Coronavirus and the Host Response

The SARS-CoV-2 pandemic continues to accelerate in the U.S. and many other countries. As a potential vaccine is likely over a year away, there is great interest in finding an effective antiviral drug. Numerous antiviral drugs were developed for other viruses and many of these are being tested. Additionally, there are many other existing drugs used for other diseases that might be repurposed for use against SARS-CoV-2. The problem is that we know very little about how this new virus actually causes disease. Consequently, testing existing drugs is mostly trial and error to see if anything shows efficacy against this new virus. Understanding the pathology of this new disease might reveal pathways and targets for novel therapeutics to treat these infections. Much scientific attention is now focusing on the disease mechanisms at work during COVID19 so that therapeutic drugs can be rationally designed rather than randomly screened.

Blanco-Melo et al. posted an interesting study last week on bioRxiv¹ that examined the cell’s reaction to SARS-CoV-2 infection at the mRNA level. Whenever viruses infect our cells the infection triggers a complex program of events called the antiviral response. This antiviral response is designed to thwart viral reproduction and ultimately destroy all the viral particles so that the disease stops. Part of this antiviral response involves turning on mRNA production for specific genes whose protein products have antiviral activity. Many of these antiviral genes express at low levels or not at all in uninfected cells since they aren’t needed in healthy cells, so the amount of mRNA for these genes is normally low. When a cell becomes infected these genes increase their mRNA production so that the mRNAs can be translated into the antiviral proteins. The overall pattern of mRNAs present in cells under any given condition is known as the transcriptome because the process that produces mRNAs is called transcription.

Blanco-Melo et al. compared the transcriptome of cultured human lung cells with and without SARS-CoV-2 infection and correlated this with the response to two other respiratory viruses: influenza and respiratory syncytial virus (RSV). All three viruses evoked an antiviral response that elevated the mRNA levels of many known antiviral genes. However, SARS-CoV-2 showed significantly lower expression of the genes for interferons type I and type III. A similar reduced interferon response was seen in infected ferrets, an animal model system widely used for mimicking human influenza infections. Interferons are proteins that are critical for providing resistance to viruses early in infection while our bodies are slowly developing protective antibodies. The authors speculate that this reduced interferon response may contribute to the more severe disease in the elderly. People under 50 years old generally have a more robust immune system, so even a partially reduced interferon response may still leave sufficient antiviral activity to control the infection. In contrast, elderly individuals whose immune response is already diminished may have too limited of an interferon response to be effective against SARS-CoV-2. This may allow the virus to replicate longer and to higher levels that eventually overwhelms the individual’s defenses, resulting in severe disease or death.

A second important observation made by these researchers is that SARS-CoV-2 infection raised the mRNA levels of the genes for EDN1 and TNFSF15, while influenza and RSV did not. Both EDN1 and TNFSF15 encode proteins known to promote respiratory inflammation and therefore could be contributing to the severe lung pathology seen with SARS-CoV-2 and not with the other two viruses. However, this increase was not seen in the ferrets so its relevance to human disease is still very uncertain. Nonetheless, more studies of this kind should help pinpoint significant effects of SARS-CoV-2 on our cells and suggest pharmacological approaches to block these effects and defeat this infection.

¹bioRxiv (pronounced bio archive) is a site where scientists can post their manuscripts prior to publication in scientific journals. These manuscripts have not been peer-reviewed so their findings and conclusions should be regarded as preliminary.