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Understanding Cold and Flu Viruses

There are many viruses that are responsible for cold and flu like illnesses. With exposure to these viruses on a regular basis, our bodies are constantly fighting off these invaders to keep them at bay. Usually this is successful and without any impact on our wellbeing.  Of course, many of us come to expect some level of discomfort and general malaise from one or more bouts of illness during the annual cold and flu seasons.

Whilst Cold and flu are both caused by types of virus that cause infections of the upper respiratory tract, namely the nasal passages, throat and into the bronchial tubes (and potentially the lungs and other organs), there is a remarkable variety within this broad virus classification and the extent of their impact on us. Viruses have been ever present and endemic within the human population and wild and domestic animals. In recent years, global health crises such as SARS, Swine flu and Covid-19 continue to keep these viruses in the everyday headlines.

What is a Virus?

A virus is a very simple type of micro-organism that invades living cells and hijacks the cells own machinery to replicate and proliferate. Although a virus can survive outside of cells in droplets or on surfaces, given suitable conditions for up to days, it cannot replicate without a host cell. Once many viral particles are created, they burst out of the cell to infect other cells and continue the cycle.

A virus consists of a protein shell, which may have an envelope that is derived from the cell it infects, and within this protein shell called the capsid and  the viral genome that encodes the virus components. Genomes of viruses may be simple, but they are diverse, since they can be either RNA or DNA, single or double stranded and vary in size.

How can viruses be imaged?

Viruses are in the order of 20-400 nm in size making them very challenging to visualize.

Traditionally imaging of viruses would be done using an electron microscope. This has been useful to help characterize the structure and improve our understanding, but this technique is quite limited in providing only a snapshot of events within fixed cells. A number of super-resolution techniques have emerged such as dSTORM TIRF, and SIM that allow imaging of fluorescently labelled viruses. This allows for a much wider range of experiments to be conducted within live cells over time. A key part of these techniques is the use of highly sensitive EMCCD imaging cameras. These are capable of detecting single photons and hence suitable also for imaging of viruses with appropriate labels. Imaging highly sensitive EMCCD CAMERAS to visualize and track viruses in real-time within living cells using fluorescent labels. Although more common sCMOS cameras can be used for some studies, the signal levels are typically so low that EMCCD cameras remain the definitive detector for such studies.

Learn more about Andor and Imaris Solutions for Imaging and Visualization of Viruses

How do you know if you have a cold or a flu?

It is well known that many people will claim the flu was responsible for them feeling so bad and taking them out of action for some time, but it is much more likely to have been a bad case of the cold. And it goes without saying that getting cold in temperature does not directly cause the common cold, but like becoming tired or run down it can certainly contribute to becoming susceptible to a virus and subsequently getting ill.  While molecular testing is required to find the true culprit, it is possible to make some general observations on the symptoms caused by cold and flu like illnesses and point to what may have been the cause.

Colds are caused by a number of viruses and normally have milder symptoms which are mainly restricted to the upper respiratory tract i.e. nasal passages, throat and sometimes into the upper bronchial tubes. In fighting off these infections, the body will feel weakened due to the efforts involved and the body’s own systems trying to fight the virus. Colds may last from several days to as long as 10 days, however it can take much longer to feel fully recovered.

Flus are caused by influenza viruses and have typically a more severe impact. Symptoms may often be felt across the whole body, including aching muscles and joints. Flu virus is a serious health concern for vulnerable age groups and those that are immunocompromised or have other underlying health conditions. The CDC report that 250,000 to 500,000 people die annually due to the normal seasonal flu and the complications arising from the flu.

Occasionally more virulent strains of the usual cold and flu viruses appear. However, even the less virulent cold viruses are of significance in terms of economic impact from loss of productivity through staff absence. A larger economic impact and stress on health systems is felt by pandemics and the panic and disruption to supply chains that this creates.

How do viruses infect cells?

The overall scheme of infection and replication is shown in the following illustration:

  • He J, Sun E, Bujny MV, Kim D, Davidson MW, Zhuang X. Dual function of CD81 in influenza virus uncoating and budding. PLoS Pathog. 2013;9(10):e1003701. doi:10.1371/journal.ppat.1003701
  • Burkard, M.H. Verheije, O. Wicht, S.I. van Kasteren, F.J. van Kuppeveld, B.L. Haagmans, L. Pelkmans, P.J. Rottier, B.J. Bosch, C.A. de Haan Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner PLoS Pathog., 10 (2014) e1004502
  • Yang, L. Du, C. Liu, L. Wang, C. Ma, J. Tang, R.S. Baric, S. Jiang, F. Li. Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc. Natl. Acad. Sci. U. S. A., 111 (2014), pp. 12516-12521

What are the main Types of Cold and Flu Viruses?

Rhinovirus

By far the most common virus that causes cold symptoms are the rhinoviruses. It has been estimated that 40- 50% of cold-like illnesses humans have are due to this virus. The rhinovirus is among the smaller viruses at around 30 nm in size. It is non-enveloped and has a single stranded RNA genome. This virus is normally restricted to the upper respiratory tract, especially the nose as it prefers cooler temperatures that are less than that of the normal human body temperature. The name rhinovirus stems from the greek rhin meaning nose.

Infection and incubation are usually fast, with infection to time of first symptoms usually being within 2-3 days. As the rhinovirus spreads through the epithelial cells, the damaged cells cause the release of cytokines and chemokines and inflammatory response. This gives rise to the classic cold symptoms we are all too familiar with. The symptoms of colds caused by this virus peak at around 3 days but may take a further week to get back to normal. There are no vaccines available for rhinovirus, this is in part due to the number of serotypes of rhinovirus (150+) without significant genetic conservation and thus any means of having shared immunity across them. Thankfully, rhinoviruses are not usually as serious as the other cold and flu viruses described in this article.

Adenovirus

Another very common cause of cold-like illnesses is due to adenovirus. Over 50 adenovirus serotypes have been classified and while most only cause mild cold like illness, some of these have been linked to outbreaks that have been more severe, affecting the lower respiratory tract, bladder and digestive system. Adenoviruses are a medium sized virus at around 100 nm in size. They are an example of a double stranded DNA virus. Adenovirus was initially isolated and characterized from infected “adenoid” tissue which is found in the nasal cavity, leading to their name.

The adenovirus is one of the more resilient viruses capable of surviving for relatively long periods of time (up to several days) in the environment. Vaccines have been developed for military use for some serotypes of adenovirus, but there are none currently available to the wider public.

Coronavirus

Normally causing only mild cold-like symptoms coronavirus has been at the heart of several major global heath events through Sars-CoV, Mers-coV and most recently Covid-19. Coronavirus has a relatively large single stranded RNA genome and is a medium sized virus at around 120 nm in diameter. The characteristic spiky crown/corona like surface projections led to their name.

Coronaviruses may be spread from numerous animals hosts to humans. Initially they infect the epithelial cells of the nose but may progress to the upper respiratory tract. If this is contained, the body should be able to stop the infection from proceeding further and cold like symptoms may only last a few days. The problem is when the virus gets into the lungs.

Coronavirus attacks the goblet cells that secrete protective mucus and the cilia cells of the trachea and bronchia that help sweep the mucus and any virus contained away from the lungs to be destroyed in the stomach. If the goblet and cilia are killed this has a number of effects: the mechanisms by which the virus and any opportunistic pathogenic bacteria are prevented entering the lungs are impacted alongside the excess mucus being eliminated from the respiratory tract. Subsequently, the body’s own immune system may overreact and cause further damage to cells within the lung. This situation may quickly get worse as once the virus enters the lungs they affect the body’s ability to repair the vital oxygen exchanging cells. Within days, this can affect multiple organs of the body and whole systems can start to fail. Since this is a viral pneumonia, antibiotics will not work.

Despite several pandemics and global health concerns, coronavirus currently do not have any effective vaccines. While the use of antiviral drugs developed for Ebola and HIV are being used in current outbreaks their effectiveness has not yet been determined.

Flu (influenza) virus

The Flu is caused by influenza viruses and generally they create more severe respiratory disease and symptoms than cold viruses.  Influenza viruses are very contagious and spread easily via air borne droplets or via surfaces. Influenza viruses are around 80-120 nm but show some variation in length and their morphology. They have a multi-segmented single stranded RNA genome rather than the typical contiguous sequence. They are classified into four types: Type A, Type, Type C and Type D according to the variants in their surface antigens.

They have a fairly complex naming convention that includes the following:

  • Influenza type classification (A, B, C or D)
  • Species in which it was isolated (for humans none is given)
  • Region of origin
  • Strain number
  • Year strain was isolated
  • For Influenza A only, the subtype (H or N)

This system is described in more detail on the CDC Flu Virus Types page.

Influenza A viruses are the most common flu viruses affecting the human population. Influenza A viruses are endemic within many animals from birds to pigs, meaning that there is a large reservoir of virus. There is also a high level of mutation within influenza A viruses. This “antigenic shift” means that the virus can evade previous immunity that may have been gained by an individual in the past. For this reason there is a need for the flu vaccine to be continually revised to best match what the expected profile of the virus for the next flu season will be, and thus confer suitable immunity across vulnerable populations such as the elderly, pregnant or very young. The most common influenza A has two major surface receptor antigens haemagglutinin (HA) and neuraminidase (NA). Haemagultinin is involved in the initial attachment of the virus to the cell. Neuraminadase is involved in the release of the virus from the host cell. Neuroamindase inhibitors such as oseltamivir are therefore a target for antivirus drugs as these act to inhibit the release of virus from the cell and slow the spread of virus to other cells.

Influenza B in contrast, has been isolated from only a few animal species that humans would be in less contact with- such as seals, and exhibits less genetic variation so once immunity has been achieved, it is maintained for much longer. Therefore, influenza B infections are found much less frequently than influenza A.

Influenza C is found mainly in humans but is much less common and typically only causes mild illness in the general population. Influenza D has not yet been reported to cause illness in humans though it may have a capacity to do so. It has so far only been isolated from cattle.

Above: Live tracking of influenza virus as visualized by iSPIM using an iXon EMCCD Camera and Imaris Software. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003971 (Lakdawala SS et al. (2016) Open Access)

References

  • Zhou J, Scherer J, Yi J, Vallee RB (2018) Role of kinesins in directed adenovirus transport and cytoplasmic exploration. PLoS Pathog 14(5): e1007055. https://doi.org/10.1371/journal.ppat.1007055
  • Hidalgo P, Anzures L, Hernández-Mendoza A, Guerrero A, Wood CD, Valdés M, Dobner T, Gonzalez RA. 2016. Morphological, biochemical, and functional study of viral replication compartments isolated from adenovirus-infected cells. J Virol 90:3411–3427. https://doi:10.1128/JVI.00033-16
  • Gunaratne GS, Yang, Y, Li F, Walsetha TF, Marchant JS. (2018) NAADP-dependent Ca2+ signaling regulates Middle East respiratory syndrome-coronavirus pseudovirus translocation through the endolysosomal system. Cell Calcium Volume 75, November, Pages 30-41. https://doi.org/10.1016/j.ceca.2018.08.003
  • Vahey MD and Fletcher DA. Low-Fidelity Assembly of Influenza A Virus Promotes Escape from Host Cells (2018) Cell Vol. 176: Issue 1-2, Pages 281-294 https://doi.org/10.1016/j.cell.2018.10.056
  • Gadalla MR, Abrami L, van der Goot FG, Veit M (2020) Hemagglutinin of Influenza A, but not of Influenza B and C viruses is acylated by ZDHHC2, 8, 15 and 20. Biochem J 17 January; 477 (1): 285–303. doi: https://doi.org/10.1042/BCJ20190752

What is a vaccine and how are they created?

A vaccine is an agent that stimulates the immune system to produce an immune response and the subsequent immunity to a specific disease. A vaccine contains an attenuated form of the virus (or bacteria) that have been processed so they will not cause the disease itself, but present the antigenic properties that will stimulate the immune system. A live attenuated vaccine may still cause the illness, but it will only be a much milder form. The immune system will then produce antibodies to these milder virus components and if exposed to the virus at a later stage the immune system will thus, recognize it and quickly produce antibodies to mount an effective response.

A vaccine can be created by weakening the virus so that it has impaired ability to replicate, for example, the virus can be inactivated by treating with a chemical, or only part of the virus can be used, usually surface antigens. However, it is difficult to create a vaccine as a stable and effective product.

Components of a vaccine

Component Description Example
The “Antigen” Active component The agent that stimulates the appropriate immune response Inactivated virus
Preservative To prevent vaccine becoming contaminated Phenol
Adjuvant Boost the immune response and enhance the production of protective antibodies Aluminum hydroxide or phosphate salts
Stabilizer Maintain stability and effectiveness of the vaccine during storage until use Inorganic salts, Sorbitol
Residual components Trace levels of other material- e.g. from culture of cells. The levels of these components are much lower than found in foods and other products. Antibiotics (e.g. Neomycin), Formaldehyde & Cell culture media

References

Complications of cold and flu viruses: Secondary Infections

While the immune system is occupied fighting off the cold or flu, it becomes more vulnerable to other infections. Indeed, bacterial infections from Streptococcus pneumoniae, Haemophilus influenza and Staphylococcus aureus are the most common. These and many other bacteria are a normal part of the body’s microbiota and when all is working normally do not cause any harm, and it has becoming apparent that these bacteria may actually prevent other pathogens from gaining a foothold.

Pneumonia is possibly the most well-known complication, whereby the alveoli – the small sacs within the lungs responsible for gas exchange become inflamed. In the case of a viral infection such as by Coronavirus, the globlet and cilia become damaged by cytotoxic actions of the virus and the mechanisms by which potentially harmful bacteria and fluid are swept clear of the lungs are compromised. Bacteria may more readily invade and proliferate in the damaged cells. The immune system may also release a flood of cytokines which may overstimulate the immune system and cause further inflammation. The net effect of this is to create difficulty breathing and potentially progressing to complications such as abscesses or sepsis unless antibiotic treatment is successful. Pneumonia has been well described throughout history and effective treatment was observed with modern antibiotics for bacterial pneumonia, however with increasing antibiotic resistance becoming commonplace our ability to tackle it is in decline. Thankfully there is an effective vaccine against Haemophilus influenza “Hib-B” as this is a common cause of bacterial pneumonia.

References

  • Morris DE, Cleary DW, Clarke SC. Secondary Bacterial Infections Associated with Influenza Pandemics. Frontiers in Microbiology (2017) Vol. 8 pages 1041. https://doi.org/10.3389/fmicb.2017.01041
  • Joseph C, Togawa Y, Shindo N. Bacterial and viral infections associated with influenza. Influenza and Other Respiratory Viruses (2013) 7(Suppl. 2), 105– 113.

Outbreaks, Epidemics and Pandemics

What is the difference between outbreaks, epidemics and pandemics?

Classification Description Example
Outbreak A single instance of disease that is spreading from a single source or case Inactivated virus
Epidemic An epidemic is usually described as a disease that is spreading and often, but not always, limited to a single country Zika virus Brazil 2015-2016
Ebola West Africa 2013-2016 epidemic
Pandemic The World Health Organization (WHO) defines a pandemic as “an outbreak of a new pathogen that spreads easily from person to person across the globe” SARS in 2002
H1N1 Flu 2009
Covid-19 (2019-)

However, these do not take into consideration of how lethal the disease is. Therefore, a disease that is labelled as an epidemic or pandemic and may create more fear and panic in the population than it should since it may only pose a low level of severity. But this may also prompt regional health authorities to scale their delay and containment actions more appropriately to the potential threat.

The R0 value – Transmissibility and Severity

The R0 value (basic reproduction number) is used to help model and estimate the speed at which a disease may spread in a population. Effectively this is how many susceptible people an infected person will infect during the duration of their illness, without any control measures being in place. If a value is less than 1 it will die out, but if it is greater than 1 the virus has potential to spread.

Because the ability of a virus to infect others is situation dependent, R0 will vary- for example a city vs a countryside population. Factors that influence the infectivity level include:

  • The infectious period- i.e. the time someone is contagious for
  • Mode of transmission- e.g. air-borne transmission is higher than via bodily fluids
  • Contact Rate- how many people will the infected person come into contact with
Virus Estimated R0 Value
Measles 12-18
SARS 2-5
HIV 4
MERS ~2.5
Covid-19 1.4-3.9
(Wuhan outbreak 1.6-2.6)
Norovirus 1.6-3.7
Ebola 2
Seasonal Flu 1.3

An example of a virus with a high R0 value is Measles and this highlights how important vaccination is to control this virus in the population. The R0 does not compare the severity of illness. For example, Flu and Ebola both have low R0 values but are very different viruses. Ebola typically appears in sporadic outbreaks of very high lethality of 25 to as high as 90% with many of the infected dying before the virus can spread more widely. Seasonal flu is less severe but allows for a greater transmission resulting in an annual cycle globally. The transmissibility and severity of the virus are both used to determine what control measures should be put in place for managing an outbreak or epidemic.

Notable Pandemics

Spanish Flu (1917-1918)

Spanish flu was responsible for more deaths globally than in World War I with estimates being that as much as 50% of the world’s population was affected and 50 to 100 million fatalities. A variant of H1N1 influenza A, it is of note that the 20-40 year-old age group was affected by this pandemic. Normally this age group is not a high risk of severe impact. It is speculated that it may have been the overreaction of the stronger immune systems in this population group that created a “cytokine storm” and increased cell damage within lungs resulting from this. It should also be noted that during this time period under wartime conditions, general health levels of the population will be lower due to such things as wartime related malnourishment, large numbers of sick and weak patients within hospitals and prison camps. This would make a much larger population vulnerable to flu virus, and the large death rate not related to the specific lethality of this specific strain.

Asian Influenza (1956-1958)

This pandemic also had a high % of infection with estimates of up to 50% of the world’s population being infected and 1-4 million fatalities. This was a H2N2 Influenza variant, but it is not certain how this variant originated. Secondary bacterial infection was strongly associated with this pandemic with some 80% of severe and fatal infections reported to be linked to bacterial pneumonia. A vaccine was developed in 1957 which helped to limit this outbreak, with a further variant appearing a few years later but with much reduced impact.

SARS- Severe Acute Respiratory Syndrome (2002-2003)

SARS was thought to be of animal origin, possibly bats (since these are known carriers of coronaviruses) though the exact reservoir is uncertain. This was first recorded in China (Guangdong province) and quickly spread worldwide reaching over 8000 reported cases. While many cases were influenza-like, more severe cases progressed to respiratory distress and failure. 

Swine Flu (2009-2010)

Swine flu originated in Mexico in early 2009 and became a worldwide pandemic. It has been estimated that 700 million to 1.4 billion were infected and there were in the region of 150,000 to 875,000 fatalities (Fatality rate <1%). This like Spanish flu, was a variant of H1N1 influenza A and was inked to reassortment of human flu with both avian, swine and Eurasian pig flu virus. Commonly referred to as swine flu but called pandemic H1/N1/09 by the WHO.

MERS Coronavirus - Middle East Respiratory Syndrome (2014 to date)

MERS is another coronavirus pandemic of recent times that causes mild to lethal infections. Mortality rates of MERS have been reported as exceptionally high – 30-36% of total recorded cases. The origin of MERS appears to be from bats, however camels are also infected by this virus and have been found with MERS reactive antibodies. It is therefore highly probable that camels infected by MERS coronavirus serve as a route of transmission to humans. There have been sporadic outbreaks through Saudi Arabia, South Korea, Philippines and Kenya from 2014 to date. The spread of the MERS has been limited outside of hospital environments indicating that its transmission rate is low. There is no vaccine for MERS and treatment with antiviral agents such as interferon do not appear to be beneficial to patient outcome. However, it is often that case that these antiviral drugs tend to be administered at later stages of the illness, and earlier treatment may have been more effective.

Covid-19 Coronavirus (2019-)

Covid-19 is the last and most recent addition to this list. Appearing in China, Wuhan province in late 2019, it quickly spread globally. It was eventually classified as a pandemic by 11th March 2020. Again, another coronavirus which is capable of minor, through to severe respiratory disease. As with other virulent coronaviruses, the risk is magnified for those with underlying health conditions such as heart disease, obesity, diabetes, or other respiratory illnesses.

Further sources of Information and guidelines on outbreaks, epidemics and pandemics

References

  • Fukumi, H. “Summary report on the Asian influenza epidemic in Japan, 1957.” Bulletin of the World Health Organization vol. 20,2-3 (1959): 187-98.
  • Zhang RQ, Hong SL, Wen CY, Pang DW and Zhang ZL,. Rapid detection and subtyping of multiple influenza viruses on a microfluidic chip integrated with controllable micro-magnetic field, Biosensors and Bioelectronics,. Volume 100, 2018, Pages 348-354, ISSN 0956-5663, https://doi.org/10.1016/
  • Zumla A, Hui DS and Perlman S. Middle East respiratory syndrome. Lancet, 386 (2015), pp. 995-1007
  • Wang D, Hu  B, Hu  C,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.  Published online February 7, 2020. https://doi:10.1001/jama.2020.1585
  • Kucharski AJ, Russell TW, Diamond C, Liu Y, Edmunds J, Funk S and Eggo RM
  • Early dynamics of transmission and control of COVID-19: a mathematical modelling study. The Lancet, published online March 11, 2020 DOI:https://doi.org/10.1016/S1473-3099(20)30144-4

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