Since the beginning of 2020, the coronavirus disease 2019 (COVID-19) pandemic has taken an enormous toll on public health and the economy in many parts of the world. The causal agent of the pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
A large amount of research has been conducted to understand the origins of SARS-CoV-2, its molecular structure, and the mechanism by which it infects humans. We have made a significant amount of progress but, unfortunately, we are still a long way from developing a holistic understanding of SARS-CoV-2.
One of the pressing questions scientists currently trying to answer is whether the current vaccines will remain effective against the emerging SARS-CoV-2 variants of concern. A new piece of research has been published in the journal Biomedicines, which discusses the knowledge we have gained thus far and the questions that researchers should address in future work.
Several studies have documented that bats act as natural reservoirs for coronaviruses, and this time is no different. It is possible that the infection first spread to an intermediate host before passing on to humans. Since the first outbreak of SARS in 2002, many similar viruses have been identified in bats. These viruses have the ability to infect humans, which means that future outbreaks are possible.
Through 2020, scientists also conducted extensive research to identify new SARS-CoV-2 variants that may bring about a spike in the number of cases. The English variant (B.1.1.7) and the South African variant (B1.351) are two such examples that have a mutation in the receptor-binding domain (RBD). B1.351 has two additional mutations (E484K and K417N) that enable the evasion of neutralizing antibodies. Several tests are currently being conducted to ensure that the current set of vaccines (e.g., Pfizer BioNTech, Moderna, and Oxford AstraZeneca) is effective against the existing and emerging variants.
The spike glycoprotein is formed by two subunits: S1 and S2. The S1 subunit further consists of an N terminal subunit (NTD) and the RBD. The S2 subunit is essential for the membrane fusion between the virus’s envelope and the late endosome membrane. Scientists have demonstrated that the host cell receptor angiotensin-converting enzyme 2 (ACE2) is used by SARS-CoV-2 as the main gateway into cells.
After fusion with the lysosome, cathepsin-L brings about the proteolytic cleavage of the spike glycoprotein, which activates the S2 subunit. Subsequently, membrane fusion occurs, releasing the viral RNA into the cytoplasm of human cells. The viral RNA and structural proteins build a new virus that has the potential to infect other cells. Besides ACE2, other receptors could play a role in disease severity (e.g., Meplazumab and Neuropilin 1).
There are several laboratory abnormalities associated with COVID-19 patients, such as neutrophilia, lymphopenia, increased C- reactive protein, etc. The latest research suggests that the activation of the immune response starts with recognizing the virus’s components and that MDA5 is the primary sensor that brings about the recognition of SARS-CoV-2.
The activation of the immune response is crucial to fight the infection. But, the overproduction of pro-inflammatory cytokines, also known as a “cytokine storm,” has the potential to cause tissue damage. This phenomenon is often observed in critically ill patients.
However, what causes the overactivation of the immune system? Previous research has shown that, while IL-8 is constantly elevated in COVID-19 patients, the increase in IL-6 and IL-10 is correlated with the severity of the infection. The same holds true for the chemokine Interferon-y protein 10 (IP-10). Scientists have proposed a mechanism that could explain the overproduction of pro-inflammatory cytokines. This could be the dysregulation of the RAAS caused by SARS-CoV-2-dependent ACE2 internalization. More research is warranted in this area to understand the mechanism better, and that will enable us to devise new strategies to combat the current and future pandemics.
More research is needed to find multiple new therapeutic options to treat COVID-19. This is especially true in the case of individuals who have comorbidities, such as hypertension, diabetes, and obesity. Currently, there are no targeted treatments for COVID-19, and most strategies being used now are supportive. More than five thousand clinical trials are underway, and half of these focus on individuals older than 65 years. Some of the drugs being used in some parts of the world currently include Ivermectin, Doxycycline, Azithromycin, Favipavir, Remdesivir, etc.
The best long-term strategy to combat SARS-CoV2 infection is to attain herd immunity with the help of deploying a specific vaccine to the entire world population. Several approaches have been used to develop vaccines, such as non-replicating viral vectors, messenger RNA (mRNA), inactivated whole-virus, etc.
As mentioned earlier, concerns have been raised regarding the efficacy of the current vaccines against the newly identified SARS-CoV-2 variants. It is important to clearly understand the mechanism of SARS-CoV-2 infection, which will help us to develop more efficient vaccines as well as identify the most effective therapeutic approaches.