COVID-19 is caused by a coronavirus called SARS-CoV-2. Coronaviruses belong to a group of viruses that infect animals, from peacocks to whales.
They’re named for the bulb-tipped spikes that project from the virus’s surface and give the appearance of a corona surrounding it.
A coronavirus infection usually plays out one of two ways: as an infection in the lungs that includes some cases of what people would call the common cold, or as an infection in the gut that causes diarrhea.
COVID-19 starts out in the lungs like the common cold coronaviruses, but then causes havoc with the immune system that can lead to long-term lung damage or death.
SARS-CoV-2 is genetically very similar to other human respiratory coronaviruses, including SARS-CoV and MERS-CoV. However, the subtle genetic differences translate to significant differences in how readily a coronavirus infects people and how it makes them sick.
SARS-CoV-2 has all the same genetic equipment as the original SARS-CoV, which caused a global outbreak in 2003, but with around 6,000 mutations sprinkled around in the usual places where coronaviruses change. Think whole milk versus skim milk.
Compared to other human coronaviruses like MERS-CoV, which emerged in the Middle East in 2012, the new virus has customized versions of the same general equipment for invading cells and copying itself.
However, SARS-CoV-2 has a totally different set of genes called accessories, which give this new virus a little advantage in specific situations.
For example, MERS has a particular protein that shuts down a cell’s ability to sound the alarm about a viral intruder.
SARS-CoV-2 has an unrelated gene with an as-yet unknown function in that position in its genome. Think cow milk versus almond milk.
How the virus infects
Every coronavirus infection starts with a virus particle, a spherical shell that protects a single long string of genetic material and inserts it into a human cell.
The genetic material instructs the cell to make around 30 different parts of the virus, allowing the virus to reproduce.
The cells that SARS-CoV-2 prefers to infect have a protein called ACE2 on the outside that is important for regulating blood pressure.
The infection begins when the long spike proteins that protrude from the virus particle latch on to the cell’s ACE2 protein.
From that point, the spike transforms, unfolding and refolding itself using coiled spring-like parts that start out buried at the core of the spike.
The reconfigured spike hooks into the cell and crashes the virus particle and cell together. This forms a channel where the string of viral genetic material can snake its way into the unsuspecting cell.
It would be appropriate to go into specifics ….
Three coronaviruses have crossed the species barrier to cause deadly pneumonia in humans since the beginning of the 21st century: severe acute respiratory syndrome coronavirus (SARS-CoV) (Drosten et al., 2003, Ksiazek et al., 2003), Middle-East respiratory syndrome coronavirus (Zaki et al., 2012) (MERS-CoV), and SARS-CoV-2 (Huang et al., 2020, Zhu et al., 2020).
SARS-CoV emerged in the Guangdong province of China in 2002 and spread to five continents through air travel routes, infecting 8,098 people and causing 774 deaths. In 2012, MERS-CoV emerged in the Arabian Peninsula, where it remains a major public health concern, and was exported to 27 countries, infecting a total of ∼2,494 individuals and claiming 858 lives.
A previously unknown coronavirus, named SARS-CoV-2, was discovered in December 2019 in Wuhan, Hubei province of China and was sequenced and isolated by January 2020 (Zhou et al., 2020, Zhu et al., 2020).
SARS-CoV-2 is associated with an ongoing outbreak of atypical pneumonia (Covid-2019) that has affected over 90,000 people and killed more than 3,000 of those affected in >60 countries as of March 3, 2020. On January 30, 2020, the World Health Organization declared the SARS-CoV-2 epidemic a public health emergency of international concern.
MERS-CoV was suggested to originate from bats, but the reservoir host fueling spillover to humans is unequivocally dromedary camels (Haagmans et al., 2014, Memish et al., 2013). Both SARS-CoV and SARS-CoV-2 are closely related and originated in bats, who most likely serve as reservoir host for these two viruses (Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Yang et al., 2015a, Zhou et al., 2020).
Whereas palm civets and racoon dogs have been recognized as intermediate hosts for zoonotic transmission of SARS-CoV between bats and humans (Guan et al., 2003, Kan et al., 2005, Wang et al., 2005), the SARS-CoV-2 intermediate host remains unknown.
The recurrent spillovers of coronaviruses in humans along with detection of numerous coronaviruses in bats, including many SARS-related coronaviruses (SARSr-CoVs), suggest that future zoonotic transmission events may continue (Anthony et al., 2017, Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Menachery et al., 2015, Menachery et al., 2016, Yang et al., 2015a, Zhou et al., 2020).
In addition to the highly pathogenic zoonotic pathogens SARS-CoV, MERS-CoV, and SARS-CoV-2, all belonging to the β-coronavirus genus, four low-pathogenicity coronaviruses are endemic in humans: HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. To date, no therapeutics or vaccines are approved against any human-infecting coronaviruses.
Coronavirus entry into host cells is mediated by the transmembrane spike (S) glycoprotein that forms homotrimers protruding from the viral surface (Tortorici and Veesler, 2019). S comprises two functional subunits responsible for binding to the host cell receptor (S1 subunit) and fusion of the viral and cellular membranes (S2 subunit).
For many CoVs, S is cleaved at the boundary between the S1 and S2 subunits, which remain non-covalently bound in the prefusion conformation (Belouzard et al., 2009, Bosch et al., 2003, Burkard et al., 2014, Kirchdoerfer et al., 2016, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2016a).
The distal S1 subunit comprises the receptor-binding domain(s) and contributes to stabilization of the prefusion state of the membrane-anchored S2 subunit that contains the fusion machinery (Gui et al., 2017, Kirchdoerfer et al., 2016, Pallesen et al., 2017, Song et al., 2018, Walls et al., 2016a, Walls et al., 2017b, Yuan et al., 2017).
For all CoVs, S is further cleaved by host proteases at the so-called S2′ site located immediately upstream of the fusion peptide (Madu et al., 2009, Millet and Whittaker, 2015). This cleavage has been proposed to activate the protein for membrane fusion via extensive irreversible conformational changes (Belouzard et al., 2009, Heald-Sargent and Gallagher, 2012, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2017b).
As a result, coronavirus entry into susceptible cells is a complex process that requires the concerted action of receptor-binding and proteolytic processing of the S protein to promote virus-cell fusion.
Different coronaviruses use distinct domains within the S1 subunit to recognize a variety of attachment and entry receptors, depending on the viral species. Endemic human coronaviruses OC43 and HKU1 attach via their S domain A (SA) to 5-N-acetyl-9-O-acetyl-sialosides found on glycoproteins and glycolipids at the host cell surface to enable entry into susceptible cells (Hulswit et al., 2019, Tortorici et al., 2019, Vlasak et al., 1988).
MERS-CoV S, however, uses domain A to recognize non-acetylated sialoside attachment receptors (Li et al., 2017, Park et al., 2019), which likely promote subsequent binding of domain B (SB) to the entry receptor, dipeptidyl-peptidase 4 (Lu et al., 2013, Raj et al., 2013).
SARS-CoV and several SARS-related coronaviruses (SARSr-CoV) interact directly with angiotensin-converting enzyme 2 (ACE2) via SB to enter target cells (Ge et al., 2013, Kirchdoerfer et al., 2018, Li et al., 2005a, Li et al., 2003, Song et al., 2018, Yang et al., 2015a).
As the coronavirus S glycoprotein is surface-exposed and mediates entry into host cells, it is the main target of neutralizing antibodies (Abs) upon infection and the focus of therapeutic and vaccine design.
S trimers are extensively decorated with N-linked glycans that are important for proper folding (Rossen et al., 1998) and for modulating accessibility to host proteases and neutralizing Abs (Walls et al., 2016b, Walls et al., 2019, Xiong et al., 2018, Yang et al., 2015b).
We previously characterized potent human-neutralizing Abs from rare memory B cells of individuals infected with SARS-CoV (Traggiai et al., 2004) or MERS-CoV (Corti et al., 2015) in complex with SARS-CoV S and MERS-CoV S to provide molecular-level information of the mechanism of competitive inhibition of SB attachment to the host receptor (Walls et al., 2019).
The S230 anti-SARS-CoV Ab also acted by functionally mimicking receptor attachment and promoting S fusogenic conformational rearrangements through a ratcheting mechanism that elucidated the unique nature of the coronavirus membrane fusion activation (Walls et al., 2019).
We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2).
Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. We identified the presence of an unexpected furin cleavage site at the S1/S2 boundary of SARS-CoV-2 S, which is cleaved during biosynthesis—a novel feature setting this virus apart from SARS-CoV and SARSr-CoVs.
Abrogation of this cleavage motif moderately affected SARS-CoV-2 S-mediated entry into VeroE6 or BHK cells but may contribute to expand the tropism of this virus, as reported for several highly pathogenic avian influenza viruses and pathogenic Newcastle disease virus (Klenk and Garten, 1994, Steinhauer, 1999).
We determined cryoelectron microscopy (cryo-EM) structures of the SARS-CoV-2 S ectodomain trimer and reveal that it adopts multiple SB conformations that are reminiscent of previous reports on both SARS-CoV S and MERS-CoV S. Finally, we show that SARS-CoV S mouse polyclonal sera potently inhibited entry into target cells of SARS-CoV-2 S pseudotyped viruses.
Collectively, these results pave the way for designing vaccines eliciting broad protection against SARS-CoV-2, SARS-CoV, and SARSr-CoV.
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SARS-CoV-2 spreads from person to person by close contact. The Shincheonji Church outbreak in South Korea in February provides a good demonstration of how and how quickly SARS-CoV-2 spreads.
It seems one or two people with the virus sat face to face very close to uninfected people for several minutes at a time in a crowded room. Within two weeks, several thousand people in the country were infected, and more than half of the infections at that point were attributable to the church.
The outbreak got to a fast start because public health authorities were unaware of the potential outbreak and were not testing widely at that stage. Since then, authorities have worked hard and the number of new cases in South Korea has been falling steadily.
How the virus makes people sick
Immune responses to CoVs
The entire human population generally lacks immunity to SARS-CoV-2 and hence is susceptible to the novel virus. Currently, no detailed study has been reported regarding the immunological response to SARS-CoV-2.
Thus, we can only refer to previous studies on other CoVs, especially SARS-CoV and MERS-CoV (Fig. (Fig.4). In general, after a virus invades the host, it is first recognized by the host innate immune system through pattern recognition receptors (PRRs) including C-type lectin-like receptors, Toll-like receptor (TLR), NOD-like receptor (NLR), and RIG-I-like receptor (RLR) 28.
Through different pathways, the virus induces the expression of inflammatory factors, maturation of dendritic cells, and synthesis of type I interferons (IFNs) which limit the spreading of the virus and accelerate macrophage phagocytosis of viral antigens 28. However, the N protein of SARS-CoV can help the virus escape from the immune responses 29.
Soon, the adaptive immune response joins the fight against the virus. T lymphocytes including CD4+ and CD8+ T cells play an important role in the defense.
CD4+ T cells stimulate B cells to produce virus-specific antibodies, and CD8+ T cells directly kill virus-infected cells. T helper cells produce proinflammatory cytokines to help the defending cells.
However, CoV can inhibit T cell functions by inducing apoptosis of T cells. The humoral immunity including complements such as C3a and C5a and antibodies is also essential in combating the viral infection 30,31.
For example, antibodies isolated from a recovered patient neutralized MERS-CoV 32.
On the other hand, an overreaction of the immune system generates a large number of free radicals locally that can cause severe damages to the lungs and other organs, and, in the worst scenario, multi-organ failure and even death 33.
SARS-CoV-2 grows in type II lung cells, which secrete a soap-like substance that helps air slip deep into the lungs, and in cells lining the throat.
As with SARS, most of the damage in COVID-19, the illness caused by the new coronavirus, is caused by the immune system carrying out a scorched earth defense to stop the virus from spreading.
Millions of cells from the immune system invade the infected lung tissue and cause massive amounts of damage in the process of cleaning out the virus and any infected cells.
Each COVID-19 lesion ranges from the size of a grape to the size of a grapefruit. The challenge for health care workers treating patients is to support the body and keep the blood oxygenated while the lung is repairing itself.
SARS-CoV-2 has a sliding scale of severity.
Patients under age 10 seem to clear the virus easily, most people under 40 seem to bounce back quickly, but older people suffer from increasingly severe COVID-19.
The ACE2 protein that SARS-CoV-2 uses as a door to enter cells is also important for regulating blood pressure, and it does not do its job when the virus gets there first.
This is one reason COVID-19 is more severe in people with high blood pressure.
SARS-CoV-2 is more severe than seasonal influenza in part because it has many more ways to stop cells from calling out to the immune system for help.
For example, one way that cells try to respond to infection is by making interferon, the alarm signaling protein.
SARS-CoV-2 blocks this by a combination of camouflage, snipping off protein markers from the cell that serve as distress beacons and finally shredding any anti-viral instructions that the cell makes before they can be used.
As a result, COVID-19 can fester for a month, causing a little damage each day, while most people get over a case of the flu in less than a week.
At present, the transmission rate of SARS-CoV-2 is a little higher than that of the pandemic 2009 H1N1 influenza virus, but SARS-CoV-2 is at least 10 times as deadly. From the data that is available now, COVID-19 seems a lot like severe acute respiratory syndrome (SARS), though it’s less likely than SARS to be severe.
What isn’t known
There are still many mysteries about this virus and coronaviruses in general – the nuances of how they cause disease, the way they interact with proteins inside the cell, the structure of the proteins that form new viruses and how some of the basic virus-copying machinery works.
Another unknown is how COVID-19 will respond to changes in the seasons. The flu tends to follow cold weather, both in the northern and southern hemispheres. Some other human coronaviruses spread at a low level year-round, but then seem to peak in the spring. But nobody really knows for sure why these viruses vary with the seasons.
What is amazing so far in this outbreak is all the good science that has come out so quickly. The research community learned about structures of the virus spike protein and the ACE2 protein with part of the spike protein attached just a little over a month after the genetic sequence became available.