ISRRT elearning platform (2023)

Table of contents

• 1. What is a Virus?
• 2. How do viruses replicate?
• 3. Immune Responses to Virus.
• 4. How do Viruses Cause Disease?
• 5. How are viruses transmitted?
• 6. Why do some viruses only affect certain host species?
• 7. Vaccines
• 8. How are Viruses Studied?

1. What is a Virus?

Viruses are the smallest infectious agents, ranging from 20 nm to 400 nm in diameter. By comparison, the average size of a bacterial cell is 1 µm, hence 2-50 times bigger. Viruses are not cells: they are not capable of self-replication and are not considered “alive”. Viruses do not have the ability to replicate their own genes, to synthesise all their proteins or to replicate on their own; thus, they need to parasitise the cells of other life-forms to do so. Viruses invade cells then hijack the cell’s machinery to promote their replication. Newly formed viruses are then releasedfrom the host cellto invade more cells.

Viruses are simple, and are made up of up to three constitutive elements:

1. A genome, made up of nucleic acids that can be DNA (like humans) or RNA. RNA is very similar to DNA; both are made up of of chains of nucleotides (ACGT/U) that make up genes that are translated in proteins.
2. The genome is protected by a protein coat, called a capsid. The capsid proteins (capsomeres) assemble around the viral genome in different arrangements, termed either helical (e.g. influenza or coronavirus) or icosahedral;amore complex 20 sided shape(e.g. herpes or norovirus).
3. Some viruses possess an outer lipid envelope, which is derived from the host cell and can take many forms. Coronaviruses, like SARS-CoV-2, are spherical, Ebola virus is long and filament shaped. Enveloped viruses are more susceptible to destruction of the lipid through the use of soap or alcoholic hand-gels, than viruses without lipid envelopes.

2. How do viruses replicate?

Viruses recognise and bind to target cells by the interaction of molecules on their surface, with those on the target cell. These are called “surface receptors” – and work a little like a lock and key: a virus can only invade a cell is its surface molecule (the key), matches the receptor (the lock) on the host cell. The SARS-CoV-2 key is the spike protein which matches the ACE2 receptor lock on target cells.

After binding to target cells, virus particles enter the cell either by fusion of the lipid envelope with the host cell membrane (e.g. HIV) or receptor-mediated endocytosis (e.g. influenza virus or coronavirus), in which receptor binding triggers the cell to engulf the virus particle. Once inside the cell, the viral capsid dissolves, uncoating the viral genome, which can then be replicated. New viruses are now made by the host replication and synthesis machinery. Finallymature virus progeny exit the host cell. Enveloped viruses do this by budding, picking up a coating of lipids from the host cell membrane on the way out.Box 1 shows the size of virus particles, but also some of the surface receptors on coronaviruses and influenza virus.

3. Immune Responses to Virus.

4. How do Viruses Cause Disease?

Most viral infections do not result in disease, but a small number can cause extensive damage. This can be either because of the virus action against the cell, or the immune response to infection, and both can lead to symptoms. Indeed, symptoms can develop a number of ways from mild, self-limiting disease, to severe or lethal in the absence of treatment. Viral diseases in humans range from the common cold and warts to more profound, life-threatening syndromes such as measles, mumps, influenza, HIV, a range of enteric illnesses and haemorrhagic fevers (such as Lassa Fever, Marburg or Ebola). The severity of outcome will depend on the infectivity of the virus, but also on several host factors, including variation in cellular receptors and immune status.

The immune response is of course essential, but it can also be a problem. When viruses infect cells, they shut down the normal cellular processes, disrupting regulatory balances to focus on replication and synthesis of new virus particles. This causes a major stress response in the infected cells that can trigger cell death (apoptosis, cell “suicide”), but also sends out signals (cytokines) to alert the immune response. Cytokines attract immune cells to the affected area to kill virus-infected cells and trigger the production of antibodies that can neutralise the virus. However, sometimes this response can go into overdrive, causing a cytokine storm, which leads to damage of healthy as well as infected cells.

5. How are viruses transmitted?

There are many different ways in which a virus can spread from person to person. The mode of transmission is usually related to the location of virus replication. A virus will only infect cells that possess the correct surface receptors. For example gastro-intestinal viruses target and replicate in the cells that line the gut, causing damage which leads to diarrhoea. The newly-replicated virus progeny will be shed in the diarrhoea, and can be spread via the faecal-oral route due to poor hygiene or through contaminated water systems. Viruses such as HIV infect and replicate in specific immune cells and are present in blood (CD4+ Tcells or macrophages). They can only be spread by direct contact with blood or other bodily fluids e.g. during un-protected sex. Respiratory viruses, such as SARS-CoV-2 or influenza virus infect and replicate in cells that line the airways. Virus progeny are shed into respiratory droplets which are aerosolised and spread to others via a cough or sneeze.Virus-loaded droplets can travel ~2 metres and remain for some time on surfaces that they come in to contact with. This means that SARS-CoV-2 can transmit from one person to another directly by inhalation of virus-loaded respiratory droplets but can also be transmitted by hands that have touched contaminated surfaces. This is why it is so important to contain coughs / sneezes, dispose of tissues properly, and to maintain strict handwashing policies.

6. Why do some viruses only affect certain host species?

Several viruses have a narrow host range and will, for instance, only infect certain animals. For example: Human papilloma virus (HPV); Human Immunodeficiency Virus (HIV); or measles virus only infect humans. Viruses, in general, do not achieve anything by killing their host, as they can no longer replicate if their host has died. Therefore, many viruses have co-evolved with their hosts and do not cause severe disease. [Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411105/.]

Sometimes, a virus can jump the species barrier and infect a host that it doesn’t usually infect. This often results in a more severe disease as the virus is not adapted to this host and/or the host immune system will not have previously encountered the new virus. For example, although some types of influenza A virus typically replicate in birds, humans or pigs, occasionally, a “mutant” avian (bird), or a pig (swine) influenza virus emerges that is able to infect humans. Most mutants are “less-competent” viruses, unable to transmit or replicate well in host cells, and only very occasionally does one arise that is capable of efficient transmission and replication in humans. That’s why these species-jumping events are carefully monitored as they can lead to the evolution of new dangerous viruses that can cause pandemics. Many are famous: Spanish flucaused over 50 million deaths in 1918; In 1957, Asian ‘flucaused > 1 million deaths; H1N1 “swine” ‘flu infected 60 million people in 2009, but only caused 12,000 deaths. When a highly infectious virus jumps the species barrier, there is no pre-existing immunity in the new host population, so it can potentially have a major impact. The implications of species-jumps in the context of the origins of SARS-CoV-2 will be discussed later.

7. Vaccines

Vaccines have been developed to prevent several different viral diseases. They work by exposing the body to sufficient amount of virus to trigger an immune (antibody) response but not cause disease. This means that when a vaccinated person becomes infected with the virus for real, they can mount a faster, stronger immune response. Different types of vaccine have been developed; some use viruses that have been "attenuated", which means that they have been artificially evolved in the laboratory to be less able to cause disease. Others use inactivated virus or purified virus components that are incapable of replication in the body. These are safer, but less efficient at priming the immune response. It takes a long time to develop a safe and effective vaccine, because they need to be tested – first in the laboratory, then in animals and then in human clinical trials. Because vaccines tend to be very specific for the virus they are targeting, if a new variant of that virus appears, it may not be recognised by the antibodies produced against the virus used in the vaccine. For some very important viruses, the emergence of new variants is commonplace. For example, vaccines against influenza virus need constant re-configuration to best match the variants in circulation at the time, and this is why need a ‘flu shot every year.

An effective vaccine must be administered to a high enough percentage of the population to successfully protect a population. This is called herd immunity.

Antibiotics target specific aspects of bacterial replication, so are completely useless at treating viral infections. Antivirals prevent viral replication by targeting the host-cell machinery, meaning that they are often quite toxic.

8. How are Viruses Studied?

Viruses are much harder to isolate and grow in the lab than other microorganisms such as bacteria or fungi. This is because viruses need to be grown inside an appropriate host cell and maintaining cultures of host cells requires much technical skill. Furthermore, whereas bacterial ands fungal cells can be observed using light microscopy, such is the small size of viruses that powerful transmission electron microscopes are needed to see them. There are several different virus classification schemes. Initially these schemes were based on comparison of virus shape and size, or the types of cells that they infect, but today viruses are classified according to their genomes, and their great diversity has required the description of over 250 different families to accommodate them.