New studies show genetic factors influencing susceptibility to coronavirus
The following is based on the articles 'Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells' by Z. Daniloski et al., first published in Cell on October 24 2020, and 'Genome-wide CRISPR Screens Reveal Ht Factors Critical for SARS-CoV-2 Infection' by J. Wei et al., first pubilshed in Cell on October 20 2020. Links to those articles and other relevant reads can be found in the 'Read more' section below this post.
From economics to international travel to the amount of time we spent outside each day, there were very few elements of our lives unaffected by SARS-CoV-2 (Covid 19) this past year. Unsurprisingly then, it has dominated medical and biological literature this year, with determination to fast track a vaccine dominating both medical journals and news stations alike (two things that, in my lifetime, don’t usually have a lot of overlap). So it’s natural to talk about it here, too, to give some insights from a genetics perspective on where the latest research is taking us. This isn’t an article on the vaccine and any thoughts on that, because I really know very little about the vaccine itself and I’d rather read up on at least some immunological principles before I throw my hat in that ring. This is instead about some recent research published in Cell which investigates how host genetics (the genetics of host organisms to the virus, such as humans) influence susceptibility to SARS-CoV-2.
Why is this important?
In a field of research defined by immediate real-world urgency, this question is more valid than ever. Luckily, there is a good answer. Understanding which genes (and, by extension, which proteins and cellular systems) are depended upon by the virus to infect host cells can help us understand more about the mechanistic operation of SARS-CoV-2 and provide us more methods of attack. What’s more, understanding these mechanics can help us understand why there is such a range of outcomes in infected patients. This has potential benefits for future treatment plans, amongst other things.
How is this tested?
In the two articles in Cell, a technique known as genetic screening was used. Genetic screens are ways of seeing what happens when one gene is mutated, and how this affects the operating of an organism (or just the cell itself). There are a number of types of genetic screen, and the type used in this experiment was a genome-wide screen. This means that, using a large range of cells, each cell had a different gene ‘mutagenised’ (altered in some way), until every gene in the cell was accounted for. This was done using CRISPR technology, which is capable of finding specified locations of DNA and cutting them (CRISPR can do many more things, but that’s for a different article). The DNA then repairs at that location, but inevitably with a few bases missing. This makes that cell a ‘knockout’ for that gene – it no longer has a functioning copy of that gene, and we can then observe how that cell operates without that gene. Many genes are essential, of course, and knockouts result in lethality pretty quickly, but many genes aren’t. Our genomes aren’t the seemingly indestructible Nakatomi Plaza, but neither are they a fragile house of cards.
Each of the studies performed genome-wide screens on different cells: one focused on lung cancer cells, and the other chose a cell line from monkeys (this study focused on not only SARS-CoV-2 but also other coronaviruses). Once a collection of cells with different genes knocked out had been created (creating a library of cells), and each of the cells was exposed to the virus, with the results being noted.
What was found?
The following contains a couple of protein names which may look daunting to the uninitiated, but don’t worry. You don’t need to know why they have those names or what they mean. They’re just names.
One gene was already known to be essential for infection by SARS-CoV-2 – the gene encoding for the ACE2 protein (the gene is also called ACE2, but italicised). The ACE2 protein is a protein involved in cutting up the angiotensin hormone and exists in the cell membrane (the big bubble-looking structure the cell exists within). It is also the gateway which SARS-CoV-2 uses to connect to cells. When the ACE2 gene was knocked out, cells were no longer infected by coronavirus, as predicted. Certain other knockouts also had very promising effects.
These knockouts generally included proteins involved in endocytosis (a cellular process which collapses parts of the cell wall to bring in outside molecules – see video attached, much easier to understand visually) and endosomal movements around the cell, that is, moving vesicles (small bubbles containing molecules) around the cell. These processes may be involved in the in-cell lifecycle of SARS-CoV-2, but the relationship may also be less clear. A knockout of the gene coding for the protein RAB7A GTPase was shown to reduce infection by SARS-CoV-2 as it had a prominent role in delivering ACE2 to the cell membrane, and so without it there was less ACE2, and less entry points for the virus.
So what’s next?
Both papers showed antiviral effects of small molecules targeting proteins which were ‘hits’ in the study (proteins which were shown to enhance infection by SARS-CoV-2). This is already extremely promising work, and could lead to more antiviral drugs which can reduce susceptibility to coronavirus. Obviously more cell lines will need to be tested to see if the results are consistent across a whole organism, but this is already a fantastic start.
Read more:
https://www.cell.com/cell/fulltext/S0092-8674(20)31392-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420313921%3Fshowall%3Dtrue - Article by Wei et al.
https://www.cell.com/cell/fulltext/S0092-8674(20)31394-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420313945%3Fshowall%3Dtrue - Article by Daniloski et al.
https://www.youtube.com/watch?v=DuDmvlbpjHQ - Video showing endocytosis
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