There is an exponential growth in data pertaining to SARS-CoV-2 pathophysiology. The above has highlighted under-explored consequences of the ‘cytokine storm’ and their priming by pre-existent conditions, upon which wider bodies of data may be integrated, including data on the role of coagulation and embolisms in SARS-CoV-2 fatalities.
3.1. AhR, Platelets, ROCK, and SARS-CoV-2 Severity/Fatality
Accumulating data indicate that ‘embolism emergence’ is a significant contributor to SARS-CoV-2 infection fatalities 
. As AhR activation primes platelets for coagulation and aggregation, as well as increasing thrombin and fibrin (ogen) 
, clearly increased AhR activation will contribute to COVID-19 fatalities. As well as regulating the melatonergic pathway via CYP1B1 induction and 14-3-3ζ/δ suppression, the AhR also acts via the induction of sphingosine kinase (SphK)-induced sphingosine-1-phosphate (S1P) and S1P3 receptor (S1P3r) activation, thereby increasing the small GTPase, RhoA, and RhoA-associated kinase (ROCK) 
. S1P modulates pulmonary epithelial cell infection responses 
, with RhoA/ROCK dysregulating the renin-angiotensin system and thereby driving the development of pulmonary embolisms 
. Overall, AhR priming of platelets and RhoA-ROCK pathway induction in endothelial cells, thereby slackening tight junctions, increasing immune cell chemotaxis, and heightening inflammatory activity form the underpinnings to embolism formation 
AhR ligands and antagonists will therefore have significant impacts on processes driving SARS-CoV-2 severity/fatality. Cytokine- and stress-induced kynurenine, as well as air pollutants and TCDD exposure, will contribute to embolism-associated fatality via the AhR activation and the induction of the S1P3 receptor/RhoA/ROCK pathway, including via AhR effects in platelets. The high levels of circulating amyloid-beta (Aβ) in elderly COVID-19 patients will also raise platelet RhoA levels and the prothrombin, pro-coagulation platelet phenotype 
, suggesting that the raised circulating Aβ levels in the elderly will contribute to SARS-CoV-2 severity and embolism-linked fatalities (see Figure 5
). A number of common nutriceuticals, including green tea polyphenols, resveratrol, and vitamin B12, are AhR antagonists, suggesting that variations in their dietary intake may modulate SARS-CoV-2 severity (see Treatment section).
Figure 5. AhR activation and heightened Aβ levels in the elderly will contribute to platelet activation via decreased melatonin and upregulation of microRNA (miR)-155 and the S1P3r/RhoA/ROCK pathway. The resultant increase in coagulation, thrombin and new embolism formation contribute to SARS-CoV-2 severity/fatality. Racial discrimination stressors may contribute to such processes, given the heightened association of embolism-linked fatalities in African-American deaths during surgery for other types of medical conditions.
3.2. AhR, Acetyl-CoA, COX2, and Specialized Pro-Resolving Mediators (SPMs)
The induction of SPMs is important to the resolution of immune inflammation. Interestingly, SPM regulation overlaps with the regulation of the melatonergic pathway, with both being upregulated by increased acetyl-CoA availability. SPM induction will also act to suppress the SphK1 and S1P/RhoA/ROCK pathway that underpin the emergence of SARS-CoV-2 embolisms 
. Elevations in acetyl-CoA and Sphk1 allows acetyl-CoA to bind the sphingosine in SphK1 to form N-acetyl-sphingosine (N-ASph). N-ASph acetylates cyclooxygenase (COX) 2, thereby dampening COX2-induced inflammatory processes and upregulating SPMs 
. In immune cells, N-ASph and acetylated-COX2 drive the shift from an M1-like pro-inflammatory phenotype to an M2-like phagocytic phenotype 
. As acetyl-CoA is a necessary co-substrate for AANAT in the initiation of the melatonergic pathway, this indicates that the raised acetyl-CoA levels underpinning N-ASph production can be co-ordinated with AANAT stabilization and melatonergic pathway activation. As such, SPM induction may be intimately linked to cytoplasmic and mitochondrial melatonin production via increased acetyl-CoA and therefore with TCA cycle ATP, OXPHOS, and mitochondrial metabolism. Factors acting to dysregulate mitochondrial metabolism, and therefore acetyl-CoA levels, will therefore impact on the co-ordinated induction of the melatonergic pathway, N-ASph, and SPMs and therefore COX2 and immune phenotype regulation.
This may be exemplified in macrophages where autocrine melatonin switches M-like pro-inflammatory macrophages to an M2-like phagocytic phenotype 
. As to how SPMs and autocrine melatonin interact to downregulate activation associated glycolysis, whilst upregulating OXPHOS will be important to determine. It would seem likely that the acetyl-CoA stabilization of mitochondria AANAT is intimately linked to the regulation of mitochondrial sirtuins and SOD2, as well as the mammalina target of rapamycin (mTOR) pathway, which is important to glycolysis regulation 
. However, the temporal and spatial interactions of melatonin with SPMs require clarification, including as to how these interactions are modulated during the SARS-CoV-2 ‘cytokine storm’. This will be important to determine, given that the COX2-PGE2 pathway, regulated by melatonin, N-ASph and SPMs, is an important driver of macrophage and neutrophil activation and migration, in association with cytoskeletal regulation driven by RhoA/ROCK and the RhoA/ROCK induction of COX2 
. As raised glucose levels, often evident in obesity/type II diabetes, activate macrophages via the RhoA/ROCK pathway 
, macrophages may be primed for heightened responsivity in these SARS-CoV-2 high-risk conditions. There is currently no direct data looking at the role of the AhR in the regulation of N-ASph, or indeed of the SPMs. Clearly, the AhR suppression of melatonin would dramatically alter such proposed acetyl-CoA driven interactions of SPMs and melatonin in the regulation of these key cells that drive the ‘cytokine storm’.
It should be noted that SPMs suppress the AhR and AhR-induced genes, including COX2 
. Many AhR effects are mediated via COX2 induction 
, including in air-pollutant-activated macrophages 
and in dendritic cells where AhR activation-induced COX2 is crucial to the induction of the high-inflammation and autoimmune-associated Th17 cells 
. COX2 is also a significant regulator of NK cell function, both directly and via COX2 effects in dendritic cells 
. As such, acetyl-CoA levels, via N-ASph acetylation of COX2, can have dramatic effects on pro- vs. anti-inflammatory activity in immune cells, with concurrent impacts on levels of melatonin production, release, and autocrine effects that modulate the immune cell phenotype, with acetyl-CoA also driving paths that optimize mitochondrial metabolism and suppress AhR activity and effects. Previous data indicating both pro- and anti-thrombotic effects of COX2 
may also be attributed to its distinct effects that are dependent upon its state of acetylation, and therefore on the levels of acetyl-CoA and N-ASph. (See Figure 6
Figure 6. AhR-induced cyclooxygenase (COX) 2/PGE2/EP4 has differential effects in anti-viral cells vs. cells of the ‘cytokine storm’. Levels of acetyl-CoA may be significant determinants of AhR effects via the COX2/PGE2/EP4 pathway via acetyl-CoA using sphingosine from sphingosine kinase (SphK) to produce N-acetyl-sphingosine (N-ASph), which, like aspirin, acetylates and inhibits COX2. Acetyl-CoA, as a co-substrate for AANAT, also increases melatonin, which also inhibits this AhR-driven pathway. As such, acetyl-CoA may act to co-ordinate N-ASph and melatonin production and effects, with their differential consequences in NK cells and CD8+ t cells vs. macrophages, neutrophils, and mast cells. This would suggest that variations in acetyl-CoA in these cells will determine their differential activation in SARS-CoV-2 infection, as well as in cancers. The suppression of melatonin by the AhR in all of these cell types will contribute to their dysregulation in SARS-CoV-2 infection, whilst the suppression of pineal melatonin, via a decrease in Bmal1-induced PDC and therefore acetyl-CoA production, will be important in driving the dysregulated immune response in the aged population as well as in those with high-risk, pre-existent medical conditions. N-ASph can also increase SPMs in macrophages, which, along with autocrine melatonin, switches activated macrophages to a more quiescent phagocytic phenotype.
Kynurenine activation of the AhR induces COX2-PGE2 and EP4 receptor activation in NK cells, leading to the suppressed/‘exhausted’ NK phenotype that is typical in the tumour microenvironment 
, and which is paralleled in severe SARS-CoV-2 infection. The COX2-PGE2 pathway inhibits NK cells migration, cytotoxic effects and IFNγ secretion 
, with similar effects in CD8+ T cells 
and γδ T cells 
. As to whether acetyl-CoA in NK cells or CD8+ T cells modulates N-ASph production to increase acetylated-COX2, thereby decreasing PGE2 and EP4 receptor activation will be important to determine. As acetyl-CoA is linked to mitochondrial metabolism and the initiation of the melatonergic pathway, alterations in melatonin, TCA cycle, and OXPHOS will be intimately associated with N-ASph and acetylated-COX2 in the regulation of NK cells and CD8+ T cell and γδ T cell anti-viral and anti-cancer responses. Although the activation and cytotoxicity of these cells requires the upregulation of glycolysis, the maintenance of OXPHOS is crucial to the prevention of a suppressed/’exhausted’ NK cell phenotype. As PGE2 production by nearby cells, including macrophages 
, may allow neighbouring cells to suppress NK cells and CD8+ T cells, it is likely that inhibition of COX2-PGE2 more widely may be of use. This has been the rationale for the extensive use of COX2 inhibitors in cancer treatments.
The roles of different SPMs over the course of NK cell and CD8+ T cell activation/deactivation have still to be clarified. SPMs have significant immune-regulatory functions relevant to COVID-19 and cancer pathophysiologies. The RvE1 receptor, CMKLR1, is expressed on NK cells, where its activation leads to NK cell attraction and activation that resolves lung inflammation 
. However, by acting to dampen macrophage/neutrophil/mast cell activation, RvD1 and RvE1 also decrease the chemoattraction and activation of NK cells and CD8+ T cells, under some experimental conditions 
. The temporal regulation of SPMs across different immune cells over the course of SARS-CoV-2 infection will be important to determine. SPM regulation may also be important in how pre-existent high-risk conditions for SARS-CoV-2 fatality mediate their susceptibility. Weight loss in obese patients increases neutrophil RvE1 release two-fold 
. This seems of importance as a significantly increased RvE1 dose is required to dampen inflammation in the neutrophils of type II diabetic patients 
. Such data indicate a role for pre-existent high-risk medical conditions–induced variations in SPMs in the suboptimal initial ‘cytokine storm’ and later anti-viral response evident in these patients. Pre-existent, cytokine-, or stress-induced increase in gut dysbiosis/permeability may be relevant to this, given that gut permeability-induced HMGB1 suppresses the RvD1 resolution of activated neutrophils 
. Chronic heart failure patients show a decrease response to RvD1 and RvD2 in activated CD8+ T cells, mediated by a decrease in the GPR32 receptor 
. Such data highlight how ongoing medical conditions modulate SPM levels and the SPM regulation of the immune response, with consequences that partly arise from the metabolic dysregulation in immune cells.
Dendritic cells are important regulators of patterned immune responses, and data in these cells also highlight the importance of mitochondrial metabolism in determining cellular function. Acetyl-CoA carboxylase (ACC) leads to the irreversible carboxylation of acetyl-CoA, with AhR activation increasing ACC via Synphilin-1 degradation 
. The suppression of sirtuin-1 in dendritic cells also increases ACC levels and decreases acetyl-CoA, with consequent alterations in mitochondrial metabolism that lead to dendritic cells inducing deficient anti-viral responses 
. ACC blockade in this study led to dendritic cell metabolic reprogramming that ameliorated mitochondrial dysfunction and restored a more appropriate anti-viral response 
. Such data highlights the important role that acetyl-CoA and its regulation by ACC have in determining and fine-tuning mitochondrial function 
, and the impact that alterations in mitochondrial function have on the immune regulatory responses of dendritic cells. This is also relevant to ageing, as ACC inhibition prevents accelerated ageing in a preclinical model 
, suggesting that the association of ageing with both cancer and SARS-CoV-2 infection fatality may be linked to suppressed acetyl-CoA levels in dendritic cells and the consequences that this has for patterned immune responses, including within cells determining anti-viral and anti-cancer responses. It should be noted that increased ACC will also suppress the melatonergic pathway, which will also have consequences for the regulation of immune cells, SPMs and sirtuins.
Overall, alterations in the regulation of acetyl-CoA will have impacts on AhR effects, acetylation levels of COX2, SPM levels, and melatonergic pathway activity, with consequences that will determine mitochondrial function in immune cells and associated variations in patterned immunity, thereby modulating inflammation as well as anti-viral and anti-cancer responses.
3.3. AhR, COX2, SPMs, Acetyl-CoA, and miR-155
Although the ‘cytokine storm’ increases LPS and pro-inflammatory cytokines that will raise miR-155 levels 
, there is no data pertaining to miR-155 following SARS-CoV-2 infection. miR-155 has a number of effects important to SARS-CoV-2 pathophysiology and anti-viral/cancer responses, including Bmal1 suppression 
, and therefore suppression of the Bmal1/PDC/OXPHOS/TCA cycle linked to increased acetyl-CoA production. Elevations in miR-155 are evident in COVID-19 high-risk, pre-existent conditions, including obesity 
, type II diabetes 
, hypertension and CVDs 
, and most human cancers 
. Raised miR-155 levels promotes inflammatory cytokine production in macrophages and microglia, in association with a decrease in sirtuin-1 
, linking increased miR-155 to a heightened and prolonged ‘cytokine storm’, including from a primed elevation of miR-155 in high-risk conditions. Preclinical data show the raised miR-155 levels in immune cells to accelerate ageing and decrease longevity via an increase in aerobic glycolysis and associated induction of pro-inflammatory processes 
. The miR-155 inhibition of sirtuin-1 may be important to ageing via ACC upregulation and acetyl-CoA suppression 
, suggesting that miR-155 will associate with lower N-ASph, melatonin and acetylated-COX2. Melatonin increases sirtuins and decreases miR-155 levels 
, highlighting the importance of suppressed melatonin, including pineal and immune-derived melatonin.
miR-155 has been proposed as ‘master regulator’ of dendritic cell function and of the role of dendritic cells in modulating patterned immune responses. miR-155 over-expression enhances the the initial cytotoxicity of CD8+ cells 
and NK cells 
. Such data indicate the importance of miR-155 in the raising the glycolytic metabolism crucial to immune cell activation. However, as the maintenance of OXPHOS is necessary for prolonged immune activation in these cells, the suppression of OXPHOS mediated by miR-155 upregulation of COX2-PGE2 and EP4 receptor activation, coupled to its suppression of Bmal1-linked OXPHOS will contribute to ‘exhaustion’. Data in CD8+ T cells support this, with the long-term persistence of exhausted CD8+ T cells being maintained by raised miR-155 levels during chronic infection 
. It should be noted that miR-155 has distinct effects in different cells types, as indicated by its differential effects on an array of standardized mRNAs in B-cells, T cells, dendritic cells, and macrophages 
. The evolved interactions of melatonin with miR-155 in different cell types may suggest that melatonin is a more viable treatment regulator of miR-155 than miR-155 targeted pharmaceuticals. However, AhR activation, by suppressing acetyl-CoA and melatonin whilst increasing COX2/PGE2 and EP4 receptor activation, will act to suppress any miR-155 associated initial activation of anti-viral cells, whilst potentially augmenting miR-155 induced activation of macrophages, neutrophils and mast cells in the ‘cytokine storm’. The interactions of miR-155 and other miRNAs with variations in mitochondrial metabolism, acetyl-CoA levels, and melatonergic pathway activity will be important to determine in individual immune cell types and in the interactions of different types of immune cells.
To date, there is no data on the interactions of inflammation resolving SPMs and inflammation-inducing miR-155. However, indirect data indicates that this interaction may be of some importance. miR-155 binds COX2 and induces COX2 reporter activity, whilst maintaining COX2 mRNA stability 
. The high similarity of COX2 and miR-155 effects in cancers 
, would indicate that the miR-155 upregulation of COX2 is an important aspect of miR-155 driven changes. Consequently, N-ASph acetylation of COX2 will modulate/inhibit the diverse effects of miR-155, in conjunction with increasing SPM production. Clearly, N-ASph and SPM effects on miR-155/COX2 in CD8+ T cells, NK cells, and γδ-T cells will be important to determine, as will their suppression of platelet activation 
, where different SPMs can have differential effects 
. Pro-resolving ALX/FPR2 receptors, activated by Lipoxin-A4, are present on NK cells where their activation regulates NK activity 
. Overall, AhR effects will be significantly modulated by the interactions of acetyl-CoA levels, N-ASph, melatonin, miR-155, and COX2-PGE2 with consequences for SPM induction and anti-viral/cancer cell OXPHOS, glycolysis, and associated cytotoxicity.
3.4. Gut Dysbiosis: Interactions with Acetyl-CoA, COX2, SPMs, and AhR
As sodium butyrate epigenetically suppresses COX2-PGE2 via its inhibition of HDAC5/6 
, this would suggest a role for gut dysbiosis in the regulation of miR-155 and AhR modulation of the immune response to the SARS-CoV-2 virus. Butyrate also regulates the mRNA binding protein, HuR, to decrease COX2 mRNA and protein expression 
. Such data indicates a role for variations in the gut microbiome in the modulation of COX2-PGE2 effects on the immune response, including directly and via other cells, on CD8+ T cells, NK cells and γδ T cells. Butyrate can also be converted to acetyl-CoA (via acyl-CoA synthetase), indicating that gut-microbiome-derived butyrate may modulate N-ASph levels, acetylated-COX2, SPMs, and the melatonergic pathway via its conversion to acetyl-CoA 
. Such data would indicate a gut dysbiosis relevant modulation of these crucial cells in cancers and SARS-CoV-2 infection. Butyrate also inhibits cells involved in the ‘cytokine storm’, including macrophages and neutrophils 
, with its inhibition of COX2-driven attachment of monocytes to endothelial cells 
, indicating an impact of butyrate on embolism formation and atherosclerosis 
. In the lung, butyrate suppresses HMGB1 induction to infection, suggesting that it will act to prevent the HMGB1 inhibition of RvD1 and the RvD1 resolution of activated neutrophils 
. It has been recently proposed that the effects of gut dysbiosis are crucially mediated by its regulation of systemic mitochondrial function, especially in immune cells 
. The data above would suggest that this is partly driven by butyrate’s regulation of acetyl-CoA, and the consequences that this has for the AhR, COX2, SPMs, and melatonergic pathways.