by p53 dependent RAS-KKS cross-talk may also implicate AT1R on NK cells to secrete growth disrupting or growth promoting factors in response. SARS-CoV2 bound to ACE2 reduces its availability to convert angiotensin 1 to angiotensin 1-9, which normally enhances BK. The resulting imbalance and increase in circulating angII may directly implicate a NK cells' AT1R RAS response to a CoV2-ACE2 bound cell with disabled p53 promoter of GPCR expression. This cell with a crippled BK2 KKS, hypotension-vasodilation response offers no counter to the the AngII induced NK RAS vasoconstrictive function, affecting local tissue blood pressure thus failing to become a NK target. 

The Cancer Effect On P53 and Natural Killer Cells

Naked Mole Rat Without NK Cells

New evidence elucidated the mechanisms of growth promoting and disrupting modes of Natural Killer (NK) cells especially in Tumor Micro Environments (TME). In a previous article on cancer exploiting modes of reproduction I explained that NK cells have an innate capacity to effect reproduction during the early stages of Blastocyst implantation and placental development. These include NK cells secreting growth promoting factors and near simultaneous disruption of epithelial cells lining spiral arteries, that penetrate the decidua to expose maternal blood to extravillous cytotrophoblasts of the developing fetal placenta.

Extravillous cytotrophoblast invasion involves a cellular transition from an epithelial to mesenchymal phenotype. Villous cytotrophoblasts undergo a partial epithelial to mesenchymal transition (EMT) when differentiating into extravillous cytotrophoblasts and gain the capacity to migrate and invade. 

An antagonistic relationship between transforming growth factor (TGF)-β and tumor necrosis factor (TNF)-α provides a glimpse into cancers influence over NK cells to permit and promote survival, extravasatation and metastasis. Multiple studies report synergism between TGF and TNF in EMT to cancer. Spatiotemporal regulation of DeltaNp63 by TGF regulated miRNAs is essential for cancer metastasis and the interplay between different p63 isoforms, related mutant p53 proteins, and p53 family members can largely determine overall anti-metastatic activity.

Mutant p53 that is co-expressed with WT p53 in human bronchial epithelial cells inhibits the response of  cancer cells to TGF. However, overexpression of mutant p53 on a p53-null background is able to attenuate the response to TGF. Mutant p53 is also implicated is chronic inflammation, a well-accepted hallmark of cancer. Numerous studies showed that the TME has a significant impact on perpetuation of the chronic inflammatory state. Mutant p53 is able to enhance the activation of NF-κB by TNFα, while concomitantly suppressing the pro-apoptotic effect of TNFα, which leads to increased invasiveness of the cancer cells. 

Blockade of TNF improved NK cell activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia. Rats with depleted NK cells had decreased serum and placental levels of TNF support that NK cells secrete TNF, indicating an autocrine effect. Additionally findings suggest that elevated decidual TGF suppresses the activation of specific subsets of decidual NK cells which in turn contributes to pathology associated with the onset of preeclampsia. A study looked at the cytokine profile of NK cells in early human pregnancy including TGF  and TNF and found two highly specific NK cells in peripheral blood and decidua were most likely responsible for maintenance of pregnancy by regulation of maternal immune function. 

The cancer resistant Naked Mole Rat possess no NK cells, but has a stable p53 half-life more than 10X  that found in human and mouse embryonic fibroblasts. The stability of p53 was determined to result from protein extrinsic factors yet response to DNA damage was classic, via p53 sequestration from nucleus to cytoplasm. How mole rats reproduce without decidual NK cells is an open question? p53 stability may have demoted a need for the mammalian equivalent of allorecognition at the site of Blastocyst implantation. The need for the maternal-fetal decidual NK cell mediation may have been replaced by more direct mechanisms. One option is via pheromone sensing. 

p53 and two related transcription factors p63 and p73 exhibit significant sequence similarity, can bind to the same consensus sites in DNA and activate the same target genes. However, unlike p53, with a paramount role in cancer suppression, p63 and p73 play more central developmental roles. p63 and p73 nullizygosity results in lethality, but p73-nullizygosity also causes pheromone-sensing defects that impede breeding.

Increasingly evidence points to the intricate interplay of p53, its related proteins and NK cells as primary targets for reproductive success and reducing death through cancer.

Oil and Water and Cellular Function

Genetic DNA are single acid nucleotide's stringed along a sugar-phosphate spine that winds around proteins, called histones and collapses into a chromosome assembly. At specific 'gene' locations DNA are often unwound and replicated into smaller, related RNA strings that can be incorporated by clustered proteins to attract and assemble amino acid combinations that may fold into functional proteins. Aqueous proteins aggregate in complex units and interact with DNA, RNA, amino acids and other proteins to build life on planet earth. 

Entropy can disrupt the order of liquid-liquid phase separation (LLP) and other density based separations that govern events effecting DNA and are central to cellular bio-physics. Since the discovery of DNA in 1869 and its double helix structure in 1953, research has been directed to decipher the vast string assemblies of billions of these ordered acid combinations that govern cells of different species. Recently research has more beautifully described how orders of short repeating DNA sequences govern cellular mechanics and provides insight to the delicate balance in aqueous separations.

Chromosomes of cells that divide and replicate are tethered via centromere including concentrated short, ordered DNA combinations repeated at extending distances along the sugar-phosphate spine. They attract proteins and other epigenetic factors that may direct the cells centrosome - a protein tube geared to a vast cytoskeleton spindle to move chromosomes and the cells skeletal structure in response to activity on its centromere and distant regions.

Intron regions of genes are considered regulatory since exons or DNA coding regions, when replicated into RNA exclusively translate combinations of amino acids for protein. The intron regions of yeast centromeres were found to promote formation of centromeric heterochromatim - DNA wound around histones and methylated to repress regions and maintain lineage during replication. 

A study of centromere heterochromatin surprisingly showed that distant euchromatic regions enriched in repressed methylated genes also interacted with the hierarchical organization of centromeric DNA. These 3D spacial interactions are likely mediated by LLP (similar to how oil and vinegar separate in salad dressing), resulting liquid-like fusion events and can influence the fitness of individuals. Repressed gene's were identified as Transposable Elements (TE's), sequences often associated with pathogenic DNA insertions that have been persistently retained.  

A study found 96.3% of TEs enriched in 156 gene bodies overlapped introns, in line with the normally observed distribution of introns and exons in the human genome. Across cells in different tissues, genes that are consistently replicated are less likely to be associated with TE's. Multiple TE's in tissue-specific, active regulatory regions are enriched in intron enhancer sequences to attract and bind protein transcription factors as master replication regulators.

TE's have mostly been analyzed by the frequency of short identical repeating sequences, but methods have not revealed the full extent of the TE repeat hierarchy. When any part of TE's are replicated and released from their sugar-phosphate spine the hierarchy of repeats may effect dissociation. Codondex built a uniform analytic to tease out the inherent hierarchy of repeating sequences that may expose separation potential whether or not the DNA is classified as a TE.  

As outlined, repressed DNA regions with more frequent repeats are less actively replicated into RNA. Therefore, actively transcribed regions yield more RNA for coding proteins and edited intron RNA can accumulate to concentrate in the liquid nucleus, be transported to the cytoplasm or be degraded. A cell's machinery must be finely tuned to process the RNA remnant of DNA replication, but mutations and aberrant separations can disrupt the order of these finely tuned micro-organisms. 

If repeats define a universal separation hierarchy that is heavily weighted toward regulatory introns then de novo chromosome and gene repeat analysis may identify distant and centromeric influences to the centrosome. The iScore(TM)  algorithm repeatedly explodes any DNA or RNA string into its ordered, theoretical hierarchy of repeats until the smallest required string length and may provide a structural basis for liquid separations. A repeat-hierarchy, for any gene would have to also relate to its chromosome repeats for inherent, universal influence over 3D spacial interaction and potentially cell function.

The complete record of repeats for an average length gene explodes to 100,000,000+ ordered strings representing its iScore signature. If a repeat hierarchy does exit for aqueous aggregations, a gene transcripts' intron iScore should be sufficient to measure and compare its inherent repeat potential to other transcripts. Significant consecutive iScore variations with any of the 100,000,000+ strings could be used to expose systemic, structural separation differences for that transcript in context of other transcripts in their aqueous environments. 

Blood Pressure by Natural Killer Cells and SARS-CoV2

A meta-analysis of gene expression signatures for diastolic, systolic blood pressure and hypertension found that out of 7717 unique, related genes 34 were most differentialy expressed across 7017 individuals from 6 international studies. No less than 20% of the 34 gene's, were located on Chromosome 19. Enrichment analysis for the diastolic and systolic gene group's associated to Natural Killer (NK) Cell mediated cytotoxicity and 13 other pathways including antigen processing and inflammatory response, pointing strongly to innate and adaptive immunity. 

I covered the NK origin of MHC and antigen immunity and reproduction at Chromosome 19 on a previous blog, now the meta-analysis adds infection, immunity and blood pressure to this location. Evolutionary detectives tracked events from Chromosome 19 to 1,6 and 9 via transposon re-combination events, which provided further direction for interpreting the blood pressure meta-analysis. A review of the genes and pathways involved increasingly characterized innate immunity as an integrated core component of almost every aspect of our skeletal, circulatory, tissue and neuronal systems. 

Blood pressure is enormously complex, but its governance of entropy under the mechanical laws of molecular diffusion and disassociation reign supreme. Renin-Angiotensin (RAS) genes are widely recognized to be the cornerstones needed for blood pressure. Innate immune cells including NK have been confirmed to possess and express RAS genes. Macrophages, a member of innate immune system have been linked to angiotensin signaling neuropathic pain as well as bacterial infection inducing pain suppression by angiotensin 2 receptor (AT2R).  Maternal NK cells AT1R and AT2R have been implicated in the control of localized blood pressure in placental tissues leading to preeclampsia a condition in pregnancy.

In various studies, including in disease conditions it has been shown and suggested that different male:female ratios between AT1R and AT2R in monocytes and other innate cells is an important factor in the determination of blood pressure that has been extensively studied in heart and lung conditions. AT2R plays a critical role in satellite cell differentiation and skeletal muscle regeneration via myoblasts, which may be the reason it's expressed ubiquitously in developing fetal tissue. It's likely that balance between AT1R and AT2R signaling is critical for normal muscle regeneration.  

In addition to the role of NK cells in blood pressure a study using lung-intravital microscopy linked pulmonary NK cells to the control of neutrophil intravascular motility, response to acute inflammation and diminished pathogenic accumulation. NK cell derived IFN-γ plays an important role in the activation and maturation of monocytes into macrophages and dendritic cells, an amplifying mechanism in the early innate inflammatory response. Angiotensin II can induce rapid neutrophil infiltration via AT1R that also stimulates leucocyte–endothelium interactions. Inhibited IFN-γ signaling ameliorated Angiotensin II induced cardiac damage, which led to a finding that NK-cells play an essential role in the induced vascular dysfunction.

Ace2 Expression Patterns in Covid19

Pathophysiology of Covid19 demonstrates that NK cells are depleted and neutrophils infiltrate into lung tissue leading to tissue damage and escalation of the disease. By SARS-CoV2 binding the Ace2 receptor of vascular epithelial and other cells, the conversion of Angiotensin II is blocked (image above), therefore upregulated. Increased levels of Angiotensin II were shown to induce NK cells to release IFN-γ. On recruitment to inflammatory sites, NK-cells release IFN-γ and engage with monocytes in a reciprocal program of activation in which monocytes mature into macrophages and dendritic cells. NK exhaustion results and is a known outcome that may relate to IFN-γ levels. However, in patients with high expression of Ace2, NK cell counts are lower and cytokine expressions do not show up during the initial disease state pointing to the role of accumulating Angiotensin II.  

Covid19 Meta Analysis

The image above shows distribution of expression (y axis) for ACE2, PCSKs (blood pressure mediation) and TMPRSS2 (CoV2 S1 cleavage) across lung cell types (x axis). It completes the picture that Corin-Furin mediated control over blood pressure normalization is a significant component of Covid19 disease progression and NK cells are a central player.

Molecules targeting RAS are a major focus of inhibitory or complementary therapeutic design, but a modified NK cell that is shielded from SARS-CoV2 may be the tool-in-the-shed our immune systems need. 

Is The Natural Killer our Anti-Cell?

Lymphocyte

Natural Killer (NK) cells may be our innate, anti-cell sentinels that first arise in the yolk sac between day 8 and 10. Simultaneously maternal, uterine NK cells promote fetal development by secreting growth promoting factors. Distinct sets of NK cells mature during early fetal development by associating with differentiating cells and tissue environments. Typically NK cells mature in around 25-35 days. By comparison, the developing embryonic heart begins pumping blood around day 22. The transcriptome, lineage and variety of each terminally differentiated embryonic NK cell and whether, in adults they continue to exist is unknown and genetically undefined.

The prospect of innate immune memory is a developing interest that has been shown to link innate and adaptive cell sets by epigenetic responses. Natural Killer cells have been a particular focus of this research because they were once considered innate and non-adaptive. Recently there is an emerging body of evidence that suggests otherwise. Whether NK cell memory arises and which NK cells participate in its establishment is not established science. Without more research whether and to what extent very narrow NK cell protein expressions distinguish cell and tissue lineages will continue unanswered. However, some good research supports the important idea of NK memory and conserved lineage.

A study on the heterogeneity of NK cells, by transcriptome in human bone marrow identified distinct NK populations, including one expressing higher levels of immediate, early genes indicative of a homeostatic activation.  Analysis identified a transitional population between CD56bright and CD56dim NK cells. Most interesting they reported on a donor with GATA2-T354M mutation who exhibited a reduced percentage of CD56bright NK cells with altered transcriptome and elevated cell death indicating the smaller number of CD56bright NK cells were contributing to the donors disease progression.

In a mouse model of CMV infection, a specific population of NK cells expands, contracts after control of the virus and generates long-lived “memory” NK cells that are more protective during a second encounter. Other reports indicate antigen specificity and antibody dependent NK mediated cytotoxicity in autoimmune disease by a sub-population of NK cells expressing a combination of specific receptors that was associated with apoptosis and the depletion of IgG in individuals with autoimmune thyroid disease.

Coronavirus Lung Cells

In Covid19 admitted patients NK cells and lymphocytes were depleted including by apoptosis and exhausted. This late stage condition developed for some time prior to admission. The published research identified two receptors as particularly important for CoV2 viral entry into a cell. Ace2 to which CoV2 binds and TMPRSS2 that cleaves its Serine protein enabling entry. Only one report, so far provided useful information about expression of these genes in NK cells of lungs. From the 57,020 lung cells on the UMAP plot only NK cells expressing Ace2-TMPRSS2 connected Muscle, Fibroblasts, T-Cells and Macrophages.

A four year experiment tracked bar-coded NK cells introduced to rhesus macaque's. The results indicated that during homeostasis and moderate proliferative stress, peripheral, compartmentalized, self-renewal can maintain the composition of distinct, differentiated NK cell sub-populations.

Blunted categorizations of NK receptor expressions may be a sub-set limitation, but the good news is that more recent research is defining NK cells in increasingly diverse ways. We are also learning to identify diseases that infect NK cells including influenza, that induces apoptosis, HIV, Hepatitis c and Epstein Bar. A study found peptide specific recognition of human cytomegalovirus strains control expansion of adaptive NK cells. Another Covid19 study compared the transcriptome in lung tissues of older patients, including NK cells and concluded that genes induced by SARS-CoV-2 infection tend to increase in expression with aging, and vice versa.

Although still a little abstract for science, its plausible that a cell contracting a disease could recall its NK 'memory cell', its NK anti-cell counterpart to annihilate it because it differentiated beyond its NK anti-cell phenotype range. If true, an indiscriminate disease that also targeted the NK anti-cell and eliminated it would prevent annihilation of its phenotype differentiated counterpart cells. By example, SARS-CoV2 would also bind the Ace2-TMPRSS2 expressing NK anti-cell, infect and kill it then NK immune resistance would be compromised and cell differentiation may rapidly progress to become lethal.

Does SARS-CoV2 Strangle P53 to kill Natural Killer Immunity?

Codondex iScore

It's intriguing to speculate why p53 regulates the cardiac transcriptome and the ATIP gene, at least to transcribe ATIP1 a human isoform of the Angiotensin II AT2 Receptor Interacting Protein? The gene's different names describe its various functions including; Mitochondrial tumor suppressor 1 (MTSG1) or Microtubule-Associated Scaffold Protein 1 (MTUS1). Expression of MTUS1 was reported lost in various types of human malignancies such as colon, ovarian, head-and-neck, pancreas, breast cancers, bladder, gastric, and lung cancers.

AT2 is a receptor associated with Renin-Angiotensin System (RAS) and vasodilation that confers potential benefits in pathogenic conditions. It is not highly expressed on Natural Killer (NK) cells, but has been detected and was shown in a rat model of myocardial infarction to reduce injury and have dampening effects on inflammation. The AT2 receptor, in combination with ATIP1 is also reported as a tumor suppressor. New experimental evidence showed interaction defects between ATIP1 and two mutant forms of the AT2 receptor identified in cases of mental retardation. The studies point to a functional role of the AT2-ATIP1 axis in cognition.

p53 is a major transcription factor and the TP53 gene is the most mutated in cancer. It has been the extended subject of this blog and our research into relationships between p53 and Natural Killer cells. Our interest is p53 genetic signatures used to select specific diseased cells to co-culture and educate NK cells that can be applied as custom, target therapy against various diseases.

As reported in a previous blog entry, RAS is a cornerstone of blood pressure which has been directly implicated in Coronavirus patients whose NK cells have also been severely depleted. Transcriptomic analyses identified several immune pathways and pro-inflammatory cytokines induced by SARS-CoV-2 infection evidencing a sustained inflammation and cytokine storm. Pathway analysis revealed that patient’s lymphopenia may be caused by activation of apoptosis and p53 signaling pathway in lymphocytes.

If, as reported the RAS of NK cells contributes to the control of blood pressure via the localized ratio of AT1:AT2 expression. Then, in the capillaries of tissue micro-environments the delicate balance of vasoconstriction<>vasodilation signaling may be exploited by NK cells scanning the affected cells to deliver their innate inflammatory response. Cytokine directed vascular changes that effect local blood pressure may be another varied contributor.

So, with these time-bound, localized, micro-pressure effects in progress how does an innate NK cell go about killing an infected target that may have also motivated its AT1:AT2 response? AT2 was found to be an AT1 antagonist, which adds complexity to the function and ratio effects of this diverse protein. ATIP is an agonistic factor of AT2 to exert opposing effects to AT1, such as organ-protective and anti-inflammatory effects. We know ATIP's including ATIP1 binds AT2's cytoplasmic tail and impacts signaling that results from Angiotensin II (AngII) binding AT2's extracellular domain. We also know p53 transcribes at least ATIP1 and that ATIP3 is directly implicated in microtubule organization.

ATIP1 has been previously reported to localize either at the mitochondria or the Golgi. These apparently discordant results might be reconciled if ATIP1 were a microtubule-associated protein. Indeed, mitochondrial organelles are highly enriched on microtubules that ensure their intracellular transport. On the other hand, the Golgi apparatus is located at the nuclear periphery close to the microtubule organizing center (MTOC). ATIP1 might thus associate with microtubules and provide a direct link between the AT2 receptor at the cell membrane and the cytoskeleton.

The prospect that RAS related signaling and p53 are tied in both lymphocytes and broader cell biology is tantalizing. Among the cellular signaling pathways, p53 plays a prominent role in RAS. Activation of p53 increases Angiotensin and AT1 expression. Conversely, AngII activates p53 pathway to mediate its downstream cellular effects. Mechanically, stretch-mediated release of AngII induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. 

In Cardiometabolic Disease pathogen-associated, molecular pattern–mediated metabolic reprogramming can be considered a manifestation of innate immune signal reprogramming a conserved phenomenon that changes how we think about the biology and function of the innate immune network including indispensable acetylation that destabilizes p53 and its inhibitor MDM2.

In Coronavirus patients, SARS-CoV2 binding ACE2 receptors may modify processes associated with the ACE2/Ang-(1-7)/Mas axis and acute, chronic inflammation, including reported leukocyte influx. The mechanical stretch of vasoconstriction<>vasodilation could cause AngII to activate p53. Therefore, if SARS-CoV2 impedes the AngII-ACE2-AT2-ATIP1 pathway that under normal circumstances in NK cells may direct microtubules to form an immune synapse for target killing, then the rapidly multiplying virus binding ACE2 may simultaneously render NK ineffective and by mechanical-stretch affect cardiomyocytes by p53 activation, which would lower AT2 ratios, including in vascular epithelial cells to induce apoptosis or G2/M cell death. A potent cocktail indeed!

SARS-CoV2, Blood Pressure and Natural Killer Cells

The Cardiac Cycle

A beating heart is the first sign of life in the developing fetus. Cells of the heart's ventricular and aortic cavities express various proteins with non-active natriuretic and diuretic peptides in a pattern associated with blood pressure. Activated Corin or Furin proteins cleave these peptides into shorter active forms. The cleavage site often defines how these peptides influence cells and the cellular processes while circulating in blood. But, the heart is not the only place this mix of proteins and peptides are manufactured. From early to late pregnancy Corin level changes were greater in women who developed gestational hypertension, commensurate with diastolic and mean arterial blood pressure and it got doctors and scientists thinking?

NT-proBNP is a pro-hormone, a Corin or Furin dependent peptide from the same molecule as activated BNP. Both are released when pressure changes inside the heart. Circulating levels of NT-proBNP were higher in early and late-onset preeclampsia. BNP mRNA and protein were also detected in placentas from women with preeclampsia and controls. In normal pregnancies, BNP in plasma is stable, but in severe preeclampsia it is elevated. In 181 preeclampsia patients higher levels of Corin were expressed, also secreted from synctiotrophoblasts and extravillous trophoblasts of the placenta.

The secretion of NT-proBNP, and BNP mRNA and receptors were investigated in cultured primary trophoblasts. Low levels of NT-proBNP were found in the supernatants of term, but not first-trimester trophoblasts. In preeclampsia patients Corin mRNA and protein in uterine tissue were significantly lower, but plasma Corin higher, compared to normal pregnancies. These apparently conflicting reports may relate to local blood pressure.

A paper studying Atrial Natriuretic Peptide (ANP) identified that Corin and ANP promoted trophoblast invasion and spiral artery remodeling in the developing placenta. Pregnant Corin or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of preeclampsia. Further, trophoblast invasion and uterine spiral artery remodeling were markedly impaired. Consistently ANP potently stimulated human trophoblasts invading in Matrigels. That Corin is up-regulated with stromal cell decidualization and strongly localized provides compelling evidence to support localized, but not circulating Corin activating ANP within these uterine cells. This may then invite trophoblast and Natural Killer (NK) cell invasion and the ultimate handshake of fetal trophoblasts with maternal endothelial cells lining spiral arteries of the developing placenta.

In early pregnancy NK cells expand to become the largest population of immune cells in decidua lining the uterus (uNK). They are closely associated with the development of blood vessels including spiral artery remodeling and possess a functional Renin- Angiotensin system, cornerstones of blood pressure. ANP antagonizes Angiotensin II receptor type 1 (AT1) leading to vasoconstriction. The ratio of uNK cells expressing AT1 markedly changed between gestation day 6 and 10. At day 10-12 ANP strongly co-localized to uNK cells at implantation sites, immediately after spiral arterial modification. Expression of vasoregulatory molecules by uNK cells suggests they contribute to the changes in blood pressure that occur between days 5 and 12 coincidental with their expansion during normal pregnancy in mice.

Studies of patients with Pulmonary Arterial Hypertension have also implicated BNP in the decline of NK cells and CD8+ T-Cells. A similar depletion was recently reported in Coronavirus  patients and expression of NT-proBNP was significantly elevated.  It is reasonable to infer that blood pressure and NK cells are associated especially in the tight confines of pulmonary capillaries or placental tissue.  Perhaps its their capacity to express molecules that participate in Corin activated vasoregulation through natriuretic peptides and to be immunoreactive, or perhaps their reaction to kill infected cells results from it - who knows?

In addition to the well documented natriuresis, diuresis and vasodilation, BNP may also modulate immune and inflammatory reaction to cardiac injury. BNP depletes monocytes, B lymphocytes and NK cells in peripheral blood. BNP regulates the chemotaxis of monocytes and production of inflammatory molecules by macrophages. BNP may promote cardiac neutrophil infiltration and also have direct effects on matrix remodeling and wound healing. All of these characteristics have been observed in lungs of critical care and deceased Coronavirus patients.