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COVID-19 and cellular biology: How does the virus enter cells, and what potential ways are there to stop it?

Elsa Champion
Four questions for Ludger Johannes, Director of the Cellular and Chemical Biology unit (INSERM-CNRS)
Ludger Johannes

Your team decrypts the mechanisms of endocytosis, the process that particles such as viruses use to enter human cells. Can you explain how coronaviruses enter cells and what happens to them once inside?

My team does indeed work on the fundamental mechanisms of endocytosis, as you say. Our work is generic, in the sense that our findings apply to a large variety of external products, whether endogenic (nutrients, signaling molecules, etc.) or exogenic, such as pathogens.

SARS-CoV2, the virus behind the coronavirus 2019 disease (COVID-19), has characteristics that lead us to believe that the way in which it enters a patient’s target cells might draw on specific features related to our research. In particular, we have developed a theory to explain how a cellular protein (galectin) interacts with sugars to open the doorways to cells via endocytosis. The surface of the virus features galectin derivatives and the SARS-CoV2 receptor is a glycoprotein (which contains sugars). We still need to directly assess whether or not our theory also applies to SARS-CoV2.

Once they enter cells, viruses – such as SARS-CoV2 – find themselves in subcellular structures (endosomes). They then need to overcome a number of barriers in order to propagate and ultimately wreak cellular damage. In particular, the virus needs to undergo conformational changes on proteins that decorate its surface to escape from endosomes and to move even deeper into cells where it then replicates. This process is more or less effective depending on the reaction conditions it is met with inside the endosomes. My team also specializes in honing tests capable of quantitatively measuring the effectiveness with which internalized particles (viruses and others) succeed in breaking through barriers. This type of test could be useful in better understanding the SARS CoV2’s intracellular progression.

Going forward, different treatment possibilities are being examined. Can you tell us about them?

The grail would obviously be a vaccine. However, we know that immunity from the members of the coronaviridae family that trigger common colds only lasts a short period: just one to three years. It remains to be seen whether the same would apply for SARS-CoV2. Antiviral drugs will aim to inhibit the components of SARS-CoV2, just as Tamiflu does for the flu, and triple therapy does for HIV. Studies for COVID-19 treatment via Remdesivir are currently under-way. This product interferes with a viral enzyme that is essential to RNA viruses such as SARS-CoV2 to replicate. Other categories of medication can modify the reaction conditions I referred to earlier, the conditions the viruses rely on for breaking through intracellular barriers. This category includes chloroquine, which has garnered a lot of media attention lately. Finally, it would seem that the severity of illness seen in some patients is a result of an extremely high immune response to the virus complete with exacerbated inflammatory reaction. Treatment protocols that aim to inhibit this reaction via cytokine antidotes (such as IL-6R, IL-1 and IL-17 interleukins) are currently being studied.

How does chloroquine work?

Endosomes – the subcellular structures in which the virus finds itself once it has entered cells – are characterized by their acidity. In various different ways, this acidity is needed to allow the components of the virus’s surface to change shape, thereby allowing it to pass through the intracellular barriers that would otherwise stop it from multiplying. Chloroquine reduces acidity levels, which slows down SARS-CoV2’s intracellular progression. This is what we currently know for the time being, based on a very small number of studies. It is also important to note that the effects of chloroquine on SARS-CoV2 have, so far, only been observed in tests on cultured cells. This means we cannot know for sure that this drug – which is also used to prevent malaria and treat auto-immune diseases – will be effective for use in the clinical management of COVID-19. Only controlled clinical trials can allow us to judge how useful this molecule might be in this case.

It is early days, but you are working on innovative treatment strategies for therapeutic tumor vaccination. In the longer term, this research could be useful for other pathologies, including coronavirus infections. Could you talk us through your research?

Vaccines were one of the greatest medical advances in the history of humanity. When it comes to infectious illnesses such as COVID-19, we immediately think of antibody-inducing prophylactic vaccination. But as mentioned earlier, prophylactic vaccines for the coronaviridae behind common colds only offer short-term protection, which might also be a problem in terms of developing a new vaccine for SARS CoV2. Furthermore, it is not clear at the moment whether the antibodies that are produced against this virus are effective in neutralizing it. There are other types of vaccinations that aim to eliminate aberrant cells in human beings. The main actors are in this case so-called cytotoxic T cells. Along with my colleague Eric Tartour (INSERM Cancerology Anti-Angiogenic Treatment and Immunotherapy team, U970), we are working on developing this type of vaccination as part of an anti-tumor immunotherapy program. Applied to the case of COVID-19, the aberrant cells to be eliminated would be those infected by SARS-CoV2, and the vaccine would thereby help to protect people who are exposed to the virus, and maybe even speed up the recovery process for those who have developed the disease. It should, however, be noted that the positive impact of a “cytotoxic” response to the effectiveness of vaccines for intracellular pathogens such as SARS-CoV2 is still far from being established.