When in doubt, turn to science.
With conflicting reports from various news sources, I found myself unsure of who to trust and what to believe. No, putting a hairdryer down one’s throat and blasting hot air is not a treatment. And when in doubt, I turn to science. As a result, this essay will only cite articles from Nature, the premier scientific journal. These are articles published by the scientists themselves, unfiltered through politics, the press, religion, or well-meaning relatives with crazy and often dangerous DIY cures. The scientific method is tried and true and I have always trusted these peer-reviewed articles with reproducible results. Let’s see what we can figure out with these sources and all I remember of studying cell biology and genetics.
The following is from one of the earliest reports[1], when a patient was admitted into the Central Hospital in Wuhan on December 26, 2019:
Epidemiological investigations by the Wuhan Center for Disease Control and Prevention revealed that the patient worked at a local indoor seafood market. Notably, in addition to fish and shellfish, a variety of live wild animals — including hedgehogs, badgers, snakes and birds (turtledoves) — were available for sale in the market before the outbreak began, as well as animal carcasses and animal meat. No bats were available for sale. While the patient might have had contact with wild animals at the market, he recalled no exposure to live poultry.”
We can gather it’s not an avian flu, and the market didn’t have bats for sale. However, this strain is most closely related to viruses found in bats:
Metagenomic RNA sequencing of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
So yes, COVID-19 is related to bat viruses, but not because the guy ate a bat. Regardless, my grandfather was from Hubei, the province that Wuhan is in, and on behalf of Asians everywhere, I’m sorry we have these markets.
Here is a graphic that puts the relationship to two similar viruses in better detail:
WHCV has since had its name changed, but you can guess what it stands for. Its similarity to the other viruses gives us an idea of where it might’ve come from. Sections 1a and 1b are preserved across all three, and you can see in the green and gray bits that even though their placements are slightly different, much is conserved.
Now that we have a better understanding of where it came from, let’s look at another article, also published on February 3, 2020[2]. This one will show us what we’re dealing with.
Viral particles in ultrathin sections of infected cells displayed a typical coronavirus morphology, as visualized by electron microscopy (Extended Data Fig. 6g).
Here’s Figure 6g:
a, b, Vero E6 cells are shown at 24 h after infection with mock virus (a) or 2019-nCoV (b). c, d, Mock-virus-infected © or 2019-nCoV-infected (d) samples were stained with rabbit serum raised against recombinant SARSr-CoV Rp3 N protein (red) and DAPI (blue). The experiment was conducted twice independently with similar results. e, The ratio of the number of reads related to 2019-nCoV among the total number of virus-related reads in metagenomics analysis of supernatants from Vero E6 cell cultures. f, Virus growth in Vero E6 cells. g, Viral particles in the ultrathin sections were imaged using electron microscopy at 200 kV. The sample was from virus-infected Vero E6 cells. The inset shows the viral particles in an intra-cytosolic vacuole.
The text describing the pictures is fantastic, as we see the scientific method in action. a and c are controls, in which cells were infected with a mock virus. b and d are infections with COVID-19. The 500-micrometer zoom is a cross-section of the coronavirus itself, and you can see the spiky protrusions that give it its name. These spike proteins are important because now we’re going to see how it infects cells:
ACE2 is known to be a cell receptor for SARS-CoV. To determine whether 2019-nCoV also uses ACE2 as a cellular entry receptor, we conducted virus infectivity studies using HeLa cells that expressed or did not express ACE2 proteins from humans, Chinese horseshoe bats, civets, pigs and mice. We show that 2019-nCoV is able to use all ACE2 proteins, except for mouse ACE2, as an entry receptor to enter ACE2-expressing cells, but not cells that did not express ACE2, indicating that ACE2 is probably the cell receptor through which 2019-nCoV enters cells (Fig. 3). We also show that 2019-nCoV does not use other coronavirus receptors, such as aminopeptidase N (APN) and dipeptidyl peptidase 4 (DPP4) (Extended Data Fig. 7).
Figure 3 is below:
Determination of virus infectivity in HeLa cells that expressed or did not express (untransfected) ACE2. The expression of ACE2 plasmid with S tag was detected using mouse anti-S tag monoclonal antibody. hACE2, human ACE2; bACE2, ACE2 of Rhinolophus sinicus (bat); cACE2, civet ACE2; sACE2, swine ACE2 (pig); mACE2, mouse ACE2. Green, ACE2; red, viral protein (N); blue, DAPI (nuclei). Scale bars, 10 μm.
Let’s make sense of this picture. From top to bottom, the authors tested the ACE2 of various animals; human, bat, civet, swine, mouse. From left to right, the blue are the cell nuclei, the green is ACE2 (the hypothesized cellular entrance), the red is viral protein. The far image on the right is all of these combined together. You can see that all cells were infected with the exception of mouse and the control cells (untransfected). Based on the data, yes, that’s probably how it gets in. For further proof, research was done on the spike itself and how the virus uses that spike to enter the cell.
Cell entry is an essential component of cross-species transmission, especially for the betacoronaviruses. All CoVs encode a surface glycoprotein, spike, which binds to the host-cell receptor and mediates viral entry. For betacoronaviruses, a single region of the spike protein called the receptor-binding domain (RBD) mediates the interaction with the host-cell receptor. After binding the receptor, a nearby host protease cleaves the spike, which releases the spike fusion peptide, facilitating virus entry. Known host receptors for betacoronaviruses include angiotensin-converting enzyme 2 (ACE2) for SARS-CoV and dipeptidyl peptidase-4 (DPP4) for MERS-CoV. [3]
Now we know where it comes from, what it does, and how it infects human cells. Are there potential treatments? This is from an article published on March 23, 2020[4].
It has been demonstrated that chloroquine is a broad-spectrum inhibitor of nanoparticle endocytosis by resident macrophages. Therefore, chloroquine decreases the accumulation of synthetic nanoparticles of various sizes (14–2,600 nm) and shapes (spherical and discoidal) in cell lines, as well as in the mononuclear phagocyte system of mice in response to clinically relevant doses of chloroquine. Mechanistic studies have revealed that chloroquine reduces the expression of phosphatidylinositol binding clathrin assembly protein (PICALM), one of the three most abundant proteins in clathrin-coated pits. PICALM is a cargo-selecting clathrin adaptor that senses and drives membrane curvature, thereby regulating the rate of endocytosis. Depletion of PICALM has previously been shown to inhibit clathrin-mediated endocytosis, which is a predominant pathway for synthetic nanoparticle internalization.
Chloroquine is an approved drug for malaria. It blocks objects of certain sizes and shapes from entering a cell. Note that this is not a cure, and much more testing needs to be done, but it does offer a potential therapy.
SARS-CoV-2 falls within the same size range (60–140 nm) and shape (spherical) as commonly studied synthetic nanoparticles. Therefore, it is possible that one of the mechanisms responsible for chloroquine-mediated effects against SARS-CoV-2 is a general decrease in the ability of cells to perform clathrin-mediated endocytosis of nanosized structures due to PICALM suppression (Fig. 1). Other Coronaviridae are known to enter host cells through receptor-mediated endocytosis, although direct fusion with the plasma membrane has also been reported. For example, the SARS-CoV virus identified in 2003 and the human coronavirus NL63 (HCoV-NL63) identified in 2004 bind to the angiotensin-converting enzyme 2 (ACE2) receptor, triggering endocytosis-driven cell entry. Both clathrin-mediated and clathrin/caveolae-independent endocytosis mechanisms have been described for SARS-CoV entry in human cells. SARS-CoV-2 might use similar ACE2-mediated mechanisms of cell entry.
Figure 1 is below. Also note that ACE2 was mentioned here as a potential way the virus gets into cells.
Fig. 1: Potential mechanism by which chloroquine exerts therapeutic effects against COVID-19. The proposed mechanism involves chloroquine-induced suppression of PICALM, which prevents endocytosis-mediated uptake of SARS-CoV-2.
The left picture shows normal conditions, when the virus uses its crown of spikes to dock with the cell surface. The virus enters the cell and can wreak havoc. On the right, with chloroquine already in the cell, the virus does not enter because clathrin doesn’t bind to the spikes, preventing it from entering. This is one potential method of preventing virus uptake, but again, much more research needs to be done.
There are other ways to interfere with the virus, disrupting it at different stages in its own life cycle. HIV/AIDS research has created treatments that act at those different stages, and the same principles can be applied here. However, the line between cure and poison is thin, and throwing terms and drugs around haphazardly can lead to deaths, as we’ve already seen. I am not sure how scientists are progressing with the treatment, but I’m sure they’re working on it, because there’s a lot of money, prestige, and awards if they can get something out that relieves the global tension.
Perhaps the 2nd source says it best:
Finally, considering the wide spread of SARSr-CoV in their natural reservoirs, future research should be focused on active surveillance of these viruses for broader geographical regions. In the long term, broad-spectrum antiviral drugs and vaccines should be prepared for emerging infectious diseases that are caused by this cluster of viruses in the future. Most importantly, strict regulations against the domestication and consumption of wildlife should be implemented.
Again, really sorry about the market. A big thanks to Nature for providing open and free access to these articles during this time. If you’d like to read more, please check out:
https://www.nature.com/collections/hajgidghjb
[1] Wu, F., Zhao, S., Yu, B. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). https://doi.org/10.1038/s41586-020-2008-3
[2] Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). https://doi.org/10.1038/s41586-020-2012-7
[3] Letko, M., Marzi, A. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 5, 562–569 (2020). https://doi.org/10.1038/s41564-020-0688-y
[4] Hu, T.Y., Frieman, M. & Wolfram, J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nat. Nanotechnol. (2020). https://doi.org/10.1038/s41565-020-0674-9