In-Depth Analysis of SARS-CoV-2 Variants: Implications for Cellular Senescence and Viral Pathogenicity

0
99

This comprehensive analysis examines the mutations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), focusing on the emergence of variants of concern (VOCs) such as alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529). It explores the genetic alterations in the spike (S) protein, crucial for viral entry into host cells, and their implications for cellular senescence and viral pathogenesis.

Introduction

SARS-CoV-2, the causative agent of the COVID-19 pandemic, has undergone significant genetic mutations leading to the development of various VOCs. These variants, including alpha, delta, and omicron, are characterized by distinct genetic changes, predominantly in the genes encoding the spike protein, which facilitates viral entry into host cells [1, 2].

Viral Entry Mechanisms

The entry of SARS-CoV-2, an enveloped virus, is facilitated through two primary pathways: endocytosis or fusion with the plasma membrane. The omicron variant shows a marked preference for endosomal entry via clathrin-mediated endocytosis (CME), differing from the delta variant’s mechanism [4–6]. This process is heavily influenced by the internalization of integrins, a key step in the SARS-CoV-2 infection cycle [7, 8, 9].

Cellular Senescence in the Context of SARS-CoV-2

Emerging studies have established a connection between alterations in endocytic pathways and the onset of cellular senescence [10]. Specifically, SARS-CoV-2 has been demonstrated to induce cellular senescence, a state characterized by irreversible cell cycle arrest, altered cellular metabolism and morphology, and the senescence-associated secretory phenotype (SASP) [11, 12]. Research has primarily focused on the differential impacts of the delta and omicron variants, revealing the unique propensity of the omicron variant to induce premature cellular senescence.

Methodology and Key Findings

Building upon prior research on the influenza A virus and its link to premature aging [13, 14], the current analysis employs in vitro and ex vivo models, along with analyses of human lung tissue. This approach has elucidated the effects of both the delta and omicron variants. Notably, the omicron variant, with up to 60 mutations, shows a considerable alteration in the host-entry process compared to the delta variant [3]. The investigation indicates a robust infection by both variants in epithelial and type 2 alveolar cells. However, it is the omicron variant that uniquely promotes cellular senescence in small airway epithelial cells (SAECs) and human lung slices in an ex vivo setting.

Clinical Correlations and Implications

Despite the omicron variant’s association with cellular senescence, its clinical manifestation often involves milder symptoms compared to the delta variant, particularly regarding respiratory severity [19]. This contrast raises important questions about the long-term effects of COVID-19, including risks related to lung fibrosis and long-COVID [20, 21, 22, 23, 24].

Conclusion

The mutations in SARS-CoV-2 leading to the development of variants like omicron and delta have crucial implications for the virus’s infectivity and the induction of cellular changes. The propensity of the omicron variant to cause premature cellular senescence, juxtaposed with its generally milder clinical symptoms, provides novel insights into the pathogenesis of COVID-19 and its long-term health consequences.


To provide a detailed, step-by-step explanation of the entry mechanisms of SARS-CoV-2 delta and omicron variants, it’s important to break down each component of the process, especially focusing on how these mechanisms influence cellular behavior and pathways. The overview presented here is based on the understanding of SARS-CoV-2 as of my last training data, up to April 2023.

Delta Variant Entry Mechanism

  • Cell Surface Entry: The delta variant predominantly uses cell surface entry. This involves the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface.
  • TMPRSS2 Role: The transmembrane serine protease 2 (TMPRSS2) plays a crucial role in this process. It cleaves and primes the spike protein of the virus, facilitating the fusion of the viral and cellular membranes.
  • Integrin Interaction: In the case of the delta variant, there is a downregulation of integrin activation. Integrins are proteins that facilitate cell-cell and cell-extracellular matrix interactions.
  • Cell Cycle Impact: Despite the downregulation of integrin activation, there is no significant impact on the expression of p38 and p16, which are kinases involved in cell cycle regulation. This results in a normal cell cycle progression without leading to cellular senescence.

Omicron Variant Entry Mechanism

  • Clathrin-Mediated Endocytosis (CME): The omicron variant prefers entry via CME. In this process, the virus is internalized into the host cell within clathrin-coated vesicles.
  • Cathepsin L as Protease: Once inside the cell, cathepsin L, a protease in endosomes, cleaves and activates the spike protein, facilitating the release of the viral genome into the host cell.
  • Integrin Activation: There is significant expression and activation of various integrin subunits (ITGB1, ITGB4, ITGA1, ITGA2, ITGA3, ITGA6) with the omicron variant. This activation has cascading effects on cellular signaling pathways.
  • Impact on Kinases and Cyclins: The activation of integrins leads to an increase in the central kinases p38 and p16. This upregulation affects several cyclins, proteins that regulate cell cycle progression.
  • Downregulation of Retinoblastoma Protein: The changes in cyclins subsequently lead to the downregulation of the retinoblastoma (Rb) protein, a key regulator of the cell cycle.
  • Increase in E2F Transcription Factors: As a result of Rb downregulation, there is an increase in E2F transcription factors, which are crucial for the progression of the cell cycle.
  • Cell Cycle Arrest and Senescence: The cumulative effect of these changes is cell cycle arrest and the induction of cellular senescence. This is characterized by a permanent halt in cell division.
  • SASP Induction: Additionally, these cellular changes lead to an increase in the senescence-associated secretory phenotype (SASP), which involves the secretion of pro-inflammatory cytokines and other factors that can impact the tissue microenvironment.

Conclusion

The research suggests a direct influence of the altered cell entry mechanisms of the omicron variant on cellular pathways, particularly those governing the cell cycle and cellular senescence. This detailed mechanism highlights the complexities of viral interaction with host cells and the downstream effects on cellular function and health, providing valuable insights into the pathogenesis of different SARS-CoV-2 variants.


Graphical abstract of known differences of SARS-CoV-2 delta and omicron variant entry and findings of our study obtained from mRNA sequence data of 24 h post infection. Schematic overview of entry mechanisms of SARS-CoV-2 delta and omicron variants [5]. Delta variant (right panel) uses cell surface entry, by ACE2 and the protease TMPRSS2. Own data indicate a downregulation of the integrin activation without affecting p38 and p16 expression resulting in normal cell cycle. Omicron variant (right panel) prefers to use the clathrin-mediated endocytosis (CME) and cathepsin L as protease. Our results suggest the expression and activation of integrins (ITGB1, ITGB4, ITGA1, ITGA2, ITGA3, ITGA6) resulting an increase in p38 and p16. That increase in central kinases affects several cyclins, which in turn downregulates the retinoblastoma, increases the E2F transcription factors and results in cell cycle arrest and cellular senescence. Additionally, these changes lead to an increase in senescence-associated secretory phenotype (SASP). Thus, our findings indicate an influence of the altered cell entry mechanism of the omicron variant on the cell cycle.


reference link : https://www.aging-us.com/article/205297/text

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.