Q&A section
The Covid-19
virus

Understanding the pandemic is necessary to understand how to reduce risks.

We are in the midst of the global COVID-19 pandemic, a severe respiratory disease caused by a Coronavirus called SARS-CoV-2. For a virus to cause a human pandemic, two conditions need to be met: the virus can be efficiently transmitted between humans and there is no pre-existing immunity against the new virus in the human population. In the absence of drugs or vaccines, the virus spreads unchecked. But what is this virus we have never met? Where does it come from? Why is it so infectious and how can our bodies fight it? How do we know how many of us are infected, and can we predict what the future of COVID-19 will look like?

What is a coronavirus?

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.

 

 

Where did COVID-19 come from?

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.

Why is SARS-CoV-2 so infectious?

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.

How would my body fight a coronavirus infection?

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.

What are we doing to fight coronavirus?

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.

Are COVID-19 numbers misleading?

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.

Mutation of SARS-CoV-2 – could it get worse?

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.

In the quest for a cure: success stories and challenges

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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.