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Review
. 2024 Jun 7:15:1363572.
doi: 10.3389/fimmu.2024.1363572. eCollection 2024.

New insights into the pathogenesis of SARS-CoV-2 during and after the COVID-19 pandemic

Jonatan J Carvajal #  1 , Valeria García-Castillo #  1 , Shelsy V Cuellar  1 , Claudia P Campillay-Véliz  2 , Camila Salazar-Ardiles  3 , Andrea M Avellaneda  1   4 , Christian A Muñoz  5   6   7 , Angello Retamal-Díaz  1   5   7 , Susan M Bueno  8 , Pablo A González  8 , Alexis M Kalergis  8   9 , Margarita K Lay  1   5   7
Affiliations
Review

New insights into the pathogenesis of SARS-CoV-2 during and after the COVID-19 pandemic

Jonatan J Carvajal et al. Front Immunol. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the respiratory distress condition known as COVID-19. This disease broadly affects several physiological systems, including the gastrointestinal, renal, and central nervous (CNS) systems, significantly influencing the patient's overall quality of life. Additionally, numerous risk factors have been suggested, including gender, body weight, age, metabolic status, renal health, preexisting cardiomyopathies, and inflammatory conditions. Despite advances in understanding the genome and pathophysiological ramifications of COVID-19, its precise origins remain elusive. SARS-CoV-2 interacts with a receptor-binding domain within angiotensin-converting enzyme 2 (ACE2). This receptor is expressed in various organs of different species, including humans, with different abundance. Although COVID-19 has multiorgan manifestations, the main pathologies occur in the lung, including pulmonary fibrosis, respiratory failure, pulmonary embolism, and secondary bacterial pneumonia. In the post-COVID-19 period, different sequelae may occur, which may have various causes, including the direct action of the virus, alteration of the immune response, and metabolic alterations during infection, among others. Recognizing the serious adverse health effects associated with COVID-19, it becomes imperative to comprehensively elucidate and discuss the existing evidence surrounding this viral infection, including those related to the pathophysiological effects of the disease and the subsequent consequences. This review aims to contribute to a comprehensive understanding of the impact of COVID-19 and its long-term effects on human health.

Keywords: COVID-19; SARS-CoV-2; host factors; immune response; long-COVID-19; pathogenesis; pathophysiology; variants.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
SARS-CoV-2 genome organization. The genome of SARS-CoV-2 is organized similarly to other coronaviruses, consisting of the following elements: a 5´ untranslated region, ORF1a, which encodes two overlapping polyproteins (pp1a and pp1ab). The pp1a non-structural protein corresponds to nsp1 to nsp10, while pp1ab non-structural protein comprises nsp12 to nsp16, which are further cleaved into 16 non-structural proteins (nsp1–16). The 3´ untranslated region contains the structural genes that encode four structural proteins: Spike Surface glycoprotein (S), Envelope glycoprotein (E), Nucleocapsid (N), and main protein or Matrix (M). The accessory genes are interspersed among the structural genes (79, 80).
Figure 2
Figure 2
SARS-CoV-2 cell entry and viral cycle. The viral cycle commences with the binding of the Spike (S) protein to the ACE-2 receptor, facilitated by either cell surface or endosomal entry. (2) The TMPRRS2 protease (transmembrane protease serine) mediates the fusion of the virus-cell membranes through the cleavage of protein S, allowing the virus to enter the cytosol of the host cell. (3) Once internalized, the virus undergoes uncoating, releasing the viral genome into the cytosol, where it undergoes replication and translation. (4) This process generates two polyproteins: pp1a and pp1b, which are subsequently cleaved by the viral protease present in the nonstructural proteins (nsps) encoded by the virus. (5) In endoplasmic reticulum (ER)-derived double-membrane vesicles (DMVs), the negative-stranded genome serves as a template to generate the entire positive-stranded genome and subgenomic RNA (sgRNA). Translation of sgRNA in the ER results in the synthesis of the structural glycoproteins N, S, M, and E, which are utilized for viral assembly in the ER-Golgi intermediate compartment (ERGIC). (6) Finally, the entire positive-stranded genome is encapsulated in newly synthesized virions, which are released from the cell via exocytosis.
Figure 3
Figure 3
SARS-CoV-2 innate immune response and viral evasion. During viral replication, cytosolic double-stranded RNA is detected by retinoic acid-inducible gene I (RIG-1) and melanoma differentiation-associated protein 5 (MDA5). Viral genomic single-stranded RNA is detected by toll-like receptor (TLR) 7 and TLR8 in the endosomes of plasmacytoid dendritic cells and B cells, as well as myeloid cells, respectively. Additionally, endosomal TLR3 recognizes double-stranded RNA in various cells, and TLR4 participates in the detection of oxidized phospholipids (OxPLs) induced by SARS-CoV-2 infection. These interactions lead to the activation of downstream transcription factors, most notably IRF3 and NF-κB, promoting the expression of type I and III interferons (IFNs) and proinflammatory cytokines such as TNF-α, transforming Growth Factor β (TGF-β), interleukins (IL-1β, IL-6, IL-8, IL-12, IL-18), and chemokines like chemokine (C-C motif) ligand 2 (CCL2), CCL3, CCL5, C-X-C motif chemokine ligand 8 (CXCL8), CXCL9, CXCL10. Furthermore, endosomal TLR3 can recognize double-stranded RNA in various cells, while TLR4 detects oxidized phospholipids (OxPL) induced by SARS-CoV-2 infection. SARS-CoV-2 antagonizes the innate immune response at different steps; specific viral proteins interfere with type I IFN production (shown in green) and interferon signaling (shown in purple), impairing the early antiviral state.
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Grants and funding

The author(s) declared financial support was received for the research, authorship, and/or publication of this article. We would like to thank the Regional Government of Antofagasta through the Innovation Fund for Competitiveness FIC-R 2017 (BIP Code: 30488811–0); Copec-UC 2020.R.001; National Research and Development Agency (ANID) - Millennium Science Initiative Program, Millennium Institute on Immunology and Immunotherapy (ICN09_016/ICN 2021_045; former P09/016-F); “Fondecyt Regular #1240971; and the VRIIP Strengthening Plan code ANT20992”.