Gene Associated Divergence of COVID-19 Morbidity & COVID-19 Vaccines

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), also known as COVID-19, drastically changed our everyday lives. It has indeed caused a considerable increase in morbidity and mortality rates worldwide. There is an underlying complex interplay between the infectious agents and the human host, which is related to different biological mechanisms. Phenotypic spectrums associated with SARS-CoV-2 infection or COVID-19 range from asymptomatic to severe systemic complications such as pneumonia, respiratory failure, and death. Around 15 % of cases are severe. Some are accompanied by a dysregulated immune system or a cytokine storm, and others with both. There is increasing evidence that the severe manifestations of COVID-19 might attribute to human genetic variants. Polymorphisms in genes that are related to immune deficiency and or inflammasome activation (cytokine storm) are examples of these variants. The question is, is the variability of the hosts’ genetic background the reason behind the different responses to COVID-19? Or are there other factors? Case reports and GWAS studies showed that the susceptibility to severe viral infections was associated with the genetic variants in the immune response genes. Identifying the candidate’s genes is likely to aid in explaining why COVID-19 symptoms are severe to some but not others. Not to mention that it will provide insights that help us further understand the pathogenesis of severe COVID-19, to then make it possible to come out with more effective treatments and vaccines. Global DNA methylation, ACE2 gene methylation and post-translational histone modifications drive differences in host tissue-, biological age- and sex-biased patterns of viral infection. Epigenetic changes impact genome stabilization, maintenance of cellular homeostasis, and affect the pathophysiology of the viral infection

: SARS-CoV2 infection mechanism. [11] Primary viral replication occurs when the virus reaches the mucosal epithelium of the upper respiratory tract, SARS-CoV-2 can reach lung epithelial cells where further viral replication occurs.
SARS-CoV-2 binds via its Spike (S) protein to the ACE2 receptor in the lungs (same mechanism as in airway epithelial cells) and TMPRSS2 (increases viral entry to the host). The binding interaction promotes cellular endosomal entrance via cathepsin-Ldependent endocytosis. Host proteases cleave S protein, which activates it to trigger the process of membrane fusion [5,6].
The virus can enter cells either by direct cellular entry (membrane fusion then injection of the viral genome into the host's cytoplasm) or endocytosis (material enters the host after being surrounded by an area of the cell membrane then buds off inside the cell to form a vesicle). Once inside the cell, viral-specific RNA and proteins are synthesized within the cytoplasm [7][8][9][10]. More viral proteins are then assembled from the information within the viral RNA using the host's cellular machinery, specifically the Golgi apparatus and endoplasmic reticulum [11]. New variants are then assembled by fusing to the plasma membrane and being released as vesicles by the cellular exocytic secretory processes.

COVID-19 and Age
By far, age is the strongest predictor of the risk of dying for an infected person, measured by a metric, infection fatality ratio (IFR), in which the proportion of people infected with the virus, including those who didn't get tested or show symptoms, to the people who will die as a result of the infection [15][16][17]. Age and disease severity are correlated with multiple immunological characteristics [18][19][20][21]. There are correlations between low frequencies of naive CD8 +,  sex-biased disease outcome [30]. Differences in innate and adaptive immune responses, genetic factors, and an interplay between sex hormones and immune effectors, as well as gender-specific behavior differences, particularly the immunological divergence in response to viral infection, could potentially influence not only COVID-19 pathogenesis and disease course, but also the response to antiviral drugs and vaccines [32]. This might explain why severe COVID-19 and mortality rates are higher in men than women.

COVID-19 and the Immune System
The first line of defense when a pathogenic invader enters the body is the immune system. The main course of COVID-19 disease occurs because of a misbalance of the immune response, often leading to misregulation and worsening of the infection [34].

Molecular Grade Vaccines
An efficacious vaccine is necessary to prevent the increase  (Table 3).

Opinion on Blood Clotting Caused by Astrazeneca Vaccine
Clotting dysregulation was observed in severe COVID-19 patients [42-45]. Several mechanisms may contribute to immunothrombosis, for instance, elevated levels of pro-inflammatory cytokines [46][47][48][49]. So, I think aside from some additives that supposedly trigger clotting in the AstraZeneca vaccine, patients that would have had a severe case did get immunothrombosis when taken AstraZeneca vaccine being the most immunogenic one.

Possible Treatment Methods
Clinical outcome of COVID-19 in C3S and ACE1 D allele carriers to study the role of C3 and ACE1 D/I polymorphisms in COVID-19 have potential effects on treatment response [44]. drugs enhancing ACE2 activity may become one of the most promising approaches for treating COVID-19 in the future [33]. IL-18, CCR1, CCR9, and EndoU (coronavirus protein) inhibition as a possible treatment for COVID-19.

Summary of Some Established Principles
Angiotensin-converting enzyme 2 (ACE2 "receptor") interacts with the S protein of SARS-CoV-2 which provides the entry point for the virus to hook into and infect a wide range of human cells Seniors and those with co-morbidities are prone to COVID-19 owing to immunosenescence and exaggerated inflammatory responses and possible treatment with convalescent plasma [40].
The magnitude of neutralizing antibody responses is positively correlated with disease severity (smaller in asymptomatic individuals and decreases faster than in symptomatic). Pre-existing cross-reactive immunity leads to a better prognosis [40].
Different host immune responses to SARS-CoV-2 infection explain why males and females, young and old persons infected with this virus have markedly distinct disease severity [6].
Potential regulators of ACE2 in the human lung, including genes related to histone modifications (e.g. HAT1, HDAC2, and KDM5B) are found in patients with severe COVID-19 [23]. Patients with comorbidities associated with severe COVID-19 found that ACE2 was highly expressed in these patients compared to control individuals [26].
Androgen's TMPRSS2-mediated actions might explain both the low fatalities observed in prepubertal children and the differences between sexes regarding SARS-COV2 infection. Androgen sensitivity may be a critical factor in determining COVID-19 disease severity, and sensitivity tests can, therefore, help in predicting patient outcomes [29].