Why do some people seem to handle a SARS-CoV-2 infection without developing symptoms, while being fatal to others? Some factors, such as age, have been easy to identify, but there is still a wide spectrum of responses among younger people that remains unexplained. Is there something with the patient, the virus he is infected with, or both?
To try to get more information, a group of researchers in Shanghai performed a basic characterization of more than 300 patients with confirmed SARS-CoV-2 infections, sequencing the genome of the viruses they were infected with and reviewing medical records to see what factors were correlated with results The results suggest that, at least in the early stages of the pandemic, the virus itself made little difference. In contrast, the immune system response to infection showed a strong correlation, supporting an idea that has already led to some pharmacological trials.
Not everything is in the genes.
The patient population included five asymptomatic individuals, 293 who were classified as mild cases, 12 with severe symptoms, and 16 who needed critical care. The researchers obtained basic health information about all of them and managed to obtain the coronavirus genome from 112 of them.
As the virus spreads, it picks up random mutations, creating different lineages that can be used to track its spread. The Shanghai outbreak was close to the place and time to the origin of the pandemic, so there has been less time for the virus to detect these mutations. Still, the two main lineages 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 result in the production of an altered viral protein.
Many of these mutations were so rare that they simply were not present in enough patients to allow the researchers to understand whether the mutation altered any symptoms of COVID-19. Therefore, the analysis focused on whether any of the two strains or the 13 most common variants were associated with any symptom or clinical result. They were not. They were also not associated with the time that patients continued to be infectious. It's still possible that a larger analysis, or one that includes more recently evolving strains, may find a difference, but this study certainly doesn't see it, and most of the results are far from statistical significance.
Known and suspicious associations
The researchers also checked the patients' medical records to see if any characteristics correlated with the severity of their COVID-19 symptoms. Some of the things they found had been previously observed. Age tends to make things worse, just like being a man. Having long-term health conditions also made things worse.
But another factor related to the results is still under study: immune function. There have been some suggestions that infections could cause what is called a "cytokine storm," where immune signaling molecules are released at high levels, and responses such as inflammation and immune activity end up poorly regulated. But we are still in the process of determining whether patients experience cytokine storms and (if so) what their consequences are.
While this research does not directly address the role of a cytokine storm in COVID-19, it does suggest a significant problem with the immune system. All of the researchers who saw a SARS-CoV-2 infection, including asymptomatic patients, appeared to have reduced levels of T cells. A closer 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 decreased, a pair of immune signaling molecules increased. Interleukin-6, which is related to inflammation levels in many tissues, increased levels in those infected with SARS-CoV-2, with the sharpest increase in those requiring critical care. Interleukin-8, which helps attract immune cells to infection sites, was also elevated.
But wait, there's more
The concern with studies like these, obtained in one place at the beginning of the pandemic, is that the results will not 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 patients' blood and conducting additional tests on cultured cells and laboratory animals. They also found high levels of interleukin-6 in infected people and animals, along with a collection of other changes in the immune signaling molecules.
Those researchers suggest that the changes indicate an overactivation of inflammatory responses, something that could exacerbate the problems caused by the viral infection. Furthermore, changes in signaling molecules can attenuate the activities of the innate immune system, which organizes the early response to pathogens by recognizing the general signs of an infection rather than recognizing any particular bacteria or virus.
Therefore, there is increasing evidence that at least some of the problems caused by SARS-CoV-2 are the result of how the virus manipulates the immune system to maintain an infection. It is still unclear what part of the COVID-19 symptoms it explains, nor is it obvious whether the variability in symptoms is the result of patient-specific immune responses. But in light of this growing body of evidence, it is a safe bet 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).