Genetic Predisposition and Inflammatory Inhibitors in COVID-19: History
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Subjects: Cardiac & Cardiovascular Systems
Contributor:
Marios Sagris

Genetic predisposition, as in other inflammatory diseases, might be responsible for alterations in the clinical course of COVID-19 patients through polymorphisms in crucial genes such as ACE2 and MHC class I. Components of the immune response to the virus appear to be primarily related to disease severity, whereas genes related to the binding of the ACE2 cell surface—the entry point for SARS-CoV-2—during the early stages of infection appear to be largely responsible for the varying susceptibility to SARS-CoV-2. Inflammatory inhibitors are at the forefront of pharmacological management in COVID-19, although their potential has not been fully elucidated till now. The above mentioned would have a potentially large impact on targeted medicines and, more critically, vaccine development.

  • COVID-19
  • SARS-CoV-2
  • inflammation
  • genetics
  • cytokines

1. Introduction

Coronaviruses (CoVs) are RNA viruses with a single strand that belong to the Coronaviridae family while four CoVs categories have thus far been identified: α, β, γ, δ. SARS-CoV2 penetrates human cells by attaching to the angiotensin-converting enzyme 2 (ACE2), abundant in alveolar lung cells, vascular endothelium, cardiac myocytes, and other cells [1]. The novel coronavirus disease 2019 (COVID-19) emerged as a severe acute respiratory illness and was proclaimed a pandemic on 30 January 2020, affecting primarily the residents of Wuhan, Hubei Province in China [2][3].
The course of the disease is mild in the large proportion of patients, while severe cases with hospitalization and high mortality rates also occur. Physicians have tried to classify the disease course by dividing it into four stages [4][5]. In the first stage (Stage I), fever, dry cough, tiredness, and myalgia are the most common symptoms which are, however, not specific to the disease. In the second stage (Stage II), bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities are presented on the computed tomography scan in the vast majority of COVID-19 patients with viral pneumonia [4]. A hypercoagulable state has been observed, especially in hospitalized patients in Stage III of the disease, driven by abnormal coagulation cascades’ activation [5]. Finally, multiorgan failure on top of excessive hypoxemia appears in Stage IV with hyperresponsiveness of the immune system [4][5]. This stage is characterized by rapid elevation of inflammatory circulating cytokines such as interleukin (IL)-1, IL-2, IL-6, and IL-7, tumor necrosis factor (TNF)-α, granulocyte–macrophage colony-stimulating factor (GM–CSF), macrophage inflammatory protein 1-α (MIP-1α), C-reactive protein (CRP), ferritin, and D-dimer [6]. This extreme inflammatory response causes severe adult Acute Respiratory Distress Syndrome (ARDS) and the so-called “cytokine storm” [6].
As such, the mitigation of the excessive inflammatory immune response is of high scientific interest and clinical relevance. Recently, anti-inflammatory drugs and immunomodulators have been studied as potential therapies to minimize cardiovascular and systemic adverse effects.

2. Cytokine Storm and ARDS in COVID-19

A challenge for physicians is the optimal management of an abnormal hyper-inflammatory state with elevated pro- and inflammatory cytokines, which could drive ARDS and has been described in numerous hospitalized COVID-19 patients [7]. To the best of our knowledge, a similar disorder has been described in juvenile Still disease, revealed as a cytokine storm leading to macrophage activation syndrome (MAS), secondary haemophagocytic lymphohistiocytosis (sHLH), or cytokine release syndrome (CRS) [6][8]. These pathological entities are more commonly driven by viral infections, autoimmune disorders, malignancy (HLH and MAS), sepsis, and the administration of chimeric antigen receptor T cell therapy (CRS) [9][10]. It is characterized by sudden fever, respiratory and kidney failure, hypotensive shock, and diffuse coagulation disorders, while laboratory examinations reveal anemia, neutrophilia, thrombocytopenia, and marked lymphopenia [11][12]. Multi-organ failure presented in many cases, while four molecular cascades were responsible for its course—complement, kinin, clotting, and fibrinolysis systems. A similar phenomenon has been observed in patients with severe COVID-19 pneumonia with primary HLH as the potential underlying cause [8][13].
The assumed underlying mechanism is the rocket of secreted inflammatory cytokine levels in the bloodstream of the patients. The critical pathogenic cytokines appear to vary according to illness, with IL-1β having an orchestrating role in Still disease, IL-18 in MAS, and IL-6 in CRS [14]. As far as the severe COVID-19 disease is concerned, the widespread hypothesis is that, in the early phase, failure of perforin, natural killer cells (NK), and CD8+ cytotoxic T-cells leads to cell lysis, initiating apoptosis of virally infected cells while interferon-γ (IFN-γ) causes excessive macrophage activation [13][15]. Multiple studies have revealed that the toll-like receptors (TLRs) and activated inflammasomes (Caspases) first release the primarily inflammatory component of the disease, IL-1β [16][17]. Parallel delayed secretion of type Ⅰ and Ⅲ IFNs, including IFN α/ß, in the early phase of infection and excessive secretion of pro-inflammatory cytokines from mononuclear macrophages is described in the later stage [18]. The cells release modest levels of antiviral factors—IFNs—as well as high amounts of pro-inflammatory cytokines—IL-1, IL-6, and TNF—and particular chemokines—C-C pattern chemokine ligand (CCL)-2, CCL-3, and CCL-5 [19][20]. Linear association of disease severity course and the type of elevated cytokines has not been well established yet. Several studies suggest that higher levels of IL-1β, IL-1RA, IL-7, IL-8, IL-10, IFN-ɣ, MCP-1, MIP-1α, G-CSF, and TNF-α have been observed in severe infection with marginal statistical significance [15][21]. Airway and alveolar epithelial cell apoptosis was induced by IFN-αβ and IFN-γ, increasing the inflammatory cell infiltration. Apoptosis of endothelial and epithelial cells affects the pulmonary microvascular and alveolar epithelial cell barriers, causing vascular leakage, alveolar edema, and, eventually, hypoxia [7][13]. The studies mentioned above emphasize that a failure in initial type-Ⅰ and Ⅲ IFN responses to SARS-CoV-2 leads to an excessive late immune response and severe form of COVID-19. The pro-inflammatory feed-forward loop of cytokines on innate immune cells results in a cytokine storm, coagulopathy, and acute respiratory distress syndrome (ARDS) [22][23]. On the other hand, in contrast with the widespread hypothesis of failure of the immune system, two other studies presented an interesting and quite different concept of cytokine storm onset, differentiating it into two stages. In the first, a short-term immune-deficient state is considered, followed by a second overactive immune condition which tries to counterbalance the agitated entropy from temporary immune target failure, driving to a cytokine storm [7][24]. As such, further molecular research on patients presented with cytokine storm caused by COVID-19 is required to clarify the phenomenon (Figure 1).
/media/item_content/202202/620db92c82206biomedicines-10-00242-g001.pngFigure 1. SARS-CoV-2 invasion and hyper-inflammatory state in close relation with genetic predisposition. The presence of Angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS-2) that may cleave the viral spike is required for SARS-CoV-2’s cell invasion. Increased levels of pro-inflammatory cytokines, particularly the soluble interleukin 2-receptor (IL-2R) and interleukin-6 (IL-6) have been found. Soluble IL-2R (sIL-2R) is mostly released by activated T helper lymphocytes, although it may also be secreted by endothelial cells (ECs). The capillary leak is caused by the binding of IL-6 and IL-2 to their receptors. The persistent burdening of the endothelium results in increased release of inflammatory cytokines and immune system overreaction, resulting in the so-called “cytokine storm”. The above mentioned hyper-inflammatory state is in close relation with the individual genetic profile which can potentially govern the course of the disease. Abbreviations: SARS CoV-2 = Severe acute respiratory syndrome Coronavirus-2, ACE2 = Angiotensin-converting enzyme 2, TMPRSS = Transmembrane protease serine 2, IL = Interleukin, ΡAΙ-1 = Plasminogen activator inhibitor-1, TNF = Tumor Necrosis Factor, ICAM = Intercellular Adhesion Molecule 1, MCP-1 = monocyte chemoattractant protein-1, G-CSF = Granulocyte colony-stimulating factor, IP-10 = Interferon gamma-induced protein 10, MIP-1 = Macrophage inflammatory protein-1, IFN = Interferon.

3. Genetic Predisposition

Many researchers support the position that cytokine storm in COVID-19 is related to individual genetic predisposition and vulnerability. This theory was strengthened by the evidence of genetic vulnerability in patients marked by primary HLH or cytokine storm in Still disease [25]. Failure of perforin and the activation of NK and cytotoxic T lymphocytes have been demonstrated as the main components of these pathologic entities.
Several studies have reported associations between human genes and COVID-19. ABO blood groups have been assessed in susceptibility to SARS-CoV-2, revealing a higher risk of infection for blood group A than non-A and a lower risk of infection for blood group O compared to non-O [26]. It is assumed that the formation of neutralizing antibodies against protein-linked N-glycans or indirect effects such as the stability of the von Willebrand factor have a partial impact on differing susceptibility [27][28][29]. Although the O blood type group seems to have an advantage concerning the susceptibility to SARS-CoV-2, there was no association between the ABO blood group and the severity of COVID-19 disease or mortality rate according to a recent meta-analysis [30]. As discussed above, invasion of SARS-CoV-2 is dependent on ACE2 and the transmembrane serine protease (TMPRSS2) [31]. Polymorphisms on the gene of ACE2 have been associated with adverse cardiovascular and pulmonary conditions in severe COVID-19 patients due to alterations to angiotensinogen. Furthermore, the localization of the ACE2 gene on the X chromosome may contribute to the generally higher burden observed in males as compared to in females [31]. On the other hand, a recent study illustrated that several ACE2 variants including K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L, and D509Y have less affinity to bind SARS-CoV-2 [32]. Although large cohort studies have not been completed yet and these variants are rare in the general population, this observation could be a cornerstone in the management of the disease [32]. In different populations, no polymorphisms or mutations associated with S binding protein have been documented [32]. Another analysis suggested that polymorphisms including rs233574, rs2074192, and rs4646188 would change COVID-19 binding to ACE2 expressing a protective profile [33]. Of interest is the fact that three well-known polymorphisms of ACE2 (p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg), as well as two rare variants p.(Leu351Val) and p.(Pro389His) have been identified and associated with a better course of the disease [34]. TMPRSS2 enzyme activity is important for coronavirus spread and pathogenesis in the infected host. The polymorphism p.Val160Met (rs12329760) seems to be related to increased susceptibility to SARS-CoV-2 while the oncogenic role of TMPRSS2 may be linked to poor disease outcomes [35].
The apolipoprotein E (ApoE) e4e4 homozygous genotype has been observed to enhance the risk of severe COVID-19, regardless of prior dementia, cardiovascular illness, or type 2 [36][37][38]. ApoE e4 rules the macrophage pro-/anti-inflammatory phenotypes, and it is expressed in type II alveolar cells in the lungs where the ACE2, which SARS-CoV-2 employs for cell entrance, is abundantly co-expressed [37][38]. Association of major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) and the susceptibility to SARS-CoV-2 have been observed. More specifically, assessing the binding affinity across HLA phenotypes and viral peptides, it is shown that harbors of HLA-B*46:01, HLA-A*11:01, -B*51:01, -C*14:02, HLA-DRB1*15:01, -DQB1*06:02, and -B*27:07 alleles are more vulnerable to SARS-CoV-2, and these mutations predispose patients to a worse disease course [39]. Loss-of-function variants of the X chromosomal Toll-Like Receptor 7 (TLR7) gene have been described in individuals. The primary pathophysiologic mechanism predisposing patients to severe COVID-19 disease is the impaired type I and II IFN response and the retarded immune system reaction [39]. A wide genetic analysis of blood samples of 332 COVID-19 patients in China revealed that the most significant gene loci related to disease severity were the Transmembrane protein 189 and Ubiquitin Conjugating Enzyme E2 V1 (TMEM189-UBE2V1) which play an orchestrating role in the IL-1 signaling pathway [40]. As far as the complement protein system is concerned, polymorphisms such as C3 FF, C3 FS, and C3 SS have been recognized as potentially deleterious for the susceptibility to SARS-CoV-2 and the course of the disease. These preliminary data should be confirmed by the large ongoing SOLID-C19 trial [41]. Finally, the Solute Carrier Family 6 Member 20 (SLC6A20), Leucine zipper transcription factor like 1 (LZTFL1), C-C chemokine receptor type 9 (CCR9), FYVE and Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1), C-X-C Motif Chemokine Receptor 6 (CXCR6), and X-C Motif Chemokine Receptor 1 (XCR1) are genes highly expressed in human lung cells, and polymorphisms have been related to the increased risk of respiratory failure and ARDS in severe COVID-19 cases [42][43] (Table 1).
Table 1. Genetic polymorphisms under assessment in COVID-19 disease.
Gene Polymorphism Result
ABO rs657152 Higher risk of infection for blood group A vs. non-A and lower risk of infection for blood group O vs. non-O [26].
HLA HLA-B*46:01, HLA-A*11:01, -B*51:01, -C*14:02, HLA-DRB1*15:01, -DQB1*06:02, and -B*27:07 Vulnerable to disease for HLA-B*46:01 and cross-protective T cell-based immunity for HLA-B*15:03 [39].
TMPRSS2 p.Val160Met (rs12329760) Increased susceptibility to SARS-CoV-2 [35].
ACE2 K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L, and D509Y
rs233574
rs2074192
rs4646188
(p.(Asn720Asp)
p.(Lys26Arg) p.(Gly211Arg)
p.(Leu351Val)
p.(Pro389His)		 Better cardiovascular and pulmonary course of the disease, less susceptibility to SARS-CoV-2 [31][32][33][34].
ApoE rs429358-C-C (e4e4) Severe course of the disease [37][38].
SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1 rs11385942-GA Severe course of the disease and potentially higher odds for ARDS [42][43].
Of Complement proteins C3 FF, C3 FS, C3 SS Severe course of the disease, Increased susceptibility to SARS-CoV-2 [41].
TMEM189- UBE2V1 rs6020298-A Severe course of the disease [40].
TLR7 g.12905756_12905759del and g.12906010G > T Severe course of the disease [39].
Abbreviations: ApoE = Apolipoprotein E, ACE2 = Angiotensin-converting enzyme 2, TMPRSS2 = Transmembrane Serine Protease 2, HLA = Human Leukocyte Antigen, ABO = ABO blood system, TLR7 = Toll-like receptor 7, TMEM189-UBE2V1 = Transmembrane protein 189 and Ubiquitin Conjugating Enzyme E2 V1, SLC6A20 = Solute Carrier Family 6 Member 20, LZTFL1 = Leucine zipper transcription factor like 1, CCR9 = C-C chemokine receptor type 9, FYCO1 = FYVE And Coiled-Coil Domain Autophagy Adaptor 1, CXCR6 = C-X-C Motif Chemokine Receptor 6, XCR1 = X-C Motif Chemokine Receptor 1.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10020242

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