Symptomatic —

The patients’ immune responses linked to the disease’s severity.

John Timmer

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Why do some people appear to handle a SARS-CoV-2 infection without developing symptoms, while it’s fatal to others? Some factors, like age, have been easy to identify, but there’s still a broad spectrum of responses among younger individuals that remains unexplained. Is there something with the patient, with the virus they’re infected by, or both?

To try to learn more, a group of researchers in Shanghai did a basic characterization of over 300 patients with confirmed SARS-CoV-2 infections, sequencing the genome of the viruses they were infected by and looking through medical records to see what factors were correlated with outcomes. The results suggest that, at least at early stages of the pandemic, the virus itself made little difference. By contrast, the immune system’s response to infection showed a strong correlation, supporting an idea that has already led to some drug trials.

It’s not all in the genes

The patient population included five asymptomatic individuals, 293 who were classified as having mild cases, 12 with severe symptoms, and 16 who needed critical care. The researchers obtained basic health information on all of them and managed to obtain the coronavirus genome from 112 of them.

As the virus spreads, it picks up random mutations, creating distinct lineages that can be used to trace its spread. Shanghai’s outbreak was close in place and time to the origin of the pandemic, so there has been less time for the virus to pick up these mutations. Still, the two main lineages that have been seen elsewhere were apparent in these genomes, along with a collection of additional mutations. A total of 103 of these mutations caused changes that would result in the production of an altered viral protein.

Many of these mutations were uncommon enough that they simply weren’t present in enough patients to allow the researchers to understand if the mutation altered any COVID-19 symptoms. So, the analysis focused on whether either of the two strains or the 13 most common variants were associated with any symptoms or clinical outcomes. They weren’t. They didn’t associate with how long patients continued to be infectious, either. It’s still possible that a larger analysis, or one that included more recently evolving strains, could find a difference, but this study certainly doesn’t see it, and most of the results are pretty far off from statistical significance.

Known and suspected associations

The researchers also checked the medical histories of patients to see whether any features were correlated with severity of their COVID-19 symptoms. Some of the things they found had been observed previously. Age tended to make things worse, as did being male. Having long-term health conditions also made matters worse.

But another factor linked with outcomes is still in the process of being studied: immune function. There have been some suggestions that infections could cause what’s termed a “cytokine storm,” where the immune signaling molecules are released at high levels, and responses like inflammation and immune activity wind up poorly regulated. But we’re still in the process of figuring out whether patients are suffering cytokine storms and (if so) what their consequences are.

While this research doesn’t directly address the role of a cytokine storm in COVID-19, it does suggest a significant problem with the immune system. Everyone the researchers saw with a SARS-CoV-2 infection—even the asymptomatic patients—seemed to have reduced levels of T cells. A more detailed look indicated that this included two categories of T cells: those that kill virus-infected cells and those that induce other immune cells to increase their activity (killer and helper T cells, respectively).

At the same time that the levels of these cells were dropping, a couple of immune signaling molecules were rising. Interleukin-6, which is linked to inflammation levels in many tissues, had increased levels in those infected with SARS-CoV-2, with the increase being most pronounced in those requiring critical care. Interleukin-8, which helps draw immune cells to sites of infection, was also elevated.

But wait, there’s more

The worry with studies like these—obtained at a single location early in the pandemic—is that the results won’t turn out to be general. Fortunately, that doesn’t seem to be the case here. While this work was being done, a group located in New York City was also checking the blood of patients and performing additional tests in cultured cells and lab animals. They, too, found high levels of Interleukin-6 in infected people and animals, along with a collection of other changes in immune signaling molecules.

Those researchers suggest that the changes indicate an over-activation of inflammatory responses, something that could potentially exacerbate problems caused by the viral infection. In addition, the changes in signaling molecules may tone down the activities of the innate immune system, which organizes the early response to pathogens by recognizing general signs of an infection rather than by recognizing any particular bacteria or virus.

So there’s a growing body of evidence that at least some of the problems caused by SARS-CoV-2 are the result of how the virus manipulates the immune system in order to maintain an infection. How much of the COVID-19 symptoms it explains isn’t yet clear, nor is it obvious whether the variability of symptoms is the result of patient-specific immune responses. But in light of this growing body of evidence, it’s a safe bet that researchers will be working 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).

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