virology blog
About viruses and viral disease
Vincent, Kathy and Rich discuss COVID-19 research paper overload, Moderna’s mRNA vaccine Phase I results, increase of ACE2 RNA by cigarette smoke, and answer listener questions.
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by Gertrud U. Rey
The prevalence of SARS-CoV-2, the virus that causes COVID-19, is steadily increasing around the world. Yet despite this unsettling fact, one statistic continues to hold true: most infected children experience mild symptoms, respond well to treatment, recover more quickly than adults, and have a better prognosis.
An initial report from China showed that only 965 out of 44,672 confirmed COVID-19 patients were under the age of 19. A letter to the editor of the New England Journal of Medicine reported only six cases of COVID-19 out of 366 hospitalized children. Only one of these children required admission to the intensive care unit, and all six patients recovered after an average of 8 days. According to the largest study of COVID-19 in children to date, more than 90% of children with laboratory-confirmed COVID-19 had asymptomatic, mild, or moderate disease. A comprehensive review of COVID-19 in children published on March 23 shows that even in Italy, the country with the highest number of COVID-19-related deaths so far, only 1.2% of patients were children, and none of these children died.
What is the reason for this low morbidity and mortality in children? Although the answer isn’t clear, there are a few possible explanations. Children are thought to have fewer underlying disorders and healthier respiratory tracts because of less exposure to cigarette smoke and air pollution. There is speculation that the non-specific, innate immune response that occurs upon an initial encounter with a pathogen is stronger in children. This type of immune response seems to be delayed in the elderly, and in an effort to “catch up,” may result in excessive inflammation, thereby ultimately causing more severe damage.
Another possible explanation is tied to angiotensin-converting enzyme 2 (ACE2), the host cell surface protein that serves as a receptor for SARS-CoV-2 entry into cells. ACE2 is prevalent on lung, kidney, intestinal, and arterial cells, where it normally controls blood pressure by regulating the volume of fluids in the body. ACE2 is also an important regulator of the immune response, especially in the context of inflammation. Some suggest that ACE2 is less mature in young children and thus may not function properly as a receptor for SARS-CoV-2. Furthermore, it is more abundant on cells of the lower respiratory tract, which is typically the site of severe COVID-19 disease. Consistent with this observation, data indicate that children experience more SARS-CoV-2 infections in the upper respiratory tract than the lower respiratory tract.
It has also been suggested that ACE2 is expressed more abundantly on senescent cells, which have stopped dividing and exist predominantly in the elderly. Considering that senescent cells are still metabolically active and contain all the factors necessary for virus replication, this hypothesis seems plausible.
It is also possible that early childhood vaccines provide some protective immunity against SARS-CoV-2. For example, a study from 2008 shows that the measles vaccine elicits neutralizing (virus-inactivating) antibodies against SARS-CoV, the virus responsible for the 2003 coronavirus epidemic. Immunity derived from childhood vaccines typically wanes with age, thereby possibly increasing the risk of severe COVID-19 in the elderly.
As is typical of newly emerging pathogens, many characteristics of the diseases they cause are largely unknown. As such, the exact reasons for why COVID-19 is less severe in children remain ambiguous. Hopefully the answer will become clearer as more data emerge over the next few months.
The TWiV team returns this week to SARS-CoV-2019 coverage to review the latest epi curves, the fatality rate, furin cleavage site and receptor binding domain in the spike glycoprotein, related CoV recovered from pangolins, evidence that the virus did not escape from a laboratory, and many more questions sent in by listeners.
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Download TWiV 588 (91 MB .mp3, 151 min)
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A coronavirus related to SARS-CoV-2 has been isolated from Malayan pangolins illegally imported into Guangdong province. It is not the precursor of SARS-CoV-2, but comparison of viral genome sequences provides further evidence that the virus currently infecting humans was not produced in a laboratory.
There are two important sequences in the viral spike glycoprotein (pictured) that are important for tracing the origin of SARS-CoV-2: a furin cleavage site (discussed last week) and the receptor binding domain (RBD).
The results of experiments in cells in culture have shown that the SARS-CoV-2 spike glycoprotein binds the cell receptor ACE2. Six amino acids in the RBD are critical for binding to this receptor. Five of these six amino acids differ in the RBD of SARS-CoV-2 compared with sequence from the bat virus RaTG13, the most closely related virus. The SARS-CoV-2 spike glycoprotein binds ACE2 with high affinity, an outcome not predicted by computational analysis of the RBD sequence. If someone were to engineer an RBD into a bat SARS-like CoV to allow efficient infection of human cells, they would not use the amino acid sequence in the SARS-CoV-2 spike. Rather the specific sequence was likely selected during replication in cells with human-like ACE2.
As discussed previously, the furin cleavage site in the SARS-CoV-2 spike is not present in the bat virus RaTG13. Its acquisition could allow enhanced infection of human cells. In addition to the furin cleavage site, an extra proline is also present, a change predicted to lead to the addition of O-linked glycans in the vicinity. If someone were to engineer the furin cleavage site into the spike, it is not likely that the extra proline would have been included. Furthermore, the addition of such glycans typically occurs under immune selection.
The genome sequences of CoVs recently isolated from pangolins are not close enough to SARS-CoV-2 to have been its immediate progenitor. However, the RBD of these pangolin CoVs are identical to that of SARS-CoV-2 at 6 of 6 of the key amino acids discussed above. This observation indicates that passage of CoV in a host with human-like ACE2 could select for a RBD with high-affinity binding. Such passage could also select for insertion of the furin cleavage site, which is not present in pangolin CoVs. Once a virus with the appropriate RBD and furin cleavage site arose in an animal – a bat or intermediate host – it would then replicate once introduced into humans.
Another possibility is that viruses with the correct RBD have been repeatedly jumping into humans, but efficient human to human transmission was not established until the acquisition of the furin cleavage site. Such is the scenario with MERS-CoV, which has jumped multiple times from camels to humans, but each chain of infection is short and soon ends. The virus has never become established in humans because the required mutations have not entered the viral genome. Serological surveys specific for SARS-CoV-2 might test this hypothesis for its emergence.
Could laboratory passage of a bat SARS-like virus lead to isolation and accidental emergence of SARS-CoV-2? This scenario would require starting with a virus that is very close to the current isolates. Passage in cell culture might have selected for the RBD amino acid changes to enable high affinity ACE2 binding. However this virus would have had to be very similar to SARS-CoV-2, and no such isolate is known to be present in any laboratory. Selection of viruses with a furin cleavage site would likely have taken extensive passaging in cells. Finally, it is unlikely that the O-linked glycan addition site would have emerged without immune pressure, which is absent in cell cultures.
Proving or disproving any of these hypotheses for the emergence of SARS-CoV-2 might never be possible. Nevertheless, isolation of SARS-like viruses from a variety of animals might help to clarify the steps to emergence in humans. For MERS-CoV, a priority should be to prevent human infections, perhaps by immunizing camels, to avoid the emergence of another epidemic CoV with sustained transmission in humans.
On episode #258 of the science show This Week in Virology, Matt joins the TWiV team to discuss the discovery of a SARS-like coronavirus in bats that can infect human cells, and what is going on with MERS-coronavirus.
You can find TWiV #258 at www.microbe.tv/twiv.