The coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and certain aspects of the disease it causes, COVID-19, continue to baffle doctors and researchers. SARS-CoV-2 has already been estimated to have infected more than 9 million people and has claimed more than 450,000 lives worldwide, and this pandemic has paralyzed economies worldwide. Writing in NatureZhang et al.one Present data on the evolution of two major SARS-CoV-2 lineages, along with information on the determinants of human host disease severity from their analysis of 326 people in Shanghai, China, who were infected with SARS- CoV-2.
SARS-CoV-2, which surprised the world, was initially thought to have “jumped” humans from an animal host at the Huanan Wholesale Seafood Market in Wuhan, China. When the first cases of a previously unknown disease, initially described as ‘severe pneumonia with unknown etiology’, were identified in Wuhan in late December 2019, most cases dated back to this market. The implication was that the new coronavirus had crossed the species barrier on the market for an infected live animal for sale. The Malaysian pangolin, a scaly anteater that previously lived in relative darkness, suddenly faced accusations that it was the culprit, although it is uncertain whether this protected creature was for sale on the market at the time (see Nature http://doi.org/ggpxhb; 2020). However, some cases of the disease in early December 2019 in Wuhan had no obvious links to the market.two.
Zhang et al. analyzed 94 complete sequences of the SARS-CoV-2 genome in samples obtained from people living in Shanghai who had visited a health care clinic in January or February 2020, and compared these data with 221 other sequences of the virus. The authors’ results reinforce previous observations.3 of two major phylogenetic lineages (clades) of SARS-CoV-2 during the early phase of the outbreak in China. They are distinguished by two distinctive nucleotide differences, suggesting multiple origins for human infections transmitted to people in Shanghai (which is about 800 kilometers by road from Wuhan).
The two lineages are called clades I and II (Fig. 1). Presumably they evolved independently of a common ancestor, but their ancestry in terms of how they relate to each other is unclear, as they differ at only two genomic sites. One difference involves a particular nucleotide in the sequence encoding amino acid residue number 84 in the ORF8 viral protein. If the nucleotide has a thymine base (clade I), the sequence encodes the amino acid leucine; If you have a cytosine base (clade II), the sequence encodes a serine. The other difference is in a nucleotide in the gene. ORF1ab, which contains cytosine (clade I) or thymine (clade II); both resulting nucleotide sequences encode serine.
Figure 1 | To assess the relationship between coronavirus lineages and the severity of COVID-19.Zhang et al.one studied people from Shanghai, China who became infected with the SARS-CoV-2 coronavirus in early 2020. aConsistent with previous research3, the Zhang coronavirus genome sequences et al. identified belonged to two lineages, named clade I and clade II. These differ in two nucleotides and probably evolved independently of a common ancestor. Clade I was associated with some cases linked to the Huanan wholesale seafood market in Wuhan, China, originally thought to have been the source of the outbreak, while the authors found clade II infections that had no link to the market. Both lineages could have been independently extended at the same time. yes, Zhang and colleagues classified the individuals into four groups, depending on the severity of their disease, which ranged from those unaffected by symptoms (the asymptomatic group) to the critical group (those requiring artificial ventilation to breathe). ). Both clades had the same ability to cause different groups of diseases. An increase in the severity of the disease was accompanied by a depletion of immune cells called CD3.+ T cells and an increase in proinflammatory cytokine proteins IL-6 and IL-8. High levels of cytokines can cause an intense immune response known as a cytokine storm.
Combining viral genomics with epidemiological evidence of how people might have contracted the infection, Zhang et al. show that the viral genomes of six people with established links to the Wuhan market are grouped in clade I in the SARS-CoV-2 family tree, while the viral genomes of three cases with no known market links are grouped in the clade II. These data support the idea that the market may not have been the source of the pandemic. Instead, they suggest that clades I and II originated from a common viral ancestor and spread independently at the same time: clade I through the market and clade II outside of it. Thus, animal-to-human transfer could have occurred elsewhere, sowing transmission chains that found their way to the marketplace, where the high density of stalls and susceptible humans facilitated uncontrollable spread and subsequently beyond site. .
The circulation of different ‘types’ of SARS-CoV-2 has been a controversial topic, derived from the observation of different phylogenetic lineages. However, such genetic divergence between viruses is expected, especially in the context of ‘immunologically naive’ human hosts (those who have never encountered the virus before). This can be explained by the ‘founder effect’, which is common during viral outbreaks: if a limited number of viral variants randomly enter a new geographic region where there is a susceptible population, their subsequent spread there facilitates the dominance of those variants in that moment. Location.
However, the difference in the prevalence of those variants in that particular population, compared to infected populations in other regions, does not necessarily equate to a better aptitude of those variants in terms of viral replication and transmission.4 4. According to this idea, Zhang et al. They find no evidence of any association between either of the two clades, or between any mutation in the subclades, and the clinical parameters they evaluated to classify the severity of COVID-19 disease. Although this finding is not surprising, given that the two clades differ by only two nucleotides from the approximately 30,000 nucleotides in the SARS-CoV-2 genome, it highlights the fact that different phylogenetic lineages do not necessarily indicate different viral strains with different diseases. results.
Having found no difference in clinical outcomes between infections with the two SARS-CoV-2 lineages, Zhang et al. He analyzed various parameters of immune system function in human hosts to identify factors that contribute to the severity of the disease.
The authors focused on four disease categories with well-described definitions of clinical outcomes. The least affected people were asymptomatic and had no fever, respiratory problems, or signs of lung damage on radiographs. Mild cases were those in people who had fever and signs of inflammation on x-rays of their lungs, indicating pneumonia. People with severe disease had difficulty breathing and had distinctive features of lung damage described as ‘ground glass opacities’ on radiographs. Critically ill patients had acute respiratory distress syndrome and needed mechanical ventilation to help them breathe. According to previous research5 5Zhang and colleagues found that being older, the presence of other pre-existing medical conditions (called comorbidities) and male gender were the main factors associated with a higher probability of more serious disease.
From the analysis of blood samples, the authors provide evidence of changes that characterized the severe and critical cases of COVID-19. A feature of these cases was lymphocytopenia, an abnormally low number of lymphocytes (a type of white blood cell involved in immune responses) in the blood. Zhang et al. attributed this lymphocytopenia to the depletion of a particular type of lymphocyte called CD3+ T cells, which probably reflect the movement of these T cells from the blood to the sites of infection in the tissues.
Another feature of severe and critical cases was the abnormally high levels of cytokines IL-6 and IL-8, which are small proteins that promote inflammation. High levels of proinflammatory cytokines drive an intense immune response that is commonly known as a cytokine storm. Cells of the immune system called macrophages, which are present in the lung, can produce IL-6 and IL-8, and are often the initial cellular mediators of a cytokine storm in other respiratory infections. However, the precise cell populations that contribute to the prolonged cytokine storm that occurs in some cases of COVID-19 have yet to be defined.
The inverse correlation between high IL-6 or IL-8 levels and low lymphocyte numbers suggests underlying mechanisms that could link these features of severe disease. The possibility that high levels of cytokines cause lymphocytopenia is consistent with the observation that people with COVID-19 who were treated with the drug tocilizumab, which blocks IL-6 mediated signaling, had their lymphocyte levels in the stream. blood restored to a level closer to normal6 6. However, further experimental and mechanistic studies are needed to establish whether a causal connection underlies the correlation between these cytokine levels and lymphocytopenia. Of note is the discordant timeline for changes in these two parameters: T-cell depletion is evident from the first week of overt disease, while a cytokine storm arises later, when COVID-19 has become severe.
Furthermore, neither lymphocytopenia nor cytokine storm are unique to COVID-19. Both are characteristic of many types of severe respiratory infection, including human infection with avian influenza viruses and severe acute respiratory syndrome (SARS), a disease caused by a coronavirus related to SARS-CoV-2. To delineate immunological signatures that are specific to COVID-19, more detailed cellular and molecular analyzes will be required.
Tracking the evolution of SARS-CoV-2 is essential to inform the public health policies necessary to limit the spread of disease. Dissection of underlying causes and mechanisms of disturbed immune defenses, such as CD3 depletion+ T cells and the increased proinflammatory response, as well as the determination of the crucial clinical and molecular characteristics of COVID-19, are of utmost importance for the design of effective treatment strategies and vaccines. Zhang et al. They lay down some essential foundations that should assist in these Herculean tasks, and their work raises key questions that must be answered if we are to limit this pandemic and try to prevent a future one.
