ABSTRACT
A strong link between COVID-19 severity and HLAC* 04:01 allele has been replicated in several Caucasian populations including Armenians. The results have led to an idea that HLA-C*04:01 may affect the immune response via three biological mechanisms: (i) disruption of the HLA-C mediated protection harnessing natural killer cells (NK);(ii) causing NK hypo-responsiveness through KIR2DL1;or (iii) over-activation and exhaustion of CTL and NK cells by stimulating functional KIR2DS4. To test those hypotheses, we re-analyzed HLA-genotypes and RNA-sequencing data of Overmyer et al. [Cell Systems 2021;12:23-40]. An ordinal regression of patients' status (i.e., non-COVID vs. COVIDnon- ICU vs. COVID-ICU) against HLA-C has corroborated the increase in the disease severity with increasing HLA-C*04:01 dosage (p< 0.003). DESeq2 analyses of the transcriptome (16444 loci) within COVID subset mapped 3586 down-regulated and 4031 up-regulated loci to the disease severity at FDR p<0.05. The results of enrichment analyses of those 7617 genes indicated aberrations in processes, such as T cell activation, inflammatory response, positive regulation of both NK-mediated cytotoxicity and interferon-gamma production. However, only 563 down- and 341 up-regulated loci had nominally associated with the HLA-C*04:01 carriage, reflecting its genetic association with severe symptoms. Using GTEx data and rs5010528 as proxy for HLAC* 04:01 (R2 = 0.97, 1kG EUR cohort), we found that HLA-C*04:01 was associated with multiple tissue (e.g., lung, heart and blood) RNA expressional and splicing changes in >10 protein-coding loci situated close to HLA-C. The ontology analysis of the loci implicated HLA-C*04:01 in altering antigen processing and presentation of endogenous peptide antigen via HLA class I via ER pathway (FDR p<0.0001), protection from NKmediated cytotoxicity (p<0.004), and innate immune response to other organisms (p<0.009). The work was supported by the Science Committee of RA (grant E17).
ABSTRACT
Researches aimed at finding effective means of pathogenic therapy for this viral infection are extremely relevant. Researches of the last three years have established that some human pathogenic coronaviruses - MERS, SARS-CoV and SARS-CoV-2, contain aliphatic polyamines in their structure, which participate in the packaging of genetic material (DNA, RNA), as well as the nucleocapsid. Virus-host cell interactions also provide adhesion processes on the surface of the cytoplasmic membrane of target cells. In the intra-cellular space, aliphatic polyamines actively affect the translation and replication processes of the genetic material and necessary proteins of the virus itself, as well as the formation of daughter viruses. Long-term persistence in the SARS-CoV-2 infected organism is largely due to the absorption of polyamines by corona-virus localized in target cells of the blood and parenchymatous organs. Unfortunately, the above new facts did not serve as a prerequisite for finding effective means of pathogenetic therapy for COVID-19, based on the inhibition of polyamine-dependent processes that ensure long-term persistence of SARS-CoV-2 in the infected organism. We are talking about specific drugs such as alpha-difluoromethylornithine and its ana-logues, which are successfully used in oncology in the complex treatment of malignant neoplasms with the aim of lowering the level of aliphatic polyamines in the affected areas of malignantly transformed organs. We recommend the use of polyamine-free and polyamine-deficient diets for COVID-19 for the first time. In the planned study, we will present tables with food products of animal and vegetable origin, characterized by extremely low content and/or absence of aliphatic polyamines in them. At the same time, food products with a high content of aliphatic polyamines should be excluded from the general list of products recommended for COVID-19 patients. We also recommend the use of a polyamine-deficient diet (with a preventive purpose) during the COVID-19 pandemic to a wide contingent of practically healthy individuals, convalescents, medical staff of specialized infectious disease clinics, as well as family members of SARS-CoV-2 infected patients. Copyright © 2022, Yerevan State Medical University. All rights reserved.
ABSTRACT
This article presents our views on main scientific and methodological approaches regarding the advantages of conducting mass vaccination of healthy individuals and COVID-19 convalescents. First of all, the focus is on issues regarding the antigenic potencies of SARS-CoV-2, based on which vaccines have been created over the past three years that have successfully passed preclini-cal and clinical testing, as well as licensing. The subjects of specal discussion were aspects related to the short-term effect of the main vaccines, as a result of which revaccination is recommended. It is assumed that more than one antigenic determinant is expressed on the surface of SARS-CoV-2. In the conclusion paragraph, we have presented our own concept on most topical situational issues among the population of many countries in the process of vaccination against COVID-19. 1. Is it worth getting vaccinated at all if complications can arise that lead to disability and death even in practically healthy individuals, not to mention the elderly contingent with chronic diseases? 2. In making a positive decision, the question arises in terms of choosing a vaccine, since vaccines are used in different countries, in the production of which different scientific, methodological and technological approaches are used. 3. If there is a need for re-vaccination within a short period after the first vaccination? 4. As a rule, it is recommended to re-vaccinate in 14-30 days after the first vaccination. In this re-gard, there are concerns about the low efficacy (weak selective immunogenic activity) of vaccines. 5. How expedient, if not contraindicated, is to “fully” vaccinate patients in the recovery period, as well as over the next one to two months, if they have high levels of SARS-CoV-2 antibodies? 6. In case of re-vaccination, it is necessary to find out whether it is possible to get the second vaccination using a commercial vaccine of another manufacturer, especially since many developing countries do not currently have such a vaccine that has been introduced during the first vaccination. 7. How competent is it to vaccinate a wide range of healthy individuals against COVID-19 and influenza-for the same time or with the shortest time interval?.
ABSTRACT
The SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on host immunity, in which the HLA molecules play a distinct role. The present study aimed to detect associations between HLA alleles and COVID-19 susceptibility and severity in Armenians. The study included 299 SARSCoV- 2 infected patients (75 asymptomatic, 102 mild, 122 severe). To compare the allelic frequency profiles of patient groups with those specific to the general population, we used HLA data of 2781 registered donors at the Armenian BMDR. This group was used as a control cohort for age-genotype and allele frequency analyses. Based on the conjoint approach of HLA classical loci genotype and allelic distribution analyses between Armenian population controls and COVID-19 cases we discovered an age-related protective effect of the HLAB∗ 51:01 carriage against COVID-19 severity. In contrast HLA-C∗04:01 allelic-load contributes to the risk for the severe COVID-19 independently from age and classical HLA variables. The HLA-C∗04:01 association with COVID-19 manifestation is rather in concert with female gender and older age. Along with the expected significant decrease in cumulative heterozygosity of HLA class I loci, we report a previously undescribed decrease in heterozygosity of HLA-B locus blueprinted by the HLA-C∗04:01 homozygous genotype. In patients with mild to severe COVID-19, due to high prevalence of HLA-C∗04:01, these effects provide a decrease of the HLA class I loci heterozygosity and a down-modulation of the predicted HLA class I ability to recognize SARS-CoV-2 peptides. The genomic number of HLA-C∗04:01 allele and demographic variables compose the model, in which >15% potential share in the detection of cases with adverse clinical phenotypes belongs to HLA-C∗04:01. The results of study suggest a putative role of HLA-C genetic variation in the development of a specific immune response to COVID-19.
ABSTRACT
Absrtact The search for effective strategies for symptomatic and pathogenetic therapy of the infectious process caused by SARS-CoV-2 is one of the urgent problems in modern medicine. The prepara-tion of vaccines in many countries based on the principle of active immunization (attenuated and/ or dead strains of SARS-CoV-2) is certainly a timely and demanded direction in modern virology and immunology, but the effectiveness of all vaccines must also be tested over time. So, with such an immunoprophylactic approach, it is necessary, in our opinion, to conduct a periodic assessment of the immune status, the state of at least the respiratory and cardiovascular systems, even during the period of clinical recovery and in a more distant period. Much less often, a quali-tatively different approach of the symptomatic therapy of COVID-19 is practiced, based on the principles of studying the metabolism of polyamines in an infected organism, since SARS-CoV-2 requires polyamines localized in target cells for its functional activity (adhesion on the surface of target cells, translation and replication of daughter viruses). Moreover, polyamines are involved in the nucleocapsid packaging of some coronaviruses pathogenic for humans. That is why, in our opinion, a new quite justified tactics of conducting pathogenetic therapy should be aimed at finding means that suppress the synthesis of de novo polyamines. Α-Difluoromethylornithine is recommended as such means. Apparently, in this publication, for the first time, we recommend the introduction of a “poly-amine-free” diet in the general registry of the dietary regimen of COVID-19 patients, with the inclusion in the food list with the lowest polyamine content and, at the same time, elimination of foods rich in polyamines from the diet.
ABSTRACT
In the classification of pathogenic viruses proposed by Baltimore in 1971, the leading role is given to the presence of RNA and DNA of genetic material in them, which provided new opportunities in the study of infectious diseases. In recent years, many virologists, bacteriologists and infectious disease specialists around the world have focused their attention on the newly discovered facts of coexistence and interaction of viruses, mammalian cells and positively charged aliphatic polyamines. In addition to numerous functions in the mammalian organism, polyamines also play an important role in stabilizing the negative charges of DNA and RNA, RNA transcription, and viral protein synthesis. According to the new data of many advanced specialists in various fields of modern medicine and biology, the significance and role of polyamines in the vital activity of pathogenic viruses in mammals are involved in the processes of penetration of viruses into host cells, where they perform transcription, replication and packing of their own genetic material. The presence of polyamines is also found in a number of viruses: enteroviruses, flaviviruses, bunyavi-ruses, etc. The specific role of polyamines in them is still controversial and largely incomprehensible. There is a point of view that the presence of polyamines in viral capsids is due to the processes of packing the genetic material. For many viruses, including coronaviruses, there is no information about the presence of polyamines in virions. Among the new functions of polyamines, namely, facilitating the attachment of the virus to virus-sensitive cells, as well as the penetration of the virus into target cells, are polyamine-dependent. The fact that the binding of RNA viruses to virus-sensitive cells is regulated by polyamines indicates that the binding of RNA viruses to virus-sensitive cells is suppressed by the ornithine decarboxylase inhibitor (synthe-sizes putrescine from ornithine) (ODC)-difluoromethylornithine (DFMO). It has been established that human viruses, including the pandemic SARS-CoV-2, are sensitive to polyamine depletion and require polyamines primarily for effective cellular attachment. Thus, depletion of polyamines is a strategy by which mammalian cells can partially suppress viral infec-tion. On the other hand, since the temporary depletion of polyamine reserves is relatively “painless” toler-ated by most host cells, it becomes necessary to develop a qualitatively new strategy, by using effective therapeutic agents and/or by including polyamine-deficient products in the diet of patients, to block the level of polyamines in body, which can be the reason for the limitation of the development of a viral infection. It is generally accepted that the level of polyamines in mammals is realized in three ways. The first is due to the metabolism of the macroorgan-ism cells;the second one – due to the active absorption and uptake of polyamines that have entered the gastrointestinal tract with food and the third one as a result of the synthesis and absorption of polyamines by the expanded intestinal microflora. In mammals, the amount of food polyamines is higher than that of endogenous ones, and the level of microflora polyamines depends on the biological state of the microbial flora. It is established that in malignant degenerated cells, regardless of their origin, the level of aliphatic polyamines is very high. According to many oncologists, the control of polyamine synthesis is an important step in anti-tumor therapy. Tumor cells, in addition to numerous functions, have the ability to absorb polyamines that are ingested with food, as well as polyamines produced and/or previously adsorbed by gastrointestinal bacteria. So, given the presence of polyamines (in high and low levels) in food products and the fact of their intensive assimilation by the cells of the macro-organism, many clinicians of various specialties, in polyamine-dependent pathological conditions, recommend to pay special attention to polyamine diet, as a preventive agent in addition to drugs in order to correct their required level (optimal, increased, decreased) in the microorganism. Comparing the role of polyamines in the development of malignant neoplasms and viral infections, it becomes obvious that on the basis of these diseases there is also one common tendency – an uncontrolled increased level of aliphatic polyamines. From this point of view, it seems advisable, both in the development of neoplasms and in viral infections in pandemic zones, as a preventive measure to strictly adhere to a polyamine-deficient diet, taking into account the food ration specifically in the region of residence of the urban and rural population of different countries. In the development of a viral infection or oncological disorders, different polyamines may be of key importance. For a rational choice of the correct and necessary diet, we propose to necessarily determine the level of polyamines in biological materials.
ABSTRACT
The present report provides information on aspects of the pathogenesis of the infectious process induced by SARS-CoV-2. The authors put forward a hypothesis according to which COVID-19 should be considered as an infectious disease of a systemic character. This conclusion was based on some facts, which are hardly possible to deny. Firstly, from our viewpoint, a number of authors have expressed a well-grounded opinion, according to which, “multiple organ dysfunction syndrome” occurs in COVID-19. Therefore, such a conclusion testifies in favor of systemic damage to organs and tissues. Secondly, a number of studies, also cited in this publication, provide information on the involvement of the gastrointestinal tract organs in the infectious process caused by SARS-19, which allowed the authors to put forward the concept of the existence of the lung-gastrointestinal tract axis. This conclusion is based on studies which establish that SARS-CoV-2 by receptor mechanism binds to angiotensin-converting enzyme-2, which is localized throughout the digestive system. Thirdly, in our opinion, it is possible that a similar enzyme receptor uptake mechanism of ACE-2 by SARS-CoV-2, which is competitive with angiotensin-2, is involved in many internal organs, which makes it possible to start a general pathological process, which also indicates the systemic nature of COVID-19. Fourth, it is possible that SARS-CoV-2 has a widespread cytotoxic effect on blood cells, which is also realized through the receptor mechanism. Apparently, the process of thrombus formation with partly involvement of “deformed erythrocytes” in it has systemic character, especially since SARS-CoV-2, in our opinion, for its functional activity begins to “utilize” polyamines contained in erythrocytes. This report presents our own concept of possible mechanisms of thrombus formation that occur exclu-sively in all organs involved in COVID-19 infection. Since aliphatic polyamines localized in target cells and in the very nucleocapsids of SARS-CoV-2 are given an important role in ensuring the functional activity of SARS-CoV, the authors of this publication recommend the use of drugs that prevent the synthesis of polyamines in the general treatment regimen for COVID-19. As such means, the authors of this publication support the well-founded recommendations of a number of advanced researchers who recommend the use of α-difluoromethylornithine in COVID-19, since this compound has a unique ability to suppress the synthesis of polyamines at the earliest stages of their synthesis, i.e. enzymatic transformation of ornithine into putrescine.
ABSTRACT
This report provides the authors' viewpoints on the prospects of carrying out several therapeutic and prophylactic measures aimed at least improving the health of patients suffering from COVID-19. In addition, the authors have some doubts (fears) of using vaccines, the production of which is currently involved in well-known commercial pharmaceutical enterprises and scientific institu-tions of a number of leading countries of the world. At the same time, the authors place special emphasis on the scientific and technological process of vaccine production, when, as "initial raw materials", in each specific case, are used separate variations from the general structure of viruses pathogenic for humans, including SARS-CoV-19, integral killed coronaviruses, cross reactive antibodies to SARS-CoV-19, which are obtained as a result of appropriate scientific and technological preparation of other viruses (for example, arboviruses). How effective these vaccines will turn out to be is a matter of time, primarily due to their "approbation" on a wide contingent of people of different nationalities and living in different regions of the world. According to the authors, the effectiveness of vaccines in many respects depends on the intensity degree and relatively long-term binding of specific antibodies to viruses, as well as on the results of active vaccination, especially since coronaviruses are characterized by a very wide variability of antigenic determinants, represented, in particular, by at least six antigen receptors. The authors' doubts in this aspect served as a prerequisite for recommending new scientific and methodological approaches for COVID-19 treatment, based on the principles of suppressing the functional activity of SARS-CoV-2, both at the initial stages of binding the virus to the target cell membrane of the infected organism, and in the processes of their endocytosis, translation, replication and exocytosis of daughter viruses. A detailed analysis of modern informative literary sources, as well as their own research, according to the authors, can serve as a real prerequisite for including alpha-difluoromethylornithine in the general treatment regimen for COVID-19 patients, a drug that selectively inhibits the initial stages of polyamine synthesis, thereby leading to significant suppression of SARS-CoV-2 biologi- cal activity in the infected organism.
ABSTRACT
HLA genes play a pivotal role in the regulation of innate and adaptive immune responses. Specific HLA alleles have long been associated with susceptibility to many infectious diseases. However, the potential link between specific HLA alleles and the novel Coronavirus, SARS-CoV-2, has not been yet fully studied. To test the association between HLA alleles and COVID, the Armenian Bone Marrow Donor Registry has collected the data from COVID patients who were classified into three groups according to the disease severity. The severe disease group (n = 122) were those who required critical care such as ICU or ventilator;the mild disease group (n = 102) were defined as who were hospitalized but not requiring ventilators or ICU care, or patients recuperating at home;the asymptomatic group (n = 75) were subjects with no symptoms, but who have tested positive for the virus. HLA typing was performed for HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci by NGS, using Illumina MiSeq and PacBio platforms. To have a “typical” Armenian HLA profile, we used the data of 5579 individuals that have been already collected by the Registry and typed for HLA by NGS. For statistical analysis, we used Mann-Whitney U test to compare allele frequencies. We found that HLA-B∗35:02 and HLAC∗ 04:01 are genetic risk factors for COVID severe clinical course. The alleles have a twice higher frequency rate (P < 0.01) in the patients with the severe form of the disease than in subjects from the asymptomatic group. All homozygotes for both alleles were identified in the severe disease group, while the asymptomatic group has no such cases. These results pointed to the significant role of HLA genetic variation in the development of a specific immune response to COVID. Testing for those alleles might play a vital role in identifying high-risk individuals and strengthen the strategic clinical management of the disease.
ABSTRACT
Present article is based on the analysis of very informative literary sources, which provide information on the role of aliphatic polyamines in the replication processes of a wide range of viruses pathogenic for humans. Available scientific achievements in this direction most likely indicate that some viruses pathogenic for humans contain polyamines, which are directly involved in the replication processes of daughter viruses. As the “depletion of the polyamine reserve” of viruses, the latter begin to use polyamines localized in the target cells of the infected organism to maintain replication processes. In our opinion, erythrocytes and polyamine-rich resident microorganisms migrating to the lungs as a result of bacterial translocation can act as other intracorporeal sources for persistent viruses. The possible role of bacteriophages in the “utilization” processes of bacterial polyamines is being discussed. We discuss a thesis, according to which one of the mechanisms involved in viral-bacterial coinfection, providing access to viruses of bacterial polyamines, at the depletion stage of polyamines in the target cell of the macroorganism, is bacteriophagy, manifested, at least by the presence of “transformed” viruses in the form of monovalent and typical phages (T-phages). We make the assumption that it is possible that COVID-19, like another representative of the coronavirus family - the Middle East Respiratory Syndrome (MERS-CoV), contains polyamines that are so necessary to ensure their replication in a macroorganism. In connection with the above, in case of coronavirus infection caused in patients with COVID-19, it is advisable, if not necessary, in our opinion, to conduct studies that are presented in a chronic aspect: To determine the content of polyamines in patients infected with COVID-19, in plasma, blood erythrocytes and pulmonary exudate, depending on the severity of the pathological process, After analyzing laboratory studies (conducting high-performance liquid chromatography (HPLC) for the determination of polyamines in the above biological objects) carry out clinical studies by including α-difluoromethylornithine, a known blocker of aliphatic polyamine synthesis, in the general treatment regimen for COVID-19. All patients infected with COVID-19, regardless of the pathological process severity, should be recommended a special diet, using exclusively products characterized by an extremely low (or absence) content of aliphatic polyamines. © 2020, Yerevan State Medical University. All rights reserved.