Coronaviruses are readily recognizable from their spike-like projections on the surface of the virus particle. The crown-like shape of these spikes gives these viruses their name and is critical for the virus to infect its host.
Unlike other pathogens such as bacteria, viruses are not alive. If they are left on abiotic materials such as metal or plastic surfaces, they will not multiply. However, they can cause devastating disease when they infect humans. The reason is that in their core, viruses are packages for a piece of malicious genetic code. Upon delivery to human host tissues during infection, this code drives the production of viral factors that take over infected cells, and ensure the production and release of thousands of new infectious virus particles. These new virus particles in turn infect other cells, causing rapid virus spread and disease in the infected person.
The virus that causes the disease COVID-19 (SARS-CoV-2) packages its piece of malicious genetic code inside a lipid shell that is decorated with “Spike” structures. These spikes bind to specific receptors on lung and respiratory tract cells (called ACE-2), which fuses the virus particle with the host cell, delivers the genetic code, and starts the infection cycle. The bulky ends of the spikes give these viruses a crown-like shape (corona in Latin), from which their name is derived. The lipid shell in which the Spike proteins are anchored dissolves in soap when washing hands, rendering the virus particles non-infectious.
After entry, the released viral genetic material is decoded inside the infected cell into viral factors, thereby starting the hostile take-over of the infected cell, and production of new virus particles during the viral life cycle.
In addition to the spike, coronavirus particles are composed of structural components that both encapsulate the genetic code material (nucleocapsid) and give the virus particles their structure (membrane and envelope proteins). To replicate itself, the virus also encodes an enzyme to copy its genetic code (polymerase), and factors to inhibit the host’s immune defenses (accessory proteins). The accessory proteins are often important factors in determining the severity of disease, and may explain differences in the mortality rates between coronaviruses, such as SARS, MERS and COVID-19, that have claimed many lives in the last decade.
Coronaviruses infect many animal species as well as humans. COVID-19 is what’s called a ‘zoonosis’, which means that this disease jumped species into humans, probably through close contact with animals.
The causative agent of the disease COVID-19 is a coronavirus, (SARS-CoV-2). COVID-19 is a zoonosis, which means that it can be transmitted to humans from animals. Zoonoses caused by cross-species transmission represent 60% of the emerging infectious diseases worldwide, and are often life-threatening. We all remember the influenza pandemics caused by viruses that crossed the barrier from birds or swine to humans. Cross-species transmission often occurs when animals and humans are in close contact, such as large animal farms, or crowded food markets where live animals are sold. But how do these viruses make the jump to a new species? Ultimately, to infect a new host, the viral proteins involved in transmission must be able to bind to receptors present on the surface of cells in the new species. The changes usually arise from error-prone replication of the viral genome. As an example, the gene coding for the Spike protein, which binds to the receptor of SARS-CoV-2 in humans, is a mutational hotspot. Coronaviruses, like influenza viruses, can also exchange parts of their genome with other viruses during a coinfection. When such major genomic changes happen in the right region, they can generate new chimeric viruses capable of infecting a new host.
Zoonoses become really threatening when the viruses are able to efficiently spread from human to human, usually by droplet infection, as is the case for SARS-CoV-2 and related viruses – our species doesn’t “know” the virus and is therefore not protected. Identifying the species of origin and possible intermediate hosts is extremely important to be able to control future transmission events. In the case of COVID-19, full-length genome sequences of the SARS-CoV-2 virus obtained from patients (including a worker in the now infamous food market in Wuhan) are almost identical to that of coronaviruses found in bats.
However, Coronaviruses are in many animal species besides bats, and SARS-CoV-2 is not the only one that made the jump to ours. Of the 7 coronavirus isolated from humans, 4 cause common cold symptoms; the remaining 3 cause severe respiratory disease. The most similar to SARS-CoV-2 is SARS-CoV-1, responsible for the SARS (Severe Acute Respiratory Syndrome) outbreak originating in Guangdong, China in 2002, presumably originating from civet cats sold for food in a live-animal market, which were possibly infected by contact with bats. SARS spread rapidly to more than 30 countries, but luckily there have been no SARS cases since 2004. MERS-CoV was responsible for a 2012 outbreak with a clear epicenter in the Arabian Peninsula, and was traced to dromedary camels. Both viruses took a heavy toll on human health, but COVID-19 spreads with unprecedented speed and threatens to overwhelm health systems around the world.
SARS-CoV-2, the virus that causes COVID-19, binds tightly to the surface of cells that line our respiratory tract, while asymptomatic carriers spread the infection undetected. These two factors are contributing to COVID-19 spreading with unprecedented speed around the world.
Like all viruses, SARS-CoV-2 requires a host in order to replicate itself. To replicate, the virus must first gain entry to the host cell. SARS-CoV-2 does this by latching on to a protein called ACE2, or angiotensin-converting enzyme 2, found on the surface of many cells in our bodies, including the delicate structures of the lungs that allow us to breathe. But why is Covid-19 different to other coronaviruses, including the one that caused the original SARS outbreak in 2002?
Scientists have now deciphered part of the answer to that question. The spike protein of SARS-CoV-2, which decorates the surface of the virus, binds to ACE2 on the surface of human cells 10 to 20 times more tightly than the original SARS coronavirus. Researchers have recently been able to obtain a snapshot of the spike protein bound to ACE2, revealing the reasons behind this difference. One can think of it like a jigsaw puzzle in which the two pieces fit perfectly together. The better the virus can bind to our cells, the more likely it is to gain entry.
The spread of the virus, however, is exacerbated by a second factor: asymptomatic carriers. These are people who exhibit no symptoms, but are carrying around the virus. Without knowing it, these people risk spreading the virus to others. For these reasons, the track-and-trace approach of widespread testing followed by strict quarantine, successfully employed in South Korea, is essential to contain the virus and avoid overwhelming healthcare services.
Our immune system has two arms: the rapid reaction force, called ‘innate immunity’ and a slower arm, called ‘adaptive immunity’ which mounts a highly specific attack against the pathogen. Deployment of the adaptive arm of the immune system is essential to overcome the invader and to create a memory of the virus.
Our immune system protects us with weapons that are very rapidly deployed and others that take some time to start operating. Very simply put, the rapid response slows down the propagation of a virus, but cannot entirely stop it. The slow response is very effective and usually lets us regain health by clearing the virus from our body. The rapid and slow responses of our immune system are called innate and adaptive immunity.
Many viruses, including Corona viruses, actively reduce the impact of the rapid immune response. This allows them to multiply before the slower arm of the immune response starts being protective. In addition, some viral diseases, including severe cases of COVID-19, are associated with severe inflammation of internal organs, particularly the lung. In a worst-case scenario the resulting pneumonia impairs lung function to the point of being life-threatening. A second threat is that a virally infected person becomes ‘superinfected’ with a second pathogen, usually a bacterium that exacerbates inflammation. We have no information as yet on how much superinfection contributes to COVID-19, but doctors have recommended people at high risk to be vaccinated against Pneumococcus, a frequent cause of pneumonia.
Immunity as we understand it results from the slow arm of the immune system, the adaptive immunity. Figuratively speaking, adaptive immunity builds an army consisting of antibodies and cells that search and destroy the invading pathogen, and specifically generates a memory of this invader that helps it to mount a faster and more vigorous response to a secondary infection with the same pathogen. A characteristic of immunological defence and memory is the occurrence of neutralizing antibodies in the plasma of our blood. Antibodies are proteins that bind to the virus. If they are neutralizing they prevent the virus from attaching to cells it is trying to infect.
It is still early days to form a sound judgment of immunological memory as a means to prevent re-infection with the SARS-CoV-2 virus. However, neutralizing antibodies have been found in infected persons and there is reason to hope that immunological memory will indeed mitigate the risk of getting sick again with COVID-19.
Herd immunity occurs when transmission chains are disrupted by healthy people who are immune to the virus either through vaccination or having recovered from an earlier infection. Herd immunity is essential for the eradication of diseases such as smallpox, measles and polio.
Herd immunity (also called population immunity) is a mode of protection against infectious disease. It occurs when many individuals become immune by recovering from an earlier infection or through vaccination. Immune individuals do not contribute to disease transmission so that infection chains are frequently disrupted. Consequently, the infection spread is slowed or stopped in a population in which a high percentage of individuals possess immunity. For example, herd immunity generated through vaccination was a prerequisite for the eradication of smallpox in 1977. The proportion of people who need to become immune so that herd immunity can be established is different for each infection, depending on factors such as infectivity of the pathogen or the incubation period. Herd immunity is essential to protect vulnerable people, including the elderly and immune-compromised people, against an infection.
Models simulating the spread of COVID-19 disease suggest that 60-80% people need to be immune against the SARS-CoV-2 virus to establish an efficient herd immunity. Once this threshold is reached, the high-risk population, i.e. elderly or immunosuppressed people, and people with heart or lung diseases, would be to a large degree shielded from COVID-19. Broad testing for the presence of antibodies against the SARS-CoV-2 virus in the population will provide information on the current herd immunity and its progress.
Limiting the spread of COVID-19 is essential to prevent healthcare services from being overwhelmed. Together with its partners across Vienna, the Max Perutz Labs are repurposing existing research infrastructure to increase the national testing capacity.
Like many other countries around the world, Austria is suffering from a lack of testing capacity. In South Korea, where new infections have been successfully reduced to practically none, 1 in 136 people have been tested, a worldwide high. The ability to track and trace is key to ensuring the disruption of infection chains, quarantining infected people as soon as possible, and lowering the burden on health care services. In collaboration with 20 other research institutions across Vienna, the Max Perutz Labs are repurposing existing laboratory infrastructure, reagents and manpower to increase the national testing capacity for SARS-CoV-2.
But how does one test a person for SARS-CoV-2? Like all viruses, SARS-CoV-2 carries its own genetic code around with it. The complete genetic code of SARS-CoV-2 was determined from a patient in Wuhan, China in early January this year. Detecting the genetic instructions of the virus is key to the major test being used around the world. Using small pieces of DNA, called primers, that match specific regions of the SARS-CoV-2 code, scientists can make thousands of copies of these segments, allowing them to be detected. Since the same code does not exist in our own DNA, a positive result confirms the presence of the virus in our cells. However, testing capacity is currently limited by the availability of high-grade reagents and high-throughput pipelines to cope with demand. Our mission is to do what we can to enhance the current testing capacity by diverting existing resources to the cause.
Another way to detect the virus is to detect the immune response in infected patients. The antibodies that the body makes against the virus can be detected in a test that is called an Enzyme-Linked Immuno-Sorbent Assay, or ELISA for short. A virus-specific protein, made in a laboratory, is immobilized on a surface, allowing it to be probed with a blood sample taken from the patient. If the patient is infected or has recovered from an infection, antibodies against the viral protein will bind tightly to it. These antibodies are then detected in a second step that is coupled to a light-emitting or color-changing enzymatic reaction. Development of such a test is critical for assessing the level of immunity developing in a population. Since SARS-CoV-2 goes undetected in many asymptomatic carriers, it is difficult to estimate the number of people who are infected and the proportion that develop severe disease. The Max Perutz Labs and its partners are actively working towards the development and implementation of such a test.
SARS-CoV-2 is still very new to us. Basic research is unraveling fundamental properties of the virus while clinical labs around the world are working with unprecedented speed to develop tools to stop its spread. As more and more is learned, predictions about the future of COVID-19 will become increasingly robust.
People around the world are now asking what will be the future for the COVID-19 pandemic. Will the disease and the SARS-CoV-2 virus disappear, similar to SARS-CoV in 2004 and MERS-CoV in 2012? Or will the disease become part of our lives similar to flu? Will there be a treatment and/or vaccine? Definitive answers to these important questions are not available yet because the virus and the disease are new. However, based on current knowledge it is possible to discuss likely and less likely scenarios for the future of COVID-19.
The virus appears to be highly contagious; its infectivity is higher than that of coronaviruses in previous epidemics. This property contributes to the rapid spreading of the virus around the world. Moreover, the combination of a long incubation time (up to 2 weeks) with an extended period of virus shedding in COVID-19 patients (up to several weeks according to recent reports) and a high percentage of asymptomatic infections allows dissemination of the virus under the radar, thereby further worsening the pandemic. This fast growth in the number of infected people worldwide might help establish a herd immunity relatively soon, provided that recovered patients develop immunity to the virus. Fortunately, this appears to be the case: so far there is little evidence that patients can get re-infected with the virus. Thus, it can be assumed that most people can generate a protective immunity against the virus – this is good news for the development of vaccines against SARS-CoV-2. Vaccination would further facilitate the establishment of herd immunity and, consequently, perhaps eradication of the virus. Yet, viruses often have the unpleasant property of mutating their coat such that they cannot be recognized by the immune system, which was trained to attack the previous version of the virus. This is well known from the annual flu epidemics: every year a slightly different influenza virus evolves so that a lasting immunity against flu cannot be achieved. The available data on the mutation rate of SARS-CoV-2 provide grounds for some optimism: mutations in SARS-CoV-2 occur about two to four times slower than in the flu virus suggesting that immunity (generated during an infection or through vaccination) against SARS-CoV-2 could be more persistent than against flu.
In all likelihood, lasting strategies against COVID-19 will come from the research that is now spreading around the globe as quickly as the virus. Development of new drugs, re-purposing of known drugs, vaccination and other approaches are being pursued by companies and academic institutes worldwide, including those in Austria. Several promising results have already been achieved in the treatment of COVID-19 and the first vaccination trials have been initiated. The goals are clear: defeat the virus and learn the lessons so that we are better prepared for similar challenges in the future.
The media has widely reported claims that SARS-CoV-2 did not arise naturally but may have been deliberately created and released by scientists. The evidence, however, unequivocally supports a natural origin of the virus.
In April, concerns about a high-security virus facility in Wuhan, China, the epicenter of the COVID-19 outbreak, became the focus of media attention. Conspiracy theories rapidly circulated, ranging from an unfortunate accident to the more malicious deliberate engineering of a synthetic virus, the equivalent of an act of biological warfare. So what do we know about SARS-CoV-2 that can help us understand its origins?
Scientists have already been forensically examining the sequences of thousands of SARS-CoV-2 isolates. Fortunately, we know the genetic instructions of other coronaviruses as well as their mutation rates and biological processes that can change their genetic code. By comparing the genetic code of SARS-CoV-2 to those of other coronaviruses, scientists can date relatively accurately the likely time at which viruses diverged from a common ancestor. These in-depth analyses clearly demonstrate that the SARS-CoV-2 virus could not have occurred in a lab and is unlikely to have occurred in a pangolin. Most likely, SARS-CoV-2, like its cousin SARS-CoV from 2003, arose in a bat cave in the south-west of China some four decades ago.
SARS-CoV-2 contains a four amino acid insertion in part of its Spike protein that generates what is called a “furin cleavage site”. This means that the Spike can be cleaved by an enzyme in our cells, called furin; such cleavages have been shown to promote viral entry in related coronaviruses like the MERS virus. But where did this sequence come from? Sequence analysis of the SARS-CoV-2 genome strongly indicates that the sequence almost certainly did not arise from deliberate engineering of a bat coronavirus. Instead, the insertion likely arose from an event called a copy-choice error, which can arise when two or more related virus particles infect the same cell. In this co-infected cell, the enzyme that copies the viral genome (termed RNA polymerase) jumps from one virus’s RNA to another virus’s RNA during copying. As a consequence, RNA segments from two viruses are swapped leading to a novel combination of RNA molecules that did not previously exist. Indeed, the RNA sequence of the furin site insertion in SARS-CoV-2 is almost identical to that of the bat coronavirus HKU9 isolated in 2011, suggesting that HKU9 was one of the co-infecting viruses.
In summary: neither the part of the Spike protein that binds so effectively to our cells nor the furin cleavage site in the Spike protein arose by deliberate manipulation of a related virus. On the contrary, the above analyses show that the process was an entirely natural one that is frequently observed in coronaviruses, and has strong medical relevance in other viruses such as poliovirus and HIV.
Have we flattened the curve? Can we resume our normal life? In a pandemic, the decision on how to proceed should be based on hard facts collected by epidemiologists.
Epidemiologists study patterns of disease in humans, including the number of infected individuals. These numbers have never been more available in real time than for the current COVID-19 pandemic. Many renowned institutions maintain websites through which we can watch the virus in action: how many cases in total, how many active cases – and the outcomes, recovered versus deaths. These numbers are the best we have and are used to make informed decisions. Unfortunately, however, they are at best a vague indication of our interaction with the virus.
The problem is that different countries use different methods to test and report COVID-19 cases. Why is this a problem? If we all test for the presence of the virus, we should all get the same results. However, diagnostic tests differ in sensitivity and in the probabilities of returning false positives and false negatives. In addition, some countries report both cases confirmed by laboratory tests and probable cases, defined as patients with symptoms who interacted with confirmed cases; suspected cases, i.e. patients that show COVID-19 symptoms but have neither been tested nor in contact with confirmed cases, are not reported. This also applies, of course to reporting COVID-19 as a cause of death. However, while deaths are certain, asymptomatic infections are invisible and therefore make up the largest contingent of unreported cases.
So how many COVID-19 cases are really out there? Nobody knows, but it is safe to assume that the actual number of cases is much higher than the numbers we read in the news. So if we really want to know how infectious the virus is and, by extension, what the true mortality rate is, there’s only one way: testing, testing, testing – and using standardized methods. The recent announcement by the Swiss pharmaceutical company Roche of a reliable ELISA test (see ‘What are we doing to fight coronavirus?’) is therefore welcome news.
Viruses exploit error-prone replication of their genetic instructions to drive successful dissemination in their hosts. How does this work and what do we know about this process in SARS-CoV-2?
Humans have genetic material (DNA) that codes for all the factors that build up the different cells forming our bodies. Many viruses (including SARS-CoV-2) use a similar type of genetic material (RNA) to code for different, virus-specific factors needed for their life cycle. Two opposing biological principles in the replication of genetic material drive the evolutionary success of humans and viruses.
Humans are made up of many different cells, and copy their genetic material as precisely as possible when cells double during growth. The reason for this is that mistakes in just one of the many cells in a human body could be disastrous for the whole organism, as is, for example, the case when a single cell becomes cancerous.
In contrast, viruses thrive with the opposite strategy of replicating their genetic material with less fidelity, generating billions of progeny virus particles, each one slightly different from the other. Why would this be beneficial for the virus? Most of these changes are neutral or detrimental for infectivity, and will not be transmitted to other humans. However, a few of the viral genetic variants may now multiply faster, be transmitted more efficiently between individuals, or avoid recognition by antibodies generated by our immune systems. These viral variants will spread throughout the human population more efficiently.
The full genetic code of SARS-CoV-2 isolated from several thousand different COVID-19 patients has been determined; the viral genetic code is indeed showing signs of selection pressure. One of the genetic regions with alterations is the part encoding the viral entry protein (Spike), which may increase the strength of interaction of the virus with receptors on the surface of cells, or prevent efficient binding of otherwise neutralizing antibodies to it. Other alterations could potentially interfere with some of the current diagnostics. However, the influence of these mutations on viral fitness and virus detection remain unclear and will require further investigation.
Without a vaccine, what tools do we have to treat COVID-19? Can we actually treat the disease effectively or are we simply deploying lifeboats in the most urgent cases?
The reason for the global COVID-19 crisis is the lack of effective treatments. Current medication focuses on mitigation of the disease symptoms (symptomatic treatment) rather than on targeting the cause of the disease, i.e. the SARS-CoV-2 virus. Symptomatic treatment is a common strategy against many diseases, and it can also help against COVID-19. For example, severely sick COVID-19 patients receive oxygen to compensate for their lung insufficiency. Fever-reducing agents are another class of symptomatic medications for COVID-19. Promising symptomatic treatments are medications aimed at reducing the so called “cytokine storm” which is an immune reaction that has spiraled out of control and has a high risk of life-threatening lung damage.
Nevertheless, interventions directly targeting SARS-CoV-2 would tremendously enhance our ability to treat COVID-19. One such strategy employs the administration of blood serum obtained from people who recovered from COVID-19. The anti-SARS-CoV-2 antibodies present in these sera help the patients in multiple ways (for example, by preventing the virus from entering the cells). However, this successful therapy cannot be used on a large scale since the number of healthy serum donors is limited.
In the absence of a vaccine, drugs targeting the virus represent the best means for a broad and affordable treatment. One such drug is remdesivir, which interferes with the viral replication machinery. Originally developed against the Ebola virus, the drug appears to be also partially effective against SARS-CoV-2. However, drug repurposing has a high chance of failure. Chloroquine (a common anti-malarial drug) can block SARS-CoV-2 but has significant adverse side effects in COVID-19 patients. Drugs against the flu virus are, in general, ineffective against SARS-CoV-2. Thus, the challenge is to develop new drugs that are safe and precisely target SARS-CoV-2. Scientists are therefore searching for the Achilles’ heel in the SARS-CoV-2 life cycle that could be effectively targeted.
A vaccine, when available, will certainly be the most effective measure to control SARS-CoV-2. Before we look at the approaches being taken against SARS-CoV-2, let us look at how a vaccine works.
Vaccines are our most powerful health measure to prevent viral infections and thus protect ourselves against the diseases they cause. Simply put, a vaccine simulates a real infection in the body without the disease breaking out. The body then mounts a defense against these invaders that is memorised and can be reactivated should a genuine infection take place. Vaccines that protect against viral diseases come in three basic types. The most effective ones are called live vaccines. They contain a weakened virus (termed attenuated) that can still multiply in the body but without causing disease. Examples of this type are the measles and mumps vaccines. Inactivated viral vaccines (also referred to as killed vaccines) contain virus particles that have been chemically inactivated with for example formaldehyde. In contrast to live vaccines, they do not multiply but the viral particles are still recognised as foreign bodies so that the immune system can build a response. Inactivated vaccines, such as the one against tick-borne encephalitis virus (FSME), usually have to be injected more that once to ensure protection. The third types of viral vaccine, such as the flu vaccine, contain just certain parts of the virus that are required to generate protection.
Vaccines of all three types are being developed against SARS-CoV-2 by around 70 different institutes and companies. For instance, an inactivated vaccine is being tested in monkeys by a company in China. It will be many years before an attenuated vaccine against SARS-CoV-2 can be generated. Instead, researchers have turned to other viruses that can present the SARS-CoV-2 spike protein without causing disease. One promising approach that uses a monkey virus has already been shown to generate antibodies in humans against the related MERS virus. A similar vaccine against SARS-CoV-2 is now in clinical trials in humans. Even if current trials prove safe and show that antibodies are generated, it will still take many months to produce enough vaccine for the whole world. Until, then, the best methods to prevent infection by SARS-CoV-2 will remain social distancing and hand-washing with soap.
Vaccines harness the power of our adaptive immune system, but our innate immune system can also help. Here, we take a look at ways in which our innate immune system can work against SARS-CoV-2.
Immunological memory and immunity against pathogens are usually attributed to the adaptive immune system (see: How would my body fight a coronavirus infection?). However, this is not the whole truth. Our innate immune system also remembers a previous encounter with microorganisms or viruses. This innate memory, also called trained immunity, is fundamentally different from the memory lymphocytes and antibodies produced by the adaptive immune system.
The biggest difference is that our innate immune system acts broadly and not only against the same pathogen that caused the immune response in the first place. For example, animals treated with bacterial vaccines have been found to display enhanced immunity against a subsequent viral infection. Trained immunity by the innate immune system triggered researchers from the German Max Planck Society to develop the idea of using an improved and clinically approved vaccine against Tuberculosis (Tb) to protect against SARS-CoV-2. The scientists think the bacteria in the vaccine may help to harness the innate immune system against SARS-CoV-2. Since the vaccine is already approved for use, it can be tested immediately in clinical trials.
Another potentially helpful substance is interferon (IFN). IFN is released by our innate immune system as a response to viral infection. In fact, the name stems from its ability to ‘interfere’ with viral replication inside cells. Interferons are approved clinical treatments against cancer and viral infections. Thus, they could be tested in a small cohort of COVID-19 patients and were found to increase clearance of the virus in the upper respiratory tract. However, another study cautions against the use of IFN. The authors report that IFN increases expression of the receptor for SARS-CoV-2 entry (ACE2) on airway epithelial cells. Thus, beneficial and potentially harmful effects of IFN treatment must be carefully evaluated in future clinical trials.