Tue. Nov 29th, 2022

Source of the featured photograph: https://en.wikipedia.org/wiki/File:Group_Sunrise_.jpg

How to prevent the next wave of far-right extremism in Europe and around the world

Just because a number of people have been fighting against a form of extremism, it does not necessarily mean they are not falling into an opposite form of extremism. Just like, in a low pressure system, there are extreme winds that often flow against each other to the point of reaching an area with the lowest atmospheric pressure in the system. In this case, one extreme wind is corporate-based communisto-fascism (it has all elements of extremism and dictatorship, meaning it controls all sides of extremism), another extreme wind is cultural Marxism and new movements supporting communism, and another extreme is nationalism and hate of various ethnic minorities, for various subjective reasons. Let us be clear, nationalism is not the same as patriotism. Real patriotism involves the sincere and unconditional love for one’s country and the rest of the world, just as in Christianity, believers are commanded to love their neighbours as themselves. Nationalism on the other hand, brings an attempted love of one’s nation by hating other nations, and this attempted love will not be successful because it will not be love. The solution in the overall situation is to remain outside the low pressure system and enjoy the good weather. In other words, oppose the concerned form of extremism extra-dimensionally, by informing yourself correctly, firmly opposing all forms of extremism and holding fast to the inner peace and unconditional love for the entirety of humanity. I am going to use another analogy; many people welcome light and moderate snowfalls with no wind, but many fewer welcome blizzards, given that they are harmful and that some of them could be part of a hurricane. Remember, good can never come by force, and those who believe it can are sadly deceived. An important figure of the Romanian Orthodox Christian Church once said that Romania will need a Revolution without a revolution to win against the corrupt establishment, and I believe this is the case worldwide. Discernment is crucial, especially in a world where we seem to lack it more than ever.

Just like a higher number of people would tend to prefer a blizzard if the weather was constantly warmer than average in the winter, so would a higher number of people tend to fall for more radical regimes that would come across as fighting against bad moral values. And such people would be less prone to finding out about the crimes that such a regime would commit where people could not see. But I would like to say the following again, negativity cannot be defeated by another form of negativity, and good can never come by force and by damaging people and good values. Else, it is bad disguised as “good”. Maybe this explains Dr. Jordan Peterson’s point of psychological analysis mentioned during his interview with Piers Morgan, that everybody on Earth has at least a little bit from Hitler, just as everybody on Earth has at least a little bit from the kindest and most moral person. I think an important way to heavily restrict the spread of hate and of divisive ideologies and political parties is to apprehend that, most of the time, winning is not an easy process and that it involves losing at least something. Anyone who says otherwise will very likely fall into the deceit of morally deceived and blatantly immoral people. It is important to note that there are accusations that J. Paul Getty, who was deemed as the richest man in the world, and J. P. Morgan funded the nazi regime in Germany that occurred before and during the Second World War.

How can one defeat a system of extremist movements from the outside? Thankfully, there seems to be a way. The mission displayed in the latest The Maverick movie could be an analogy to how a corrupt powerful establishment should be defeated; by positive infiltration (flight of the military plane to the valley that has the concerned military base of the enemy team), a rapid exposure of wrongdoing (a figurative shooting of the concerned base, which could actually be apprehended as showing unconditional love and sharing the truth to the best of the ability, as one united body) and then leaving the danger zone as soon as possible (gaining a lot of altitude in a short amount of time). Also, think of hurricanes; they destroy everything in their way, but there is only one area they cannot (ultimately) control; their own eye! Likewise, although they depend on the lowest point of atmospheric pressure, they ultimately cannot control it. Let us imagine there is a natural substance that quells hurricanes from their eye. In that situation, let’s say that certain trained pilots can fly nature-friendly military planes above the hurricane, then descend into or toward its eye as much as possible, then start spraying with such a substance and then immediately ascend again to cross into the outer area of the storm without touching it and overall without getting influenced by its currents. The hurricane in this case consists of hate, manipulation and division, and a single touch even on its area of influence leads to an infection with hate and manipulation. Likewise, it cannot be defeated by joining the currents (i.e. one or both of the extreme ideologies or the central power controlling both) and it can also not be defeated by joining the club of the hurricane and secretly trying to defeat it whilst being part of its foundation, just as light cannot mix with darkness. Flying inside the hurricane cloud or inside its area of influence will sooner or later lead to an airplane crash. It is better to get out of the area on time, admit defeat and return to the base than to crash and cause those around you to stumble too. Let’s think of the worldwide politico-financial system as a hurricane, which permits the development of extreme ideologies, probably by means of division and conquest. And it is very important to apprehend that the foe is not the human being, but the toxic ideas, feelings and influences that come from morally corrupt people. In this case, the weakening and defeat of the hurricane from within its eye involves a resulted physical, mental, emotional, locomotory and eventually existential blindness of the hurricane. We may call this a defeat of the enemy from within, whilst being fully dependent upon the outer. But we define this sort of defeat all by kindness; by displaying the inner light that was given freely by the Divine. Never allow yourself to be innerly exposed to negativity, lest you may be consumed and ultimately even end up playing into the hands of the enemy. This type of enemy cannot be defeated by any means of negativity, lest the fires of extremist ideologies will not recede, but will be fed and ultimately, the corrupt and negativistic system will gain even more power and become more corrupt and negativistic. Remember to keep out of the storm at all times, keep your inner peace and enjoy the sunshine.

How a correctly revolutionised vaccinology will increase the average human lifespan and weaken problematic diseases

One of the most asked questions of the 21st century is whether we will manage to live longer as we go through scientific progress. And some people are wondering whether an increase of human lifespan will be made possible via natural or less nature-friendly mechanisms. I believe that the latter mechanisms would eventually cause a significant drop in the human lifespan and bring mankind even to a lower ground than before the increase. It is interesting to know that improving the intelligence and wisdom of the immune system, by sharpening its ability to neutralise microbes whilst decreasing the extent of pro-inflammatory responses, very likely represents a major step in increasing one’s lifespan and will also significantly strengthen the cellular mechanisms of DNA repair. Furthermore, it is interesting to know that a high energy metabolism, which is associated with high levels of stress, leads to a shorter lifespan. I believe a reconnection with Nature will involve a lower energy metabolism, as people will no longer be stressed and work more than they can in order to be able to live. Nature has all the resources we need; it is us who kept trying to go farther from her and we kept bearing more fruit of consequence. Non-qualitative food and beverages are epigenetically and ultimately genetically predisposing human metabolism to switch to high-energy consumption, thereby accelerating the process of ageing. A de-connection from technology starting from the level of cognition is a must to manage to reconnect with Nature and improve human immunity, metabolism and important DNA repair mechanisms.

Numerous kinds of significant infectious diseases implicate a latter hyper-activated interferon set of responses, alongside a severe complement-mediated set of immune signals, which often result in the onset of haemophagocytic lymphohistocytosis, which is in short known as cytokine storm. The truth is that a desired extent of complement system activation also stimulates an early development of interferon signalling, which means that eventual updates in vaccinology could require the inclusion of approaches sharpening complement system-related immunity. A delayed Type I Interferon-based immune response is accompanied by an exaggerated Complement C5a-related immune response, which means that finding methods to prevent exaggerated activations in this part of the complement system will also support the development of an early Interferon I and perhaps Interferon III-based antiviral and anti-inflammatory signals. Sharpening interferon-based immune responses on an evolutionary scale is likely still enough to improve general human immunity against pathogens with tricky mechanisms of pathogenesis. Nevertheless, a prophylactic approach against a hyperactive complement system will possibly bring a further shift against pathogens with abilities of immune evasion. It is possible that a repeated set of developed early, regulated interferon-based responses over a longer time reduce the rate of cellular ageing, whilst a repeated set of developed late, exaggerate interferon-based responses increase the speed of cellular ageing, besides causing worse outcomes of various infectious diseases and resulting in the onset of autoimmune diseases.

Recent in-vitro and in-vivo research has indicated the presence of a link between Type I Interferon-based signalling and LINE-1 retro-transposition. Namely, the study suggests that Type I Interferons and LINE-1 retro-transposons regulate each other, and that an exaggerated Interferon I signalling is linked to a higher incidence of autoimmune disease. With regards to SARS-CoV-2 and the spike protein, it was previously indicated that small regions of the viral genome undergo LINE-1 reverse transcription and integration into various parts of the junk and functional DNA of the host cell and, given that long COVID is a result of a delayed and exaggerated extent of IFN I signalling, it is possible that the viral infection results in a less regulated propagation of LINE-1 retro-transposons and even that the substantially small, but still concerning, parts of the viral genome have laboratory origins. Namely, it is possible that up to 0.5-1% of the overall viral genome (including about 1% of the spike protein-encoding ssRNA) was extracted from a retroviral kind of pathogenic genome, and there are various circulating theories, including that the virus having had natural origins beforehand underwent gain-of-function research to test the way the immune system of bats would react to it. The novel coronavirus has outstanding evolutionary abilities of suppressing Type I Interferon-based signalling, which is outstandingly concerning, no matter whether it has fully natural origins or a number of inserts from other pathogens, like HIV-1. Furthermore, given the likelihood that the timing and extent of IFN I production influences the spread of LINE-1 retrotransposons, it is rather significantly possible that, the more capable a virus is of suppressing IFN I production and signalling to neighbouring cells, the more capable such a virus is of inserting fragments of its genome into the DNA of the host cell, given that the LINE-1 retrotransposon-encoding DNA represents around 17% of the human genome. In other words, the more capable a virus is of suppressing first-line immune responses, the higher the risks are that such viral infections will ultimately result in the formation of cancers.

If the interferon-based approach is proven to be successful as a prophylactic, immunising and early therapeutic method against important pathogenic agents and the onset of cancers, then it will constitute a significant step in prolonging the lifespan of humanity. The general human lifespan will possibly increase at least by 10 to 20 years over the next decades. Interferon I and III will not only wisen the immune system up, but it will significantly strengthen important DNA repair mechanisms and ultimately repair many of the past damages done upon human metabolism as well. A process of immune wisening will not only involve better first and second-line responses due to a combined approach to regulate C5a complement activation and stimulate IFN I and III may result in a decreased sensitivity of complement system activation and an increased sensitivity for Type I and III-based signalling and immune sensing of many problematic microbes, but will also stimulate a better process of V(D)J antibody gene rearrangement in developing B-Lymphocytes, which in turn will lead to the production of more qualitative IgM and IgG antibodies during challenging infections. Research has shown that the administration of interferon-alpha to pregnant mothers is safe for the foetuses and that it increases the probability that the future baby will be immunologically healthy. This possibly means the effectiveness of such interferons will cross the umbilical cord and reach the health state of the foetus as well. Likewise, updating and potentially revolutionising human vaccinology in such manner may bring a level of breakthrough the great minds in the past centuries only dreamt about, and believing in a positive outcome and paying close attention to new, conclusive evidence, represents a major step toward a desired scientific and medical progress.

The foundational factors of malignant tumours and neurodegenerative disease are immunological in nature, and the problem of immune escape represents an important stronghold of the worldwide epidemic of cancer and neurodegeneration. Immune escape not only facilitates pathogens to infect kinds of tissues that are vulnerable to mutagenesis and genome toxicity, but also prevents the apoptosis of cells that have already undergone tumour-related mutagenesis. Understanding the key mechanisms of cellular signalling resulting in the phenomenon known as “wise immune sharpening” represents the number one objective of cancer research. Weakened first and second-line immune responses are not only caused by active pathogens, but by a series of genetic factors that likely emerged as a result of a repeated exposure of ancestors with diverse immune co-morbidities to pathogens of more significant concerns. Understanding the spectrum of genetic-epigenetic factors that favour a specific outcome in offspring is also important in increasing the resolution of the details collected during applied immunological research in cancer biology.

The following represents a fragment from a research proposal that has a significant word count and that highlights the importance of building up early first-line immune responses to tackle viruses with developed mechanisms of innate and adaptive immune evasion. We demand an immediate scientific debate that includes this fragment of research proposal, that is televised and discussed transparently. We demand that real solutions will be brought immediately and without any sort of financial interest. Overall, we demand that the entire rigged System is changed from its core foundations.

“With regards to the COVID-19 pandemic, it is important to acknowledge the methods the novel coronavirus utilise to escape the host immune system by means of replication and spread to several kinds of bodily tissues. Namely, once the virus has entered the host cell, it downregulates the activities of pattern recognition receptors that detect pathogen-associated molecular patterns found on the viral genome, and the expression rate of Type I and III Interferon-encoding genes. Namely, the viral genome also produces a number of non-structural proteins that decrease the amount of produced interferons, either by means of viral self-camouflage or by means of cleaving interferon-producing mRNA. Type I Interferons include interferon-alpha, -beta, -delta, – epsilon, -kappa and -omega, whilst Type III Interferons include interferon-lambda1, -lambda2 and -lambda3. Many of the non-structural proteins are conserved in a viral pocket known as the S-Adenosyl-L-Methionine pocket. Consequently, the virus heavily downregulates the autocrine and paracrine signalling rate of Type I and Type III Interferons during critical stages of infection and replication. Some of the viral non-structural proteins also inhibit products of Interferon-Stimulated Genes that lyse the viral genome. Likewise, the developed viral evolutionary mechanisms are directly antagonising the mechanisms that Type I and Type III Interferons have to robustly induce the apoptosis of the infected cells once they have been released by the newly infected host cells to prevent further viral replication and spread. Moreover, by significantly downregulating interferon synthesis, viruses like SARS-CoV-2 gained a major stronghold over the ability of the innate immune system to create important antiviral (PKR-related) and anti-inflammatory signals, which are crucial for the correct development of the necessary further immune defenses. Moreover, the virus produces a structural protein named the spike glycoprotein, which has recently been discovered to weaken the activity of the BRCA1 and 53BP1 genes, which are implicated in cellular DNA repair mechanisms, as well as to inhibit the VDJ and VJ processes of heavy and light chain antibody gene rearrangements respectively. At the same time, the receptor binding domain of the spike glycoprotein forms a trimeric complex with the GRP78 chaperone, as well as with the ACE2 receptor, and it is the viral interaction with the GRP78 chaperone that further enhances infectivity and ultimately, virulence. Likewise, not only is it that the novel coronavirus utilises numerous methods to evade all essential areas of human immunity, but it was also discovered that the virus detects and utilises certain host proteins to increase its infective abilities (Carlos et al., 2021). Furthermore, given that early Interferon I and III-based immune signals are associated with overall high immuno-competency and in turn, to low extents of energy consumption due to low extents of induced disease, viral immune evasion could have been playing a major role in preventing a full increase of the human lifespan, particularly in world areas with higher incidences of hunger and poverty. Given that the “double-edged sword”-like immunological effects of Type I Interferons has shown visible signs of reaching areas as far as cellular metabolism and even brain ageing (via the choroid plexus), there are considerable reasons to believe that stimulating early Interferon I and possibly Interferon III-based immune signalling in large proportions of the world population by means of immunisation against infectious diseases and important forms of cancer will also play a major role in decreasing the average rates of oxidative stress, mutagenesis and metabolic acidification, leading overall to a better average quality and duration of life.
The non-structural protein 1 (nsp1) activates the phosphatidylinositol 3-kinase (PI3K) pathway to inhibit the synthesis of Type I Interferons and activate cellular stress-response proteins, like heat-shock proteins, which inhibit apoptotic pathways of host cells at first, before they stimulate such inductions of host cell death (Ehrhardt et al., 2007). This initial inhibition of apoptosis stimulates a sharp increase of the viral load in the host organism. Moreover, the virus inhibits antigen presentation via the STAT1-IRF1-NLRC5 pathway and the first class of the Major Histocompatibility Complex, thereby affecting the specialisation of CD8+ T-lymphocytes (Yoo et al, 2021). Given that the antigen presentation process is affected as a result of the targeting of the same pathway as the one induced by Type I Interferon activation, we can determine that inhibited Interferon I activation is associated with a down-regulated endogenous antigen presentation, via Class I MHC. The downregulation of pattern recognition reception affects signalling from the TLR-3, TLR-4, TLR-7, RIG-1 and MDA5 receptors to the IFNA1, IFNA2 and IFNB1 genes. The non-structural protein 1 also lyses molecules of mRNA that encode Type I Interferons, whilst the non-structural protein 16 caps the 5’ end of the viral mRNA and makes the cell less capable of recognising the viral mRNA as pathogenic. Nsp1 was also found to impair the synthesis of Type III Interferon, potentially affecting the expression of IFNL1, IFNL2 and IFNL3 gene expression during infections with rotavirus and the porcine epidemic diarrhoea virus and, given that interferon-lambda was only discovered in 2003, we have reasons to believe that the synthesis rate of this sub-type of interferons could also affected during a SARS-CoV-2 infection. In other words, the production of non-structural protein 1 by the SARS-CoV-2 and Influenza A viral genomes represents a pathogenic evolutionary trait of viruses that is essential for pathogenic preservation in the human organism, as it represents a reaction against the hidden abilities of host organisms to lyse them efficiently from the moment of the first intracellular infection. Given that the synthesis rate of interferon-gamma, which is part of Type II interferons, partially depends upon the synthesis rate of interferon-beta, the impact of the listed non-structural proteins touches the normal synthesis rate of interferon-gamma, which is responsible with a normal signalling rate from the infected cells to neighbouring cells. And such signals in turn stimulate the neighbouring cells to produce and send antiviral signals to the immune system. Non-structural protein 16 requires activation by nsp10 and hence, nsp10 is known as the activator protein, whilst nsp16 is known as the effector protein. They then dimerize to form the 2’-O-Methyltransferase complex, and such nomenclature of the enzyme complex was established because nsp16 caps the 5’ end of the mRNA molecule by attaching a methyl group to it. One study showed that SARS-CoV-2 did not induce interferon production and signalling in pHAE cell cultures. Namely, there was no detectable interferon-alpha of any subtype, and a low rate of synthesis and signalling of interferon-beta1 and interferon-lambda1, with normalised read counts that were lower than the value of 10. Furthermore, several genes involved in the pattern recognition reception and signalling cascade leading to Interferon I synthesis, including RIG-I, MDA5, TBK1, TRAF6, IRF-3 and IRF-7, displayed little to no transcription activities in response to the viral infection, which further indicates the impact of non-structural proteins 1 and 16 upon the sensitivity of the host cell to the virus (Abigail V. et al, 2020).
The methyl group is transported all the way from the S-Adenosyl-L-Methionine pocket, which is formed after joining of the S-Adenosyl molecule with the L-Methionine amino acid. The methyl group is transported to nsp13 and nsp14 before the nsp16 effector protein binds it. Non-structural protein 1 (nsp1) is the most problematic interferon antagonist because it significantly suppresses interferon-alpha and -beta synthesis, and because it was shown to suppresses interferon-lambda synthesis as well during rotavirus infection (Iaconis et al, 2021) and porcine epidemic diarrhoea virus (Zhang et al, 2018), thereby potentially amplifying the impairment of the formation of proper first and second-line immune defences. An impairment of such defences very likely have significant implications upon adaptive immune responses, and likewise, they can cause a higher incidence of moderate and severe disease. Given that Type III Interferon was only discovered in 2003, has the scientific community investigated the relationship between the viral non-structural protein 1 and interferon-lambda synthesis, and are there any odds that the SARS-CoV-2 nsp1 suppresses to any extent the synthesis of interferon-lambda, since one experiment involving a dosage of interferon-lambda2 in mice displayed positive results with regards to a mitigation of the disease (Chong et al, 2021)?
There can be three principal categories of Type I and III Interferon responses: early response, delayed response and an absent response. The first is followed by a firm restriction of viral load increase, enhanced regulation of pro-inflammatory responses and mild clinical forms of the disease. The second is followed by a dysregulated inflammatory monocyte-macrophage response, severe forms of pneumonia and lung tissue damage. A delayed and exaggerated Type I Interferon response will generally overstimulate pro-inflammatory mechanisms and stimulate the development of more severe forms of the disease. The third is followed by a high viral load, longer intensive care unit visits, invasive ventilation and a poor prognosis. Likewise, we can deduce that an administration of nasal sprays prophylactically might in turn be more important before the onset of the disease than after symptoms have occured and our hypothesis is that patients would better receive the nasal spray either before they encounter any clinical forms of the disease, in the first stages of the clinical display, before the peak of the viral load has been reached, or in any other disease stages that do not involve serious symptoms and severe disease (Fatemeh S. et al, 2021). A delayed clearance of the viral load is likely a common consequence of Type I and III Interferon-based viral immune evasion.
Given the exponential nature of the increase of the viral load and the number of infected cells as the SARS-CoV-2 infection progresses, early Type I and III Interferon responses are much lower in abundance than delayed responses, given that early responses will only implicate the production and manufacture of the chemokines in the first few infected cells. Delayed responses will involve the activation of interferon-encoding genes in many more cells, resulting in the production of an amount of interferon that will rather contribute to pathogenesis and aggravation of inflammatory disease, given that the products of interferon-stimulated genes include important pro-inflammatory chemokines, such as CXCL10, CCL2 and CCL5. An increased synthesis rate of pro-inflammatory chemokines and cytokines is highly associated with a decreased quality of immune performance. Likewise, it is important to acknowledge the “double-edged sword”-like nature of Type I (i.e. IFN alpha-2b, beta-1, delta, epsilon, kappa and omega) and Type III Interferons (i.e. IFN lambda1, 2 and 3) and hold fast to the criticality of robust first-line immune responses during SARS-CoV-2 infection. The most important sub-domains of interferons with regards to building important anti-viral and anti-inflammatory signals, alongside shaping important adaptive immunity pathways, represent interferons alpha-2b, epsilon, omega, lambda1, lambda2 and lambda3, although interferons beta1 also represent chemokines with interesting potential immunomodulatory and boosting characteristics. Given that children and young adults generally have first and second-line immune defences that are more robust in nature than old adults, and that the levels of interferon epsilon and interferon omega were found to be significantly higher during SARS-CoV-2 infections in young people than in old adults, and that SARS-CoV-2 was found to affect older people pronouncedly more disproportionately, it is likely that the two interferon sub-domains also play an outstanding role in maintaining a balance between anti- and pro-inflammatory immune factors whilst strongly stimulating the recruitment of NK cells, dendritic cells, as well as of B- and T-lymphocytes (Pierangeli et al., 2022). Nevertheless, the Omicron variant was found to affect younger people much more than the previous major variants, which possibly means that the new variant escaped interferon epsilon and omega signals significantly more. Likewise, the debate on whether interferon alpha-2b plays more relevant immunising and immunisation-adjuvant roles than interferons epsilon and omega remains strong, and further research is needed upon this matter.
Once the +ssRNA of the novel coronavirus enters in the host cell via an endosome, toll-like receptors 7 and 8 become activated as a result of the detection of pathogen-associated molecular patterns, which are either found on the pathogen’s genome or are generated during cellular infection. Following TLR7/8 activation, MyD88 binds to the pattern recognition receptor and becomes phosphorylated. As a result, three relay proteins are phosphorylated and will act as transcription factors for the synthesis of Type I and Type III interferons; AP1, IRF7 and NF-kB. Following the expression of the interferon-encoding genes in cause, the newly produced interferon proteins will undergo exocytosis and signalling, which will be autocrine and paracrine in nature. Once reaching neighbouring cells, Type I Interferons bind to the IFNAR1/2 receptor, whilst Type III Interferons bind to the IFNLR1/IL10R2 receptor. Following this event, the JAK1 and STAT2 molecules will become phosphorylated, leading to the phosphorylation of STAT1 and STAT2 and their dimerisation. IRF9 then binds to the STAT1-STAT2 phosphorylated dimer to form the STAT1-STAT2-IRF9 trimer before Interferon-Stimulated Genes will become activated. Following the signalling cascade, the ISGs will express anti-viral and anti-inflammatory signals that will be playing a critical role in shaping adaptive immune responses. Namely, the products of hundreds of activated ISGs seem to stimulate a desired level of antiviral immune responses by dendritic cells via antigenic presentation, as well as helper CD4+ and cytotoxic CD8+ T-lymphocytes via supporting plasma cells in the production of qualitative antibodies and inducing the lysis of infected cells respectively. Some of the ISG products, like the IFITM3, play major flexible roles in linking first and second-line immune responses to the adaptive immune system. Likewise, a significant impairment of Type I and Type III Interferon production and signalling result in severe implications for the adaptive immune response. The viral non-structural protein 1 (NS1 or nsp1) represents an important example of a viral component that is a result of an evolutionary response to impair first-line immune responses. Interestingly, human host cells developed anti-viral evolutionary responses to include the ability of such viruses to inhibit first-line immune responses. The 2′,5′ oligoadenylate synthase proteins 1,2 and 3, protein kinase R, nuclear factor 90 and interferon-stimulated gene product 15 represent proteins that restrict the ability of viruses like Influenza A and SARS-CoV-2 to replicate, and yet nsp1 was found to inhibit the activity of such proteins, alongside cleaving and lysing the mRNA encoding Type I Interferons. The binding capabilities of the viral RNA specifying nsp1 inhibits the activities of the 2′,5′ oligoadenylate synthase proteins and prevents RNaseL activation, leading to an inhibited process of viral RNA degradation. The viral RNA-inhibiting activities of protein kinase R and nuclear factor 90 shows how human host cells and the virus have co-evolved, and nsp1 has been helping the virus escape such proteins. Nuclear factor 90 is possibly not produced by Interferon-Stimulated Genes, which indicates that the evolutionary conflict between first-line immune defences and respiratory viruses of such nature has been more generalised than previously thought. Furthermore, interferon-stimulated gene product 15, which is produced by one of the most expressed interferon-stimulated genes, has been shown to target non-structural protein 1, as Isg15-deficient mice were shown to be more susceptible to Influenza A infection and that the pathogenic protein was recently displayed as a target of ISGylation. Moreover, Influenza A viruses also developed PB1-F2 and PA-X proteins to bypass innate immune responses, by inhibiting the process of viral RNA sensing and significantly downregulating the Type I and Type III Interferon-induced signalling cascades and the apoptotic process of infected cells (McKellar et al., 2021).
Type I Interferons have recently been found not to recruit NK cells directly, but through the activation of inflammatory chemokines and monocytes (CCL2, CCL5, CXCL10 and IMMs) (Lee AJ et al., 2019). Interferon-stimulated genes produce various inflammatory chemokines, such as CCL2 and CXCL10, which are responsible with the activation of inflammatory monocytes and dendritic cells, as well as with the recruitment of natural killer cells, which in turn activate macrophages and interferon-gamma, which belongs to the second domain of interferons, and induce the lysis of infected cells. The activation of antigen-presenting cells and the recruitment of natural killer cells will ultimately shape the processes of CD4+ and CD8+ T-lymphocyte recruitment, as well as the quality of antibody production and specification via the process of V(D)J antibody gene rearrangement in maturing B-Lymphocytes. A dysregulated synthesis rate of Type I and III Interferons result in an increased CXCL10 signalling extent, which in turn will inhibit the proliferation of myeloid progenitor cells (Khalil et al., 2021) and increase the level of p38-mediated primary T-lymphocyte apoptosis (Sidahmed et al., 2012). As a result, the risks for the development of deficiencies in myeloid cell (i.e. neutrophil and dendritic cell) and lymphoid cell ( helper CD4+ and cytotoxic CD8+ T-lymphocyte) counts, thereby increasing the probability of significant adaptive immune consequences. CCL2 and CXCL2 were found to be capable of clearing tissues from the SARS-CoV viral load without the help of helper- and cytotoxic-T-lymphocytes, as well as of neutralizing antibodies, twelve days after the moment of first-cell-infection, and this finding indicates the high importance of activating antiviral innate immune responses by recruiting neutrophils, monocytes and macrophages toward the infected tissues. It was also shown that hyper-activated interleukin-6 and interferon-gamma-related pathways were associated with a higher severity of COVID-19 (Lagunas-Rangel et al., 2020), potentially meaning that delayed Type I and III Interferon responses are associated with higher signalling rates of IFN gamma and IL-6, as a significantly higher number of infected cells would almost simultaneously produce Type I and III interferons and likewise, their number would be much higher than in the cases when interferons are produced and undergo signalling early. The fact that the levels of inflammatory chemokines like CCL3, CCL5, CCL20 and CXCL10 were considerably higher than the levels of inflammatory chemokines secreted by CD14+CD16+ inflammatory chemokines in COVID-19 patients with developed acute respiratory distress syndrome (ARDS), unlike in the case of non-COVID-19 related viral and bacterial infections that resulted in the development of ARDS, when the chemokine levels were similar, represents a significant sign that the principle immunological problem caused by the novel coronavirus is not only related to, but based upon a disrupted timing and extent of Type I and III Interferon system activation. Moreover, in the case of the SARS epidemic, the virus is also capable of inhibiting Type I and III Interferon signalling and once interferon-stimulated genes are finally expressed, inflammatory chemokines, like CCL3, CCL7, CCL8 and CXCL10 are released and also contribute to the onset of the disease, which further suggests how several respiratory viruses have co-evolved with the interferon system. Although SARS-CoV and MERS-CoV display similar chemokine profiles, performed comparative studies showed that MERS-CoV infection results in higher activation rates of the CXCL10 inflammatory chemokine, and this may be an important reason why the systemic inflammatory extent and death rate of MERS are higher. CXCL10, CXCL8 and CCL2 represent potentially important markers of SARS, MERS and SARS-CoV-2 infection and onset of infectious disease, and the activation rate of CXCL10 is particularly analysed in COVID-19 patients. Such a chemokine binds to the CXCR3 receptor to become activated and stimulate the recruitment of natural killer cells, T-helper cells 1, cytotoxic CD8+ T-cells, as well as Th1-related immune responses, and its concentration is directly proportional with the severity of the infectious disease. It was found to be positively-regulated during early stages of the SARS-CoV-2 infection, which further indicates that its extent of synthesis is dependent on the timing of Type I and III Interferon synthesis, as well as autocrine and paracrine signalling.
The option of using a UV-attenuated SARS-CoV-2 specimen with a deletion in the genes encoding the non-structural proteins 1 and 16 could have been the best vaccination candidate, had the spike protein not acted as a superantigen, caused hyperinflammation via Toll-Like Receptor 4 signalling, weakened genes implicated in DNA repair and antibody gene rearrangement, entered the lymphatic system and caused damage to the endothelium, crossing the endothelial barrier and entering the bloodstream. We believe that the main problem is the great level of toxicity the spike protein has been displaying through severe cases of COVID-19. Furthermore, during the SARS epidemic, researchers developed the TP29 small peptide to separate the activator nsp10 from the effector nsp16 to prevent a large extent of 5′ viral -ssRNA capping, as well as the oral methioninase enzyme to digest the S-Adenosyl-L-Methionine pocket of the virus in order to expose the concerned non-structural proteins to lytic factors and prevent the process of 5′ viral mRNA capping. Almost two decades after, it was discovered that the novel coronavirus produce the same non-structural proteins and S-Adenosyl-L-Methionine pocket to camouflage itself and prevent the activation of the host cell’s pattern recognition receptors. Likewise, and the two early approaches could show significant efficacy and bring insignificant financial demands in the pharmaceutical market, and researchers showed that oral methoninase displays efficacy against COVID-19 as well (Hoffman et al., 2020). Moreover, there seems to be another method to evolutionarily combat the pathogen, by manually stimulating immunisation through the development of IgM super-antibodies to directly remove the viral camouflage, by tackling the non-structural proteins 1 and 16 inside the infected cells. The immune system could be trained in this way as well to build a better interferon-based defence against viruses that gained an evolutionary advantage of suppressing it. The problems with such an approach are the massive financial demands and a precision of the intervention that might be too elevated, which means it could overall bring an increased risk of adverse reactions. Boosting the mucosal immunity, on the other hand, represents an approach that has been tested numerous times, and many of the performed tests indicated outstanding positive results, despite a number of concerns of inefficacy and high financial demands from a number of critics. Concerns include a possible relatively weak connection between the development of qualitative IgA antibodies in the mucosal immune system and the development of qualitative IgG antibodies in the systemic immune system due to a high complexity of the local immunity. However, tests implicating the stimulation of IgA synthesis have shown outstanding prophylactic efficacy, with very few clinical trial participants experiencing infection or re-infection in the future. The COVID-19 pandemic was not exempt in this case, as attempts of intranasal prophylaxis and immunisation were associated with the development of long-term immune memory against the virus and the spike protein. Results have strongly indicated the importance of developing IgA-mediated mucosal immunity in the prevention of moderate and severe disease. Moreover, the fact that oral methioninase was shown to have significant efficacy in prophylaxis and early treatment further indicates the high potential of mucosal immunity in preventing the onset of severe infectious disease. One early therapeutic approach implicated the administration of inhalable IgA immunoglobulins that had previously been exposed to the spike protein of the Omicron variant, into the nasal cavity of K18-ACE2 transgenic members of the Mus. musculus species that were infected with the Omicron variant. The approach was shown to be more efficacious than an IgG Fc-based prophylaxis and treatment, and it used IgA antibodies that had been synthesised and secreted in Pichia pastoris for cost-effectiveness purposes (Qi Li et al., 2022).”

Given the powerful effects of the combination of restricted C5a complement activation and a robust activation of Type I and III Interferon signalling, updating vaccinology accordingly may slowly reduce the intensity and morbidity of numerous diseases from “incurable” to ” flu and common cold-like” as decades and centuries pass. This may be the case given the central role of immunology in facilitating general human and animal wellbeing. COVID-19 may represent a very important opportunity to discover the hidden power of human natural immunity and to facilitate the inclusion of sharpening natural immunity into the efforts of vaccinology-related medical research. After all, it might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms, which visibly indicates that vaccinology has to be updated to help the human immune system dominate pathogenic agents of concern again. To note, for scientific and academic research, the term “sensationalisation” represents one of the most important antagonistic terms, and big words have often been disproven in front of the committee. Likewise, it is of an essence for scientists and academicians to perform their due diligence before making any scientific observation, and this study is not exempt from the obligation to perform prior due diligence.


Overall, it is considerably possible that there is major hope ahead, and it only takes a major willpower of the societal collective that a massive difference will be made in our favour, both in ideological and health planes. It is only us who can make such a difference. The only condition that this progress may happen is that we will improve our moral condition, as we went through some challenging times in the past few centuries. If we combine this possible scenario with a return to our origins, then we will not only live life to the fullest, but perceive time as slower and thereby, really experience a long life. We may call this scenario a Revolution without a (physical) revolution, and this is possible. Protesting is good, but making changes from the inner to the outer is better.


Reference list


  1. Lazear, H. M., Schoggins, J. W., & Diamond, M. S. (2019). Shared and Distinct Functions of Type I and Type III Interferons. Immunity, 50(4), 907–923. https://doi.org/10.1016/j.immuni.2019.03.025
  2. Stanifer, M. L., Guo, C., Doldan, P., & Boulant, S. (2020). Importance of Type I and III Interferons at Respiratory and Intestinal Barrier Surfaces. Frontiers in immunology, 11, 608645. https://doi.org/10.3389/fimmu.2020.608645
  3. McNab, F., Mayer-Barber, K., Sher, A., Wack, A., & O’Garra, A. (2015). Type I interferons in infectious disease. Nature reviews. Immunology, 15(2), 87–103. https://doi.org/10.1038/nri3787
  4. David Vremec, Meredith O’Keeffe, Hubertus Hochrein, Martina Fuchsberger, Irina Caminschi, Mireille Lahoud, Ken Shortman; Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells, and interferon-producing killer dendritic cells. Blood 2007; 109 (3): 1165–1173. doi: https://doi.org/10.1182/blood-2006-05-015354
  5. Odendall, C., & Kagan, J. C. (2015). The unique regulation and functions of type III interferons in antiviral immunity. Current opinion in virology, 12, 47–52. https://doi.org/10.1016/j.coviro.2015.02.003
  6. Malmgaard L. (2004). Induction and regulation of IFNs during viral infections. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 24(8), 439–454. https://doi.org/10.1089/1079990041689665
  7. Mesev, E. V., LeDesma, R. A., & Ploss, A. (2019). Decoding type I and III interferon signalling during viral infection. Nature microbiology, 4(6), 914–924. https://doi.org/10.1038/s41564-019-0421-x
  8. Ank, N., West, H., Bartholdy, C., Eriksson, K., Thomsen, A. R., & Paludan, S. R. (2006). Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. Journal of virology, 80(9), 4501–4509. https://doi.org/10.1128/JVI.80.9.4501-4509.2006
  9. Mordstein, M., Michiels, T., & Staeheli, P. (2010). What have we learned from the IL28 receptor knockout mouse?. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 30(8), 579–584. https://doi.org/10.1089/jir.2010.0061
  10. Barber G. N. (2001). Host defense, viruses and apoptosis. Cell death and differentiation, 8(2), 113–126. https://doi.org/10.1038/sj.cdd.4400823
  11. Ezelle, H. J., Balachandran, S., Sicheri, F., Polyak, S. J., & Barber, G. N. (2001). Analyzing the mechanisms of interferon-induced apoptosis using CrmA and hepatitis C virus NS5A. Virology, 281(1), 124–137. https://doi.org/10.1006/viro.2001.0815
  12. Gil, J., & Esteban, M. (2000). The interferon-induced protein kinase (PKR), triggers apoptosis through FADD-mediated activation of caspase 8 in a manner independent of Fas and TNF-alpha receptors. Oncogene, 19(32), 3665–3674. https://doi.org/10.1038/sj.onc.1203710
  13. Sträter, J., & Möller, P. (2004). TRAIL and viral infection. Vitamins and hormones, 67, 257–274. https://doi.org/10.1016/S0083-6729(04)67014-2
  14. Robbins, M. A., Maksumova, L., Pocock, E., & Chantler, J. K. (2003). Nuclear factor-kappaB translocation mediates double-stranded ribonucleic acid-induced NIT-1 beta-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptor-associated ligand (TRAIL). Endocrinology, 144(10), 4616–4625. https://doi.org/10.1210/en.2003-0266
  15. Tan, X., Sun, L., Chen, J., & Chen, Z. J. (2018). Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids. Annual review of microbiology, 72, 447–478. https://doi.org/10.1146/annurev-micro-102215-095605
  16. Roers, A., Hiller, B., & Hornung, V. (2016). Recognition of Endogenous Nucleic Acids by the Innate Immune System. Immunity, 44(4), 739–754. https://doi.org/10.1016/j.immuni.2016.04.002
  17. Luecke, S., & Paludan, S. R. (2017). Molecular requirements for sensing of intracellular microbial nucleic acids by the innate immune system. Cytokine, 98, 4–14. https://doi.org/10.1016/j.cyto.2016.10.003
  18. Ablasser, A., Hertrich, C., Waßermann, R., & Hornung, V. (2013). Nucleic acid driven sterile inflammation. Clinical immunology (Orlando, Fla.), 147(3), 207–215. https://doi.org/10.1016/j.clim.2013.01.003
  19. Mathern, D. R., & Heeger, P. S. (2015). Molecules Great and Small: The Complement System. Clinical journal of the American Society of Nephrology : CJASN, 10(9), 1636–1650. https://doi.org/10.2215/CJN.06230614
  20. Kunz, N., & Kemper, C. (2021). Complement Has Brains-Do Intracellular Complement and Immunometabolism Cooperate in Tissue Homeostasis and Behavior?. Frontiers in immunology, 12, 629986. https://doi.org/10.3389/fimmu.2021.629986
  21. West, E. E., Kunz, N., & Kemper, C. (2020). Complement and human T cell metabolism: Location, location, location. Immunological reviews, 295(1), 68–81. https://doi.org/10.1111/imr.12852
  22. Shibabaw, T., Molla, M. D., Teferi, B., & Ayelign, B. (2020). Role of IFN and Complements System: Innate Immunity in SARS-CoV-2. Journal of inflammation research, 13, 507–518. https://doi.org/10.2147/JIR.S267280
  23. Woo, S. R., Corrales, L., & Gajewski, T. F. (2015). Innate immune recognition of cancer. Annual review of immunology, 33, 445–474. https://doi.org/10.1146/annurev-immunol-032414-112043
  24. Haller O. (2015). A tribute to Jean Lindenmann, co-discoverer of interferon (1924-2015). Cytokine, 76(1), 113–115. https://doi.org/10.1016/j.cyto.2015.02.029
  25. Roumenina, L. T., Daugan, M. V., Noé, R., Petitprez, F., Vano, Y. A., Sanchez-Salas, R., Becht, E., Meilleroux, J., Clec’h, B. L., Giraldo, N. A., Merle, N. S., Sun, C. M., Verkarre, V., Validire, P., Selves, J., Lacroix, L., Delfour, O., Vandenberghe, I., Thuilliez, C., Keddani, S., … Fridman, W. H. (2019). Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth. Cancer immunology research, 7(7), 1091–1105. https://doi.org/10.1158/2326-6066.CIR-18-0891
  26. Posch, W., Bermejo-Jambrina, M., Steger, M., Witting, C., Diem, G., Hörtnagl, P., Hackl, H., Lass-Flörl, C., Huber, L. A., Geijtenbeek, T., & Wilflingseder, D. (2021). Complement Potentiates Immune Sensing of HIV-1 and Early Type I Interferon Responses. mBio, 12(5), e0240821. https://doi.org/10.1128/mBio.02408-21
  27. Bermejo-Jambrina, M., Blatzer, M., Jauregui-Onieva, P., Yordanov, T. E., Hörtnagl, P., Valovka, T., Huber, L. A., Wilflingseder, D., & Posch, W. (2020). CR4 Signaling Contributes to a DC-Driven Enhanced Immune Response Against Complement-Opsonized HIV-1. Frontiers in immunology, 11, 2010. https://doi.org/10.3389/fimmu.2020.02010
  28. Posch, W., Bermejo-Jambrina, M., Lass-Flörl, C., & Wilflingseder, D. (2020). Role of Complement Receptors (CRs) on DCs in Anti-HIV-1 Immunity. Frontiers in immunology, 11, 572114. https://doi.org/10.3389/fimmu.2020.572114
  29. Steinman, R. M., Granelli-Piperno, A., Pope, M., Trumpfheller, C., Ignatius, R., Arrode, G., Racz, P., & Tenner-Racz, K. (2003). The interaction of immunodeficiency viruses with dendritic cells. Current topics in microbiology and immunology, 276, 1–30. https://doi.org/10.1007/978-3-662-06508-2_1
  30. Lekkerkerker, A. N., van Kooyk, Y., & Geijtenbeek, T. B. (2006). Viral piracy: HIV-1 targets dendritic cells for transmission. Current HIV research, 4(2), 169–176. https://doi.org/10.2174/157016206776055020
  31. Elkon, K. B., & Santer, D. M. (2012). Complement, interferon and lupus. Current opinion in immunology, 24(6), 665–670. https://doi.org/10.1016/j.coi.2012.08.004
  32. Zhao, X., Zhao, Y., Du, J., Gao, P., & Zhao, K. (2021). The Interplay Among HIV, LINE-1, and the Interferon Signaling System. Frontiers in immunology, 12, 732775. https://doi.org/10.3389/fimmu.2021.732775
  33. Doi, A., Iijima, K., Kano, S., & Ishizaka, Y. (2015). Viral protein R of HIV type-1 induces retrotransposition and upregulates glutamate synthesis by the signal transducer and activator of transcription 1 signaling pathway. Microbiology and immunology, 59(7), 398–409. https://doi.org/10.1111/1348-0421.12266
  34. Harman, A. N., Nasr, N., Feetham, A., Galoyan, A., Alshehri, A. A., Rambukwelle, D., Botting, R. A., Hiener, B. M., Diefenbach, E., Diefenbach, R. J., Kim, M., Mansell, A., & Cunningham, A. L. (2015). HIV Blocks Interferon Induction in Human Dendritic Cells and Macrophages by Dysregulation of TBK1. Journal of virology, 89(13), 6575–6584. https://doi.org/10.1128/JVI.00889-15
  35. Tunbak, H., Enriquez-Gasca, R., Tie, C., Gould, P. A., Mlcochova, P., Gupta, R. K., Fernandes, L., Holt, J., van der Veen, A. G., Giampazolias, E., Burns, K. H., Maillard, P. V., & Rowe, H. M. (2020). The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s. Nature communications, 11(1), 5387. https://doi.org/10.1038/s41467-020-19170-5
  36. Yu, Q., Carbone, C. J., Katlinskaya, Y. V., Zheng, H., Zheng, K., Luo, M., Wang, P. J., Greenberg, R. A., & Fuchs, S. Y. (2015). Type I interferon controls propagation of long interspersed element-1. The Journal of biological chemistry, 290(16), 10191–10199. https://doi.org/10.1074/jbc.M114.612374
  37. Kuriyama, Y., Shimizu, A., Kanai, S., Oikawa, D., Tokunaga, F., Tsukagoshi, H., & Ishikawa, O. (2021). The synchronized gene expression of retrotransposons and type I interferon in dermatomyositis. Journal of the American Academy of Dermatology, 84(4), 1103–1105. https://doi.org/10.1016/j.jaad.2020.05.051
  38. Cassius, C., Amode, R., Delord, M., Battistella, M., Poirot, J., How-Kit, A., Lepelletier, C., Jachiet, M., de Masson, A., Frumholtz, L., Cordoliani, F., Boccara, D., Lehmann-Che, J., Wong, J., Dubanchet, S., Alberdi, A. J., Merandet, M., Bagot, M., Bensussan, A., Bouaziz, J. D., … Le Buanec, H. (2020). MDA5+ Dermatomyositis Is Associated with Stronger Skin Type I Interferon Transcriptomic Signature with Upregulation of IFN-κ Transcript. The Journal of investigative dermatology, 140(6), 1276–1279.e7. https://doi.org/10.1016/j.jid.2019.10.020
  39. Burns K. H. (2020). Our Conflict with Transposable Elements and Its Implications for Human Disease. Annual review of pathology, 15, 51–70. https://doi.org/10.1146/annurev-pathmechdis-012419-032633
  40. Mustelin, T., & Ukadike, K. C. (2020). How Retroviruses and Retrotransposons in Our Genome May Contribute to Autoimmunity in Rheumatological Conditions. Frontiers in immunology, 11, 593891. https://doi.org/10.3389/fimmu.2020.593891
  41. Crow M. K. (2010). Long interspersed nuclear elements (LINE-1): potential triggers of systemic autoimmune disease. Autoimmunity, 43(1), 7–16. https://doi.org/10.3109/08916930903374865
  42. Ren, Y., Cui, G., & Gao, Y. (2021). Research progress on inflammatory mechanism of primary Sjögren syndrome. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences, 50(6), 783–794. https://doi.org/10.3724/zdxbyxb-2021-0072
  43. Gamdzyk, M., Doycheva, D. M., Araujo, C., Ocak, U., Luo, Y., Tang, J., & Zhang, J. H. (2020). cGAS/STING Pathway Activation Contributes to Delayed Neurodegeneration in Neonatal Hypoxia-Ischemia Rat Model: Possible Involvement of LINE-1. Molecular neurobiology, 57(6), 2600–2619. https://doi.org/10.1007/s12035-020-01904-7
  44. Kuriyama, Y., Shimizu, A., Kanai, S. et al.Coordination of retrotransposons and type I interferon with distinct interferon pathways in dermatomyositis, systemic lupus erythematosus and autoimmune blistering disease. Sci Rep 11, 23146 (2021). https://doi.org/10.1038/s41598-021-02522-6
  45. Tsuji, R. F., Geba, G. P., Wang, Y., Kawamoto, K., Matis, L. A., & Askenase, P. W. (1997). Required early complement activation in contact sensitivity with generation of local C5-dependent chemotactic activity, and late T cell interferon gamma: a possible initiating role of B cells. The Journal of experimental medicine, 186(7), 1015–1026. https://doi.org/10.1084/jem.186.7.1015
  46. Narunsky-Haziza, L., Sepich-Poore, G. D., Livyatan, I., Asraf, O., Martino, C., Nejman, D., Gavert, N., Stajich, J. E., Amit, G., González, A., Wandro, S., Perry, G., Ariel, R., Meltser, A., Shaffer, J. P., Zhu, Q., Balint-Lahat, N., Barshack, I., Dadiani, M., … Straussman, R. (2022). Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell, 185(20), 3789–3806. https://doi.org/10.1016/j.cell.2022.09.005
  47. Dohlman, A. B., Klug, J., Mesko, M., Gao, I. H., Lipkin, S. M., Shen, X., & Iliev, I. D. (2022). A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell, 185(20), 3807–3822. https://doi.org/10.1016/j.cell.2022.09.015
  48. Di Martino, J.S., Nobre, A.R., Mondal, C. et al. A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nat Cancer 3, 90–107 (2022). https://doi.org/10.1038/s43018-021-00291-9
  49. Luo, K., Li, N., Ye, W., Gao, H., Luo, X., & Cheng, B. (2022). Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy. Molecules (Basel, Switzerland), 27(14), 4638. https://doi.org/10.3390/molecules27144638
  50. Corrales, L., McWhirter, S. M., Dubensky, T. W., Jr, & Gajewski, T. F. (2016). The host STING pathway at the interface of cancer and immunity. The Journal of clinical investigation, 126(7), 2404–2411. https://doi.org/10.1172/JCI86892
  51. Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J., & Kroemer, G. (2015). Type I interferons in anticancer immunity. Nature reviews. Immunology, 15(7), 405–414. https://doi.org/10.1038/nri3845
  52. Bracci, L., La Sorsa, V., Belardelli, F., & Proietti, E. (2008). Type I interferons as vaccine adjuvants against infectious diseases and cancer. Expert review of vaccines, 7(3), 373–381. https://doi.org/10.1586/14760584.7.3.373
  53. Abushahba, W., Balan, M., Castaneda, I., Yuan, Y., Reuhl, K., Raveche, E., de la Torre, A., Lasfar, A., & Kotenko, S. V. (2010). Antitumor activity of type I and type III interferons in BNL hepatoma model. Cancer immunology, immunotherapy : CII, 59(7), 1059–1071. https://doi.org/10.1007/s00262-010-0831-3
  54. Lasfar, A., de laTorre, A., Abushahba, W., Cohen-Solal, K. A., Castaneda, I., Yuan, Y., Reuhl, K., Zloza, A., Raveche, E., Laskin, D. L., & Kotenko, S. V. (2016). Concerted action of IFN-α and IFN-λ induces local NK cell immunity and halts cancer growth. Oncotarget, 7(31), 49259–49267. https://doi.org/10.18632/oncotarget.10272
  55. Saadeldin, M. K., Abdel-Aziz, A. K., & Abdellatif, A. (2021). Dendritic cell vaccine immunotherapy; the beginning of the end of cancer and COVID-19. A hypothesis. Medical hypotheses, 146, 110365. https://doi.org/10.1016/j.mehy.2020.110365
  56. Santini, S. M., Lapenta, C., Santodonato, L., D’Agostino, G., Belardelli, F., & Ferrantini, M. (2009). IFN-alpha in the generation of dendritic cells for cancer immunotherapy. Handbook of experimental pharmacology, (188), 295–317. https://doi.org/10.1007/978-3-540-71029-5_14
  57. Katlinski, K. V., Gui, J., Katlinskaya, Y. V., Ortiz, A., Chakraborty, R., Bhattacharya, S., Carbone, C. J., Beiting, D. P., Girondo, M. A., Peck, A. R., Puré, E., Chatterji, P., Rustgi, A. K., Diehl, J. A., Koumenis, C., Rui, H., & Fuchs, S. Y. (2017). Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment. Cancer cell, 31(2), 194–207. https://doi.org/10.1016/j.ccell.2017.01.004
  58. Lu, C., Klement, J. D., Ibrahim, M. L., Xiao, W., Redd, P. S., Nayak-Kapoor, A., Zhou, G., & Liu, K. (2019). Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes. Journal for immunotherapy of cancer, 7(1), 157. https://doi.org/10.1186/s40425-019-0635-8
  59. Cho, C., Mukherjee, R., Peck, A. R., Sun, Y., McBrearty, N., Katlinski, K. V., Gui, J., Govindaraju, P. K., Puré, E., Rui, H., & Fuchs, S. Y. (2020). Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis. Oncogene, 39(38), 6129–6137. https://doi.org/10.1038/s41388-020-01424-7
  60. Alicea-Torres, K., Sanseviero, E., Gui, J., Chen, J., Veglia, F., Yu, Q., Donthireddy, L., Kossenkov, A., Lin, C., Fu, S., Mulligan, C., Nam, B., Masters, G., Denstman, F., Bennett, J., Hockstein, N., Rynda-Apple, A., Nefedova, Y., Fuchs, S. Y., & Gabrilovich, D. I. (2021). Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway. Nature communications, 12(1), 1717. https://doi.org/10.1038/s41467-021-22033-2
  61. Odnokoz, O., Yu, P., Peck, A. R., Sun, Y., Kovatich, A. J., Hooke, J. A., Hu, H., Mitchell, E. P., Rui, H., & Fuchs, S. Y. (2020). Malignant cell-specific pro-tumorigenic role of type I interferon receptor in breast cancers. Cancer biology & therapy, 21(7), 629–636. https://doi.org/10.1080/15384047.2020.1750297
  62. Fitzgerald-Bocarsly, P., & Feng, D. (2007). The role of type I interferon production by dendritic cells in host defense. Biochimie, 89(6-7), 843–855. https://doi.org/10.1016/j.biochi.2007.04.018
  63. Ali, S., Mann-Nüttel, R., Schulze, A., Richter, L., Alferink, J., & Scheu, S. (2019). Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver’s Seat. Frontiers in immunology, 10, 778. https://doi.org/10.3389/fimmu.2019.00778
  64. Gigante, M., Mandic, M., Wesa, A. K., Cavalcanti, E., Dambrosio, M., Mancini, V., Battaglia, M., Gesualdo, L., Storkus, W. J., & Ranieri, E. (2008). Interferon-alpha (IFN-alpha)-conditioned DC preferentially stimulate type-1 and limit Treg-type in vitro T-cell responses from RCC patients. Journal of immunotherapy (Hagerstown, Md. : 1997), 31(3), 254–262. https://doi.org/10.1097/CJI.0b013e318167b023
  65. Ma, Y., Su, X. Z., & Lu, F. (2020). The Roles of Type I Interferon in Co-infections With Parasites and Viruses, Bacteria, or Other Parasites. Frontiers in immunology, 11, 1805. https://doi.org/10.3389/fimmu.2020.01805
  66. Carrero J. A. (2013). Confounding roles for type I interferons during bacterial and viral pathogenesis. International immunology, 25(12), 663–669. https://doi.org/10.1093/intimm/dxt050
  67. Sette, A., & Crotty, S. (2021). Adaptive immunity to SARS-CoV-2 and COVID-19. Cell, 184(4), 861–880. https://doi.org/10.1016/j.cell.2021.01.007
  68. Müller, L., Aigner, P., & Stoiber, D. (2017). Type I Interferons and Natural Killer Cell Regulation in Cancer. Frontiers in immunology, 8, 304. https://doi.org/10.3389/fimmu.2017.00304
  69. Zhang, Y., Gargan, S., Roche, F. M., Frieman, M., & Stevenson, N. J. (2022). Inhibition of the IFN-α JAK/STAT Pathway by MERS-CoV and SARS-CoV-1 Proteins in Human Epithelial Cells. Viruses, 14(4), 667. https://doi.org/10.3390/v14040667
  70. Xia, H., Cao, Z., Xie, X., Zhang, X., Chen, J. Y., Wang, H., Menachery, V. D., Rajsbaum, R., & Shi, P. Y. (2020). Evasion of Type I Interferon by SARS-CoV-2. Cell reports, 33(1), 108234. https://doi.org/10.1016/j.celrep.2020.108234
  71. Rashid, F., Xie, Z., Suleman, M., Shah, A., Khan, S., & Luo, S. (2022). Roles and functions of SARS-CoV-2 proteins in host immune evasion. Frontiers in immunology, 13, 940756. https://doi.org/10.3389/fimmu.2022.940756
  72. Low, Z. Y., Zabidi, N. Z., Yip, A., Puniyamurti, A., Chow, V., & Lal, S. K. (2022). SARS-CoV-2 Non-Structural Proteins and Their Roles in Host Immune Evasion. Viruses, 14(9), 1991. https://doi.org/10.3390/v14091991
  73. Shibabaw T, Molla MD, Teferi B, Ayelign B. Role of IFN and Complements System: Innate Immunity in SARS-CoV-2. J Inflamm Res. 2020;13:507-518https://doi.org/10.2147/JIR.S267280
  74. Setaro, A. C., & Gaglia, M. M. (2021). All hands on deck: SARS-CoV-2 proteins that block early anti-viral interferon responses. Current research in virological science, 2, 100015. https://doi.org/10.1016/j.crviro.2021.100015
  75. Yuen, C. K., Lam, J. Y., Wong, W. M., Mak, L. F., Wang, X., Chu, H., Cai, J. P., Jin, D. Y., To, K. K., Chan, J. F., Yuen, K. Y., & Kok, K. H. (2020). SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerging microbes & infections, 9(1), 1418–1428. https://doi.org/10.1080/22221751.2020.1780953
  76. Santerre, M., Arjona, S. P., Allen, C. N., Shcherbik, N., & Sawaya, B. E. (2021). Why do SARS-CoV-2 NSPs rush to the ER?. Journal of neurology, 268(6), 2013–2022. https://doi.org/10.1007/s00415-020-10197-8
  77. Hackstadt, T., Chiramel, A. I., Hoyt, F. H., Williamson, B. N., Dooley, C. A., Beare, P. A., de Wit, E., Best, S. M., & Fischer, E. R. (2021). Disruption of the Golgi Apparatus and Contribution of the Endoplasmic Reticulum to the SARS-CoV-2 Replication Complex. Viruses, 13(9), 1798. https://doi.org/10.3390/v13091798
  78. Hui, K., Cheung, M. C., Perera, R., Ng, K. C., Bui, C., Ho, J., Ng, M., Kuok, D., Shih, K. C., Tsao, S. W., Poon, L., Peiris, M., Nicholls, J. M., & Chan, M. (2020). Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. The Lancet. Respiratory medicine, 8(7), 687–695. https://doi.org/10.1016/S2213-2600(20)30193-4
  79. Hossain, A., Akter, S., Rashid, A. A., Khair, S., & Alam, A. (2022). Unique mutations in SARS-CoV-2 Omicron subvariants’ non-spike proteins: Potential impacts on viral pathogenesis and host immune evasion. Microbial pathogenesis, 170, 105699. https://doi.org/10.1016/j.micpath.2022.105699
  80. Grant, A. H., Estrada, A., 3rd, Ayala-Marin, Y. M., Alvidrez-Camacho, A. Y., Rodriguez, G., Robles-Escajeda, E., Cadena-Medina, D. A., Rodriguez, A. C., & Kirken, R. A. (2021). The Many Faces of JAKs and STATs Within the COVID-19 Storm. Frontiers in immunology, 12, 690477. https://doi.org/10.3389/fimmu.2021.690477
  81. Kuypers F. A. (2022). Hyperinflammation, apoptosis, and organ damage. Experimental biology and medicine (Maywood, N.J.), 247(13), 1112–1123. https://doi.org/10.1177/15353702221090454
  82. Puhl, A. C., Gomes, G. F., Damasceno, S., Fritch, E. J., Levi, J. A., Johnson, N. J., Scholle, F., Premkumar, L., Hurst, B. L., Lee-Montiel, F., Veras, F. P., Batah, S. S., Fabro, A. T., Moorman, N. J., Yount, B. L., Dickmander, R. J., Baric, R. S., Pearce, K. H., Cunha, F. Q., Alves-Filho, J. C., … Ekins, S. (2022). Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice. ACS omega, 7(36), 31935–31944. https://doi.org/10.1021/acsomega.2c02794
  83. Romano, M., Ruggiero, A., Squeglia, F., Maga, G., & Berisio, R. (2020). A Structural View of SARS-CoV-2 RNA Replication Machinery: RNA Synthesis, Proofreading and Final Capping. Cells, 9(5), 1267. https://doi.org/10.3390/cells9051267
  84. Garg, A. D., & Agostinis, P. (2017). Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses. Immunological reviews, 280(1), 126–148. https://doi.org/10.1111/imr.12574
  85. Blank, T., & Prinz, M. (2017). Type I interferon pathway in CNS homeostasis and neurological disorders. Glia, 65(9), 1397–1406. https://doi.org/10.1002/glia.23154
  86. Tresse, E., Riera-Ponsati, L., Jaberi, E., Sew, W., Ruscher, K., & Issazadeh-Navikas, S. (2021). IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1. The EMBO journal, 40(11), e106868. https://doi.org/10.15252/embj.2020106868
  87. McDonough, A., Lee, R. V., & Weinstein, J. R. (2017). Microglial Interferon Signaling and White Matter. Neurochemical research, 42(9), 2625–2638. https://doi.org/10.1007/s11064-017-2307-8
  88. Ejlerskov, P., Hultberg, J. G., Wang, J., Carlsson, R., Ambjørn, M., Kuss, M., Liu, Y., Porcu, G., Kolkova, K., Friis Rundsten, C., Ruscher, K., Pakkenberg, B., Goldmann, T., Loreth, D., Prinz, M., Rubinsztein, D. C., & Issazadeh-Navikas, S. (2015). Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson’s Disease-like Dementia. Cell, 163(2), 324–339. https://doi.org/10.1016/j.cell.2015.08.069
  89. Magalhaes, J., Tresse, E., Ejlerskov, P., Hu, E., Liu, Y., Marin, A., Montalant, A., Satriano, L., Rundsten, C. F., Carlsen, E., Rydbirk, R., Sharifi-Zarchi, A., Andersen, J. B., Aznar, S., Brudek, T., Khodosevich, K., Prinz, M., Perrier, J. M., Sharma, M., Gasser, T., … Issazadeh-Navikas, S. (2021). PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Molecular psychiatry, 26(10), 6083–6099. https://doi.org/10.1038/s41380-021-01207-w
  90. Csépány, T., & Bereczki, D. (2004). Immunmoduláns kezelés sclerosis multiplexben [Immunomodulatory therapy in multiple sclerosis]. Ideggyogyaszati szemle, 57(11-12), 401–416.
  91. Kieseier, B. C., & Hartung, H. P. (2003). Current disease-modifying therapies in multiple sclerosis. Seminars in neurology, 23(2), 133–146. https://doi.org/10.1055/s-2003-41138
  92. Flachenecker P. (2004). Disease-modifying drugs for the early treatment of multiple sclerosis. Expert review of neurotherapeutics, 4(3), 455–463. https://doi.org/10.1586/14737175.4.3.455
  93. Tintoré M. (2009). New options for early treatment of multiple sclerosis. Journal of the neurological sciences, 277 Suppl 1, S9–S11. https://doi.org/10.1016/S0022-510X(09)70004-8
  94. Brochet B. (2008). Activité à long terme de l’acétate de glatiramère dans le traitement de la sclérose en plaques : état des connaissances [Long-term effects of glatiramer acetate in multiple sclerosis]. Revue neurologique, 164(11), 917–926. https://doi.org/10.1016/j.neurol.2008.02.045
  95. Gorlé, N., & Vandenbroucke, R. E. (2019). Interferons: A molecular switch between damage and repair in ageing and Alzheimer’s disease. Mechanisms of ageing and development, 183, 111148. https://doi.org/10.1016/j.mad.2019.111148
  96. Feng, E., Balint, E., Poznanski, S. M., Ashkar, A. A., & Loeb, M. (2021). Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes. Cells, 10(3), 708. https://doi.org/10.3390/cells10030708
  97. Frisch, S. M., & MacFawn, I. P. (2020). Type I interferons and related pathways in cell senescence. Aging cell, 19(10), e13234. https://doi.org/10.1111/acel.13234
  98. De Cecco, M., Ito, T., Petrashen, A. P., Elias, A. E., Skvir, N. J., Criscione, S. W., Caligiana, A., Brocculi, G., Adney, E. M., Boeke, J. D., Le, O., Beauséjour, C., Ambati, J., Ambati, K., Simon, M., Seluanov, A., Gorbunova, V., Slagboom, P. E., Helfand, S. L., Neretti, N., … Sedivy, J. M. (2019). L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature, 566(7742), 73–78. https://doi.org/10.1038/s41586-018-0784-9
  99. Wan, D., Jiang, W., & Hao, J. (2020). Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response. Frontiers in immunology, 11, 615. https://doi.org/10.3389/fimmu.2020.00615
  100. Chen, Y., & Colonna, M. (2021). Microglia in Alzheimer’s disease at single-cell level. Are there common patterns in humans and mice?. The Journal of experimental medicine, 218(9), e20202717. https://doi.org/10.1084/jem.20202717
  101. Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S., Hou, L., Baccarelli, A. A., Stewart, J. D., Li, Y., Whitsel, E. A., Wilson, J. G., Reiner, A. P., Aviv, A., Lohman, K., Liu, Y., Ferrucci, L., & Horvath, S. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging, 10(4), 573–591. https://doi.org/10.18632/aging.101414
  102. Lim, U., & Song, M. A. (2018). DNA Methylation as a Biomarker of Aging in Epidemiologic Studies. Methods in molecular biology (Clifton, N.J.), 1856, 219–231. https://doi.org/10.1007/978-1-4939-8751-1_12
  103. Rauchhaus, J., Robinson, J., Monti, L., & Di Antonio, M. (2022). G-quadruplexes Mark Sites of Methylation Instability Associated with Ageing and Cancer. Genes, 13(9), 1665. https://doi.org/10.3390/genes13091665
  104. Choo, O.-S., Lee, Y. Y., Kim, Y. S., Kim, Y. J., Lee, D. H., Kim, H., Jang, J. H., & Choung, Y.-H. (2022). Effect of statin on age-related hearing loss via drug repurposing. Biochimica Et Biophysica Acta (BBA) – Molecular Cell Research, 1869(11), 119331. https://doi.org/10.1016/j.bbamcr.2022.119331
  105. Gupta, S., Nakabo, S., Chu, J., Hasni, S., & Kaplan, M. J. (2020). Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus. medRxiv : the preprint server for health sciences, 2020.10.29.20222000. https://doi.org/10.1101/2020.10.29.20222000

By Anonymous Graduate

A graduate from a Science-related University Bachelor's, discussing public health corruption and half-truths promoted abundantly in mainstream Academia.

2 thoughts on “Must read: Huge breakthrough is possible”

Leave a Reply

Your email address will not be published. Required fields are marked *