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Another week and more data on the immune response to SARS-CoV2 and the disease it causes, COVID-19. This information is critical for therapeutic repurposing. A short thread on interferon and repurposing interferon therapies as “immune boosters” in COVID-19.
Trials of repurposed drugs are expected to readout soon (e.g., anti-IL6R). For a short primer, read @Dereklowe ‘s blog, where he reminds us "don’t expect cures". As you will see, interferon therapies are being tested now. https://blogs.sciencemag.org/pipeline/archives/2020/04/24/the-order-of-battle
A virus inside a cell has a pattern that is different than human molecules, which triggers an immune response. SARS-CoV-2 is a single-stranded, positive RNA virus, but is packaged differently from human mRNA. @VirusesImmunity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549330/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549330/
The virus then activates the innate immune system to release type 1 interferons (IFN alpha and beta), which tells a cell to fight the virus. Indeed, interferons are named for their ability to "interfere" with viral replication.
https://en.wikipedia.org/wiki/Interferon
https://en.wikipedia.org/wiki/Interferon
Type 1 IFNs are released from a cell and bind to interferon receptors on a variety of cells, including macrophages, and activate STAT1 to turn on “interferon-stimulated genes” (or ISGs). IFNs also up-regulate antigen presentation by increasing the expression of MHC.
But viruses are smart. The coronavirus genome encodes for proteins that dampen the host interferon response.
https://www.nature.com/articles/nrd.2015.37
https://www.nature.com/articles/nrd.2015.37
IFNa is approved for treating certain viral infections such as hepatitis B and C. IFN therapy has been used to treat previous coronavirus infections (SARS, MERS), although results were inconclusive. Will IFN therapy work in COVID-19? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/
A new study in @cellcellpress demonstrates that the host response to SARS-CoV-2 fails to launch a robust type 1 IFN response, while simultaneously inducing high levels of chemokines needed to recruit effector cells.
https://bit.ly/2VXEMWn
https://bit.ly/2VXEMWn
The chemokines induced by SARS-CoV-2 have been shown to recruit and activate monocytes (CCL2, CCL8) and neutrophils (CXCL2, CXCL8). The induced cytokines include IL6 and IL1RA, which are also seen in "cytokine storm".
Does this mean that IFN therapy would be useful in boosting the immune response against SARS-CoV-2 early in infection? Maybe. The study concludes that targeting the aberrant chemokines and cytokines may be beneficial.
Another study in @CellCellPress demonstrates that SARS-CoV-2 infection induces an IFN response that in turn leads to the up-regulation of ACE2, raising concerns that repurposing interferon therapy may have a detrimental effect in COVID-19. @carlygailz
https://doi.org/10.1016/j.cell.2020.04.035
https://doi.org/10.1016/j.cell.2020.04.035
The study notes influenza virus induces ACE2 in airway cells, raising a theoretical concern that the co-occurrence of influenza and SARS-CoV-2 could lead to more severe COVID-19.
Taken together, available data do not support IFN therapy in COVID-19, although only rigorous trials will tell for sure. According to the real-time clinical trial dashboard published in @TheLancet, there are 31 ongoing trials using interferon.
https://www.covid-trials.org/
https://www.covid-trials.org/
Finally, a recent review provides a more complete picture of IFN therapy in SARS-CoV-2, concluding that clinical trials are warranted.
https://doi.org/10.1016/j.antiviral.2020.104791
https://doi.org/10.1016/j.antiviral.2020.104791
