An integrative look at SARS‑CoV‑2 (Review)

Abstract

SARS‑CoV‑2 is a newly discovered member of the betacoronaviruses and the etiological agent of the disease COVID‑19. SARS‑CoV‑2 is responsible for the worldwide pandemic which has been taking place in 2020, and is causing a markedly higher number of infections and deaths compared to previous coronaviruses, such as SARS‑CoV or MERS‑CoV. Based on updated scientific literature, the present review compiles the most relevant knowledge of SARS‑CoV‑2, COVID‑19 and the clinical and typical responses that patients have exhibited against this virus, discussing current and future therapies, and proposing strategies with which to combat the disease and prevent a further global threat. The aggressiveness of SARS‑CoV‑2 arises from its capacity to infect, and spread easily and rapidly through its tight interaction with the human angiotensin‑converting enzyme 2 (ACE‑2) receptor. While not all patients respond in a similar manner and may even be asymptomatic, a wide range of manifestations associated with COVID‑19 have been described, particularly in vulnerable population groups, such as the elderly or individuals with other underlying conditions. The proper function of the immune system plays a key role in an individual's favorable response to SARS‑CoV‑2 infection. A hyperactivated response, on the contrary, could account for the more severe cases of COVID‑19, and this may finally lead to respiratory insufficiency and other complications, such as thrombotic or thromboembolic events. The development of novel therapies and vaccines designed to control and regulate a proper immune system response will be key to clinical management, prevention measures and effective population screening to attenuate the transmission of this novel RNA virus.

Keywords: SARS‑CoV-2; COVID‑19; immune response; targeted drug delivery; prevention and clinical management.

Figure 1

Stages of SARS-CoV-2 course. As proposed by Siddiqi and Mehra (92), 3 main phases can be distinguished in COVID-19. The first one is associated with mild symptoms, and individuals infected will develop and innate and adaptatively responses, being able to eliminate the virus. If not, a more severe pulmonary stage will take place, causing a pneumonia without (IIA) or with hypoxia (IIB), with an aberrant release of cytokines. The third stage is an hyper-inflammation status, defined by a cytokine storm and possibly leading to the most severe symptoms, including ARDS, SIRS or MOF. Addressing the different complications during the various phases will be vital for a proper management of the disease. ARDS, acute respiratory distress syndrome; SIRS, systemic inflammatory response syndrome; MOF, multi-organ failure.

Figure 2

Immune response during SARS-CoV-2 infection. When there is a proper defense mechanism, the innate immunity of an individual will give rise to cytokines, while carrying out antigenic presentation, promoting and enhancing a coordinated adaptive immune response to combat the virus. SARS-CoV-2 could inhibit type I interferon-mediated signaling, affecting the innate immune system by additionally acquiring more DAMPs, thus leading to a cytokine storm. This aberrant response could promote tissue damage as well as viral sepsis, which may be detected in blood tests. A high viral load, advanced age or underlying disease are usually associated with severe cases of COVID-19, whereas a healthy lifestyle or diet, successful pharmacotherapy and an early diag-nosis could prevent the complications of COVID-19 promoting a rapid recovery by controlling the immune response. DAMPs, damage-associated molecular patterns; IL, interleukin; IFN-γ, interferon γ; MCP-1, monocyte chemoattractant protein-1; MIP, macrophage inflammatory protein; G-CSF, granulocyte colony-stimulating factor; TNF-α, tumor necrosis factor α.

Figure 3

Pathophysiology of thrombotic and thromboembolic events associated with COVID-19. Owing to the high expression of the ACE-2 receptor by endothelial cells, they could be a potential targets of SARS-CoV-2, which may lead to endothelial cell activation and finally to endothelial dysfunction. Cytokines released during a cytokine storm also promote endothelial damage, and along with inflammatory cells and their microvesicles, the extrinsic coagulation pathway may be activated through further tissue factor expression. In addition, NETs could lead to activation of coagulation pathways, acting as inhibitors of the negative extrinsic pathway regulator TFPI, besides boosting the production of proinflammatory cytokines, such as IL-6 or IL-1β, both leading to platelet coagulation and therefore to thrombosis or thromboembolisms in these patients. NETs, neutrophil extracellular traps; IL, interleukin; TFPI, tissue factor pathway inhibitor; TNF-α, tumor necrosis factor α.

Figure 4

Clinical manifestations of COVID-19. Although general symptoms, such as fatigue, fever or dry cough and respiratory problems are typically observed, other alterations may also be found like neurological, hematological, cardiometabolic, gastrointestinal, renal or skin disorders, amongst others. Understanding these symptoms and complications could play a major role in the clinical management of COVID-19 patients, hence the importance of a multidisciplinary approach to SARS-CoV-2 infection.

Figure 5

Examples of (A) nanoparticles and (B) nanotechnological strategies available or currently under development.