Enlarge /. Warning sign outside a laboratory that performs coronavirus tests.
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Why do some people seem to deal with SARS-CoV-2 infection without developing symptoms while being fatal to others? Some factors, such as age, were easy to identify, but there is still a wide range of responses in younger people that remain unsettled. Is there anything with the patient, with the virus with which he is infected, or with both?
To find out more, a group of researchers in Shanghai performed a basic characterization of over 300 patients with confirmed SARS-CoV-2 infections, sequenced the genome of the virus they were infected with, and searched medical files to determine which factors correlated with results. The results suggest that the virus made little difference even at least in the early stages of the pandemic. In contrast, the immune system's response to infection showed a strong correlation, which supports an idea that has already led to some drug studies.
It's not all in the genes
The patient population included five asymptomatic people, another 293 with mild cases, another 12 with severe symptoms and 16 with critical care. The researchers received basic health information about all of them and managed to get the coronavirus genome from 112 of them.
As the virus spreads, it picks up random mutations and creates different lines that can be used to track its spread. The outbreak of Shanghai was just before the outbreak of the pandemic, so the virus had less time to absorb these mutations. Nevertheless, the two main lines seen elsewhere were evident in these genomes along with a collection of additional mutations. A total of 103 of these mutations caused changes that would lead to the production of an altered viral protein.
Many of these mutations were unusual enough that they simply did not exist in enough patients so that the researchers could understand whether the mutation changed any symptoms of COVID-19. The analysis therefore focused on whether one of the two strains or the 13 most common variants were associated with symptoms or clinical results. It wasn't you. They also had no effect on how long the patients remained infectious. It is still possible for a larger analysis or an analysis that included newer strains to find a difference, but this study certainly does not see this, and most of the results are quite far from statistical significance.
Known and suspected associations
The researchers also reviewed the patient's medical history to determine whether features correlated with the severity of their COVID-19 symptoms. Some of the things they found had been observed before. Age tended to aggravate the situation, as did the male. Long-term health conditions also worsened the situation.
Another factor related to the results is still under investigation: immune function. There was some evidence that infections could cause a so-called "cytokine storm", in which the release of immune signaling molecules is released in high concentrations and reactions such as inflammation and immune activity are poorly regulated. However, we are still finding out whether patients suffer from cytokine storms and (f so) what the consequences are.
While this research does not directly address the role of a cytokine storm in COVID-19, it does indicate a significant problem with the immune system. Everyone they saw with SARS-CoV-2 infection – even the asymptomatic patients – seemed to have reduced T cell levels. A closer look showed that this included two categories of T cells: those that kill virus-infected cells and those that cause other immune cells to increase their activity (killer or helper T cells).
At the same time as the levels of these cells decreased, some immune signaling molecules increased. Interleukin-6, which is associated with levels of inflammation in many tissues, was elevated in those infected with SARS-CoV-2, with the increase being most pronounced among those in need of critical treatment. Interleukin-8, which helps pull immune cells to infection sites, was also increased.
But wait, there's more
The concern with studies like this that were conducted in one place at the start of the pandemic is that the results will not turn out to be general. Fortunately, this doesn't seem to be the case here. During this work, a group in New York City also examined patient blood and performed additional tests on cultured cells and laboratory animals. They also found high levels of interleukin-6 in infected humans and animals and a number of other changes in the immune signaling molecules.
These researchers suggest that the changes indicate an over-activation of inflammatory responses, which could potentially exacerbate the problems caused by the viral infection. In addition, changes in signaling molecules can weaken the activities of the innate immune system, which organizes early response to pathogens by recognizing common signs of infection rather than by recognizing certain bacteria or viruses.
So there is growing evidence that at least some of the problems caused by SARS-CoV-2 are due to how the virus manipulates the immune system to maintain an infection. How many of the COVID-19 symptoms are explained is not yet clear, and it is also not clear whether the variability in symptoms is due to patient-specific immune responses. However, with this growing body of evidence, it is certain that researchers will work hard to find out.
Nature, 2020. DOI: 10.1038 / s41586-020-2355-0 (About DOIs).
Cell, 2020. DOI: 10.1016 / j.cell.2020.04.026 (About DOIs).