Virusphere: What doesn’t kill you makes you stronger

Microbiologists had long recognised the presence of viruses before the electron microscope was invented. They found ways of detecting the presence of viruses from their effects on host cells, and they could even count their precise numbers from their cytopathic effects in cultures. It will come as no surprise to discover that the best cultures for growing rhinoviruses are cells derived from the human nasal lining, or the lining of the windpipe, or trachea. We are equally unsurprised to learn that the best temperature at which to culture cold viruses is between 33°C and 35°C, which is the temperature found within our human nostrils on a cold autumnal or winter’s day.

Rhinoviruses are highly adapted for survival in their host environment. They are also highly adapted to infect a specific host. This became apparent when scientists attempted to infect laboratory animals, including chimpanzees and gibbons, with a variety of different subtypes of rhinovirus that readily infected humans. They could not replicate the symptoms of a typical cold in any of the animals. From this we glean an important lesson about viruses: the rhinovirus is most particular when it comes to its choice of host, which is exclusively Homo sapiens. This has a pertinent significance; it means that human infection is vitally important to virus survival. Only through human to human contagion can the virus be passed on and breed new generations of rhinovirus. We are the natural reservoir of the cold virus.

But a moment or two of reflection on such exclusivity provokes a tangential thought – and a pertinent question. These minuscule polyhedral balls have no obvious means of locomotion. How can they possibly move about through our human population to effortlessly spread their infection across national and even international boundaries?

In fact, we already have the answer: it is implied in the very title of this chapter. Why do we cough and sneeze? We do so because this is what happens when our noses, throats and windpipe passages feel irritated. It is part of the natural defences against foreign material entering passages where it could block our airways and, implicitly, obstruct them and threaten our breathing. What rhinoviruses do is to provoke the same physiological responses by irritating the linings of our nasal passages. The viruses spread from person to person because they are explosively ejected into the ambient air with every cough and sneeze, to be inhaled and subsequently infect new hosts. And here, once again, we learn something vitally important about viruses. The viruses do not need any mechanism of locomotion because they hitch a ride on our own locomotion, and everywhere we go, we further oblige them by spreading their contagion by coughing and sneezing.

How clever, we are inclined to think, are viruses!

But viruses could not possibly be clever. They are far too simple to be capable of thinking for themselves. We are instead confronted by another of the numerous enigmas in relation to viruses. How, for example, could an organism some paltry 30 nanometres in diameter acquire such devious but also such highly effective patterns of behaviour as we discover in the common cold? The answer is that viruses do this through their evolution. Indeed, viruses have an extraordinary capacity to evolve. They evolve much faster than humans, even much faster than bacteria. Over subsequent chapters we shall see how that viral employment of host locomotion is one of many such evolutionary adaptations.

What then do rhinoviruses do when they get inside us?

We have seen that the rhinovirus has a specific target cell, the cilia-flapping cells lining the nasal passages. Once inhaled, the virus targets these lining cells, discovering a specific ‘receptor’ in the cell’s surface membrane, after which the virus uses the receptor to break through the membranous barrier and gain entry into the cell’s interior, or cytoplasm. Here the virus hijacks the cell’s metabolic pathways to convert it into a factory for the replication of daughter viruses. The daughter viruses are extruded into the nasal and air passages, there to search out new cells to infect and continue the invasive process. It seems to require only a tiny dose of virus to be inhaled from the expelled cough or sneeze of an infected person to initiate infection in a new individual. After arrival, the incubation period from virus entry to infected nasal cells exuding new daughter viruses can be as little as a day. We don’t have much of a chance of escaping infection once the virus has been inhaled. Virus replication peaks by day four.

Fortunately, it isn’t all one way. Even as the virus is launching its attack, the human immune system has registered the threat, and it has recognised the viral antigenic signature – what we call the serotype. The problem is that the arrival of a new serotype requires time for the immune system to recognise the threat and to build up a formidable arsenal of responses. By day six the nasal passages are the focus of a virus versus immunological war zone, with no quarter asked or given on either side. This intense immune response causes the nasal passages to shed most of their lining cells, exposing highly inflamed raw surfaces, with narrowed breathing passages exuding copious mucus, which contains rising levels of antibodies to the virus. The rhinovirus is eventually killed off by the neutralising antibodies and the ‘war detritus’ is cleared away by the gobbling action of phagocytic white cells. During this immunological conflagration the new host follows the same unfortunate cycle of being infectious to others, through coughing and sneezing, for a period of anything from one to three weeks.

There is an adage that colds will not kill you. This is largely true, but colds can make children more liable to sinusitis and otitis media, a nasty bacterial infection of the middle ear. Colds can also precipitate asthma in people constitutionally prone to it, and they can provoke secondary bacterial chest infections in people suffering from cystic fibrosis or chronic bronchitis. Nevertheless, the salutary consolation is that, in the great majority of human infections, the rhinovirus eventually passes on by and we make a complete recovery.

Is there anything we can do to minimise the risk of contracting that cold – or is there any effective treatment when we are afflicted?

In Roman times, Pliny the Younger recommended kissing the hairy muzzle of a mouse as a remedy for colds. Benjamin Franklin was more sensible, suggesting that exposure to cold and damp in the atmosphere was responsible for the development of a cold. He also recommended fresh air and avoiding the exhaled air of other people. More modern times have seen a veritable cornucopia of quack remedies for prevention or treatment of colds. One of the most popular was vitamin C, championed by the distinguished American chemist, Linus Pauling. But alas, when subjected to scientific scrutiny it proved no more effective than the mouse’s whiskers. Perhaps we should focus more on common sense? Colds are contracted from the coughs and sneezes of infected people. People in congested offices, or even relatives who find themselves ill at home, should follow the old adage: trap your germs in a handkerchief. If an individual is deemed to be at a particularly high risk from a cold, wearing a virus-level face mask would certainly reduce the likelihood of infection when exposed to an infectious source.

A pertinent question remains: why, then, if our immune system has come to recognise and react to the rhinovirus, are we still susceptible to further colds during our lifetime? In fact, there are roughly 100 different ‘serotypes’ of the rhinovirus, so immunisation to any one type would not provide adequate protection from the others. Added to this is the fact that serotypes are capable of evolving so that their antigenic properties are apt to change.

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A Plague Upon a Plague (#u05bbd12e-fc53-5e94-91fc-1b07bdd2ba3c)

In 1994 the East African nation of Rwanda erupted onto the world’s news and television screens when a simmering civil war between the major population of Hutus and minority population of Tutsis erupted into a genocidal slaughter of the minority population. But despite the deaths of half a million Tutsis, the Hutu perpetrators lost the war, causing more than two million of them to flee the country. Roughly half of these fled northwest, across the border of what was then Zaire, these days the Democratic Republic of the Congo, where they ended up around the town of Goma. Up to this point Goma had been a quiet town of some 80,000 people, nestling by Lake Kivu in the lee of a volcano. Goma now found itself overwhelmed by a desperate torrent of refugees, carrying everything from blankets to their meagre rations of yams and beans. Two hundred thousand arrived in a single day, confused, thirsty, hungry and homeless. They camped on doorsteps, in schoolyards and cemeteries, in fields so crowded that people slept standing up. Agencies from the world’s media flocked to the vicinity, reporting the chaos and the urgent need for shelter, food and water.

A reporter for Time magazine estimated that the volume of refugees needed an extra million gallons of purified water each day to prevent deaths from simple thirst, meanwhile the rescue services were managing no more than 50,000. Desperate people foraged for fresh water, scrabbling hopelessly in a hard volcanic soil that needed heavy mechanical diggers to sink a well or a latrine. Human waste from the relief camps fouled the waters of the neighbouring Lake Kivu, creating the perfect circumstances for the age-old plague of cholera to emerge. Within 24 hours of confirmation of the disease some 800 people were dead. Then it became impossible to keep count.

Viruses are not the only cause of plagues, which include a number of lethal bacteria, such as the beta-haemolytic streptococcus, tuberculosis and typhus, as well as some protists, which cause endemic illnesses such as malaria, schistosomiasis and toxoplasmosis. Cholera is a bacterial disease, caused by the comma-shaped Vibrio cholerae. The disease is thought to have originated in the Bengal Basin, with historical references to its lethal outbreaks in India from as early as 400 CE. Transmission of the germ is complex, involving two very different stages. In the aquatic reservoir the bug appears to reproduce in plankton, eggs, amoebae and debris, contaminating the surrounding water. From here it is spread to humans who drink the contaminated water, where it provokes intense gastroenteritis, which proves rapidly fatal from massive dehydration as a result of the fulminant ‘rice-water’ diarrhoea. This human phase offers a second reservoir for infection to the bug. If not prevented by strict hygiene measures, the extremely contagious and virulent gut infection causes massive effluent of rice-water stools that are uncontrollable in the individual sufferer, so that they contaminate their surroundings, and especially any local sources of drinking water, leading to a vicious spiral of very rapid spread and multiplication of the germ.

During the nineteenth century, cholera spread from its natural heartland, provoking epidemics in many countries of Asia, Europe, Africa and America. The massive diarrhoeal effluent of cholera is unlike any normal food poisoning. An affected adult can lose 30 litres of fluid and electrolytes in a single day. Within the space of hours, the victims go into a lethargic shock and die from heart failure.

The English anaesthetist, John Snow, was the first to link cholera with contaminated water, expounding his theory in an essay published in 1849. He put this theory to the test during a London-based outbreak around Broad Street, in 1854, when he predicted that the disease was disseminated by the emptying of sewers into the drinking water of the community. Snow’s thoughtful research led to the civic authorities throughout the world realising the importance of clean drinking water. Today the life of an infected person can be saved by very rapid intravenous replacement of fluid and electrolytes, but the size of the outbreak around Lake Kivu, and the relative paucity of local medical amenities, limited the clinical response. The situation was made even worse by the recognition that the cholera in the Rwandan refugee camps was now confirmed as the 01-El Tor pandemic strain of Vibrio, known to be resistant to many of the standard antibiotics. This presented immense problems for the medical staff from local health ministries and those arriving from the World Health Organization. Even though the response was one of the largest relief efforts in history – involving the Zairian armed forces, every major global relief agency and French and American army units – the spread of cholera was too rapid for their combined forces to take effect.

Three weeks after the outbreak began, cholera had infected a million people. Even with the modern knowledge and the desperate efforts of civic and medical assistance, the disease is believed to have killed some 50,000. It is hard to believe that so resistant a plague bacterium as the Vibrio cholerae might itself be prey to another microbe. But exactly such an attack, of a mystery microbe upon the cholera vibrio, had been recorded in a historic observation by another English doctor close to the very endemic heartland of the disease, a century before the outbreak at Lake Kivu.

In 1896 Ernest Hanbury Hankin was studying cholera in India when he observed something unusual in the contaminated waters of the Ganges and Yamuna Rivers. Hankin had already discovered that he could protect the local population from the lethal ravages of the disease by the simple expedient of boiling their drinking water before consumption. When, in a new experiment, he added unboiled water from the rivers to cultures of the cholera germs and observed what happened, he was astonished to discover that some agent in the unboiled waters proved lethal to the germs. It was the first inkling that some unknown entity in the river waters appeared to be preying upon the cholera bacteria.

Hankin probed the riddle further. He found that if he boiled the water before adding it to the cholera germ cultures this removed the bug-killing effect. This suggested that the agent that was killing the cholera germs was likely to be of a biological nature. He needed to know if it was another germ – sometimes germs antagonised one another – or if it was something completely different, a truly mysterious agent, that was killing the germs. Hankin decided that he would set up a new experiment using a device known as a Chamberland-Pasteur ‘germ-proof’ filter, which had been developed 12 years earlier by the French microbiologists Charles Chamberland and Louis Pasteur. The Chamberland-Pasteur filter was a flask-like apparatus made out of porcelain that allowed microbiologists to pass fluid extracts through a grid of pores varying from 0.1 to 1.0 microns in diameter – from 100-billionths to 1,000-billionths of a metre – that were designed to trap bacteria but allow anything smaller to pass through. Two years after the filter’s invention, a German microbiologist, Adolf Mayer, showed that a common disease of tobacco plants, known as tobacco mosaic disease, could be transmitted by a filtrate that had passed through the finest Chamberland-Pasteur filter. Unfortunately, he persuaded himself that the cause of the disease must somehow be a very tiny bacterium. In 1892 a Russian microbiologist, Dmitri Ivanovsky, repeated the experiment to get the same results. He refuted a bacterial cause, but still arrived at the mistaken conclusion that there must be a non-biological chemical toxin in the liquid extract. Finally, in 1896, the same year that Hankin was looking for his mystery agent in the Indian river waters, a Dutch microbiologist, Martinus Beijerinck, repeated the filter experiment with tobacco mosaic disease; but Beijerinck concluded that the causative agent was neither a bacterium nor a chemical toxin but rather ‘a contagious living fluid’. Although Beijerinck was closest of all to the truth, he was once again wrong. Today we know that the cause of tobacco mosaic disease is a virus – the tobacco mosaic virus. But thanks to Beijerinck’s mistaken finding of a ‘contagious fluid’, the current Oxford English Dictionary definition of a ‘virus’ has it as: ‘a poison, a slimy fluid, an offensive odour, or taste’.

Viruses are not poisons, or slimy fluids, or offensive odours or tastes, but rather organisms – truly remarkable organisms – that are different from bacteria, indeed utterly different from any other organisms on Earth. The great majority of viruses are very small, tiny enough to pass through Chamberland-Pasteur filters.

Of course, Hankin knew nothing of the existence of viruses when he passed the river water through the refined sieve of a Chamberland-Pasteur filter. Although he was in no position to offer a likely explanation or name for the mystery agent, he had discovered one of the most important and ubiquitous of viruses on Earth: a member of the group known today as ‘bacteriophage’ viruses, so-named from the Greek phagein, which means to devour. That is exactly what was happening to the cholera germs in Hankin’s experiments: they were being ‘devoured’ by bacteriophage viruses.

The true nature of Hankin’s discovery remained a mystery until 1915, when English bacteriologist Frederick Twort discovered a similarly minuscule agent that could pass through the Chamberland-Pasteur filters and yet remained capable of killing bacteria. By now viruses were known to exist even though biologists knew very little about them. Twort surmised that he was observing either a natural phase of the life cycle of the bacteria, the result of a fatal enzyme produced by the bacteria themselves, or a virus that grew on and destroyed the bacteria. Some two years later, a pioneering, self-taught, French-Canadian microbiologist, Félix d’Herelle, finally solved the mystery.

D’Herelle was born in the Canadian city of Montreal but considered himself a citizen of the world. Before becoming involved with viruses, he had already travelled widely, working in numerous American, Asian and African countries, to finally settle at the Pasteur Institute in Paris. At this time the discipline of microbiology was a fashionable scientific research endeavour and it was rapidly expanding its knowledge base. During his researches in Tunisia, d’Herelle had come across what was probably a virus infecting a bacterium that itself caused a lethal plague in locusts. Now working at the famous Institute, even as the First World War raged nearby, he took a particular interest in the grimy disease known as bacterial dysentery, which was killing soldiers in their muddy trenches.

Bacterial – as opposed to amoebic – dysentery is caused by a genus called Shigella, which is passed on from the infected individuals through faecal hand-to-mouth contagion. The resultant illness ranges from a mild gut upset to a severe form, with agonising griping spasms of the bowel accompanied by high fever, bloody diarrhoea and what doctors call ‘prostration’. In July and August 1915 there was an outbreak of haemorrhagic bacterial dysentery among a cavalry squadron of the French army, which was stalemated on the Franco-German front little more than 50 miles from Paris. The urgent microbiological investigation of the outbreak was assigned to d’Herelle. In the course of intensive investigation of the bugs responsible, he discovered ‘an invisible, antagonistic microbe of the dysentery bacillus’ that caused clear holes of dissolution in the otherwise opaquely uniform growth of dysentery bacteria on agar culture plates. Unlike his earlier colleagues, he had no hesitation in recognising the nature of what he had found. ‘In a flash I understood: what caused my clear spots was … a virus parasitic on the bacteria.’

D’Herelle’s hunch proved to be correct. Indeed, it would be d’Herelle who would give the virus the name we know it by today: he called it a ‘bacteriophage’. Then the French-Canadian microbiologist had an additional stroke of luck. When studying an unfortunate cavalryman suffering from severe dysentery, he performed repeated cultivations of a few drops of the patient’s bloody stools. As usual, he grew the dysentery bug on culture plates and passed a fluid extract through a Chamberland-Pasteur filter, thus obtaining a filtrate that could be tested for the presence of virus. Day after day, he tested the filtrate by adding it to fresh broth cultures of the dysentery bug in glass bottle containers. For three days the broth quickly turned turbid, confirming teeming growth of the dysentery bug. On the fourth day new broth cultures initially became turbid as usual, but when he incubated the same cultures for a second night he witnessed a dramatic change. In his words, ‘All the bacteria had vanished: they had dissolved away like sugar in water.’

D’Herelle deduced that what he was witnessing was the effects of a bacteriophage virus, which must also be present in the cavalryman’s gut – a bacteriophage virus that was capable of devouring the Shigella germ. But then he had an additional stroke of genius. What if the same thing was happening inside the infected patient? He dashed to the hospital to discover that during the night the cavalryman’s condition had greatly improved and he went on to make a full recovery. At this time bacterial infections, such as dysentery, typhoid fever, tuberculosis and the streptococcus, were a major cause of disease and death throughout the world. With no known antibiotics to treat infections, there was a desperate need for any form of therapy. His observations with the dysentery bug bacteriophage gave d’Herelle the idea that, perhaps, phage viruses might be cultivated with the express purpose of treating dangerous bacterial infections.

During the 1920s and 1930s, d’Herelle conducted extensive research into the medical applications of bacteriophages, introducing the concept of phage therapy for bacterial infections. This therapy saw widespread use in the former Soviet Republic of Georgia, and also the United States, continuing in use until the discovery of antibacterial drugs in the 1930s and 1940s. The use of drugs was much simpler to apply and proved dramatically effective, thus supplanting bacteriophage therapy. But this did not stop d’Herelle from continuing to study this marvellous if deadly entity that was so very tiny that it was completely invisible even to the most powerful light microscope, and yet appeared to be so powerful when it came into contact with its prey bacteria.

In 1926, d’Herelle published a now-historic book, The Bacteriophage, in which he described his work, and thoughtful extrapolations, concerning bacteriophage viruses. As we shall duly discover, the importance of the bacteriophage, as we recognise it today, has eclipsed all that even its pioneering researcher, Félix d’Herelle, could possibly have imagined in those early years.

In retrospect, it is remarkable that, even so many decades ago, d’Herelle clearly grasped that he was dealing with a wonder of the natural world, declaring in his book that these agents that were so dreadfully lethal to bacteria were also capable of exerting an extraordinary balancing effect in the interactions between the bacteriophage virus and its host bacterium. In his words: ‘A mixed culture results from the establishment of a state of equilibrium between the virulence of the bacteriophage corpuscles and the resistance of the bacterium. In such cultures a symbiosis obtains, in the true sense of the word: parasitism is balanced by the resistance to infection.’ This is the first use of the term ‘symbiosis’ in reference to viruses in microbiological history. In a footnote, d’Herelle took the implications further by drawing a parallel between what he was observing in the interaction of the bacteriophage virus and bacterium and the symbiosis that had recently been discovered in all land plants, where fungi in soil invade the plant roots to form a ‘mycorrhiza’, whereby the fungus feeds the plant with water and minerals and the plant feeds the fungus with the energy-giving metabolites that derive from the photosynthetic capture of sunlight. In d’Herelle’s words: ‘The respective behaviour between the bacterium and the bacteriophage is exactly that of the seed of the orchid and the fungus.’

D’Herelle is now recognised by many scientists as the father of both virology and molecular biology. But it would take many years before the world of virology, and microbiology in general, would come to rediscover d’Herelle’s original vision of the symbiotic nature of the bacteriophage.

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Every Parent’s Nightmare (#u05bbd12e-fc53-5e94-91fc-1b07bdd2ba3c)

Parents will be familiar with the anxiety that comes with childhood rashes and fevers. How natural that our hearts should falter with the beloved child tossing in a perspiring fever, the restless anxiety, racking coughs, or sickness and vomiting. We can hardly sleep with worry that something worse might happen in the dark of night. That worry is, perhaps, a residuum of a fear from times only recently gone by when unpleasant things really did happen in the dark of night to those we loved. How fortunate we are now that our families are protected by antibiotics, antiviral drugs and the vaccines that keep such terrors at bay. But these advances are relatively new to medicine and to society. We should not forget that as recently as the 1950s most of humanity, even in developed countries, ultimately died from infection.

Before its prevention, using the triple vaccine, one such major cause of parental anxiety was measles, a commonplace and highly contagious childhood fever. How astonishing it is that this appears to be a relatively new disease in humans. Hippocrates, who wrote about the common diseases in Ancient Greece in the fifth century CE, recorded clearly recognisable descriptions of common infections such as the virus-caused herpes and the protist-caused malaria, yet this very knowledgeable ancient authority gave no description to match the symptoms and signs of measles. It is hardly a disease that would be readily missed, with its striking rash and fever, high contagion and common association with childhood. There is a clue in the name, ‘measles’, deriving from an Anglo-Saxon word maseles, which means ‘spots’. The first written description of measles is attributed to the tenth-century Persian physician, Abu Becr, also known as Rhazes, who cited a seventh-century Hebrew physician, El Yehudi, as providing the first clinical description of the disease. Rhazes recognised measles as an affliction of children and he distinguished it from the equally prevalent but far deadlier rash-provoking disease of smallpox.

Symptoms typically include a high fever, with a temperature often greater than 40°C, a racking cough, runny nose and inflamed eyes. Two or three days after the start of the fever, small white spots on a red inflamed background can be seen in the mucous membranes inside the cheeks. These are known as Koplik’s spots and are diagnostic of the disease. At much the same time a flattish, bright red rash invades the skin, usually beginning on the face and then spreading to the rest of the body. The rash, and causative illness, usually persists for seven to ten days and, in fit and well-nourished children, is usually followed by a full recovery. But in a minority of cases, most commonly seen in malnourished children, and in particular children in less-developed countries with poorly developed health care facilities, measles can lead to serious complications.

Like the common cold, measles is specific to humans, although it can be artificially transmitted to monkeys by laboratory experiment. This means that we are the reservoir of measles in nature – we are the natural host. The only place measles virus can spread its infection, and produce its new brood of new daughter viruses, is in us. It really is that up close and personal. And this means that the relationship – the symbiosis – between humans and the measles virus has been evolving for a long time, and in symbiological parlance with evolutionary implications for both ‘partners’. The causative virus, or morbillivirus, comes in a variety of groups, known as ‘clades’, within the broader family of viruses, called the paramyxoviruses. Individual measles virions are spherical, rather like cold viruses, with a genome made up of a single strand of RNA. The viral genome is contained within a similar capsid type of coat, but in this case the capsid is enclosed in an additional surface ‘envelope’, which carries multiple spike-like projections that play a key role in the infectious process.

Measles is a highly infectious virus with a worldwide distribution, but it can only survive in populations as an ‘endemic’ contagion, in populations where there is a continuous supply of susceptible children. We shall return to this observation when talking about the measles vaccine. The measles virus spreads by aerosol inhalation, much like the common cold. Its initial target cells are, once again, the lining cells of the respiratory tract. But unlike the cold virus, with its focus on the nose and throat, measles heads down into the lower respiratory tract. For some unknown reason, the virus also has a predilection for the cells of the conjunctivae, which explains the inflamed eyes that are a common sign of the clinical presentation. During the first two to four days of infection, the virus multiplies locally in the target cells. The alien presence of the virus provokes local inflammation and this in turn attracts the attention of white blood cells, known as macrophages, which normally gobble up unwanted debris, dead and diseased cells and invading parasites. This process is known as phagocytosis. Unfortunately – or alas perhaps knowing a little about viruses and their behaviour, predictably – these same phagocytes now become the final target cells of the measles virus.

The virus hijacks the phagocytes, invading and then replicating inside them, and then taking advantage of their natural locomotion to the regional lymph glands, where a second phase of viral replication takes place. From the lymph glands, the virus invades another variety of white blood cells, known as leukocytes, and once again it hitches a ride aboard these infected cells into the bloodstream, thus spreading to every cell and tissue, notably the skin. It is at this stage of bloodstream spread, or ‘viraemia’, that the typical rash and high fever appear.

Just as we saw with the cold virus, the measles virus doesn’t have things all its own way. Those same cells targeted by the multiplying virus, the macrophages, are the first line of defence in our immune system. Besides phagocytosis, the macrophages play a critical role in our inbuilt ‘innate’ immunity. They also play a key role in triggering an even more powerful defence system, our ‘adaptive’ immunity, identifying foreign antigens on the surface membranes of the virus as ‘alien’ to the body’s notion of ‘self’, and presenting these foreign antigens to cells, such as lymphocytes, that set off a process of specific immune recognition followed by the production of antibodies to the virus. The antibody response is also combined with yet another key element of our immune defences, known as ‘cellular immunity’. All of these powerful elements of our immune response will ultimately work together to destroy the foreign threat.

Many years ago, as a medical student at the University of Sheffield, I conducted an experiment aimed at testing how the mammalian immune system would respond to exactly such a viral invasion into our bloodstream. With the help of my mentor, Mike McEntegart, Professor of Microbiology, I injected viruses into the bloodstream of rabbits and then observed how the rabbit immune system dealt with them. I started with a primary dose and followed this up a week or so later with a booster dose. Some readers might react with concern about hurting experimental animals, but the virus I used was a bacteriophage, known as ΦX174 – a virus that only attacks E. coli bacteria – so the rabbits suffered no illness. But their adaptive immune system responded in exactly the way a mammalian immune system should respond to any alien invader entering the bloodstream, with a build-up of antibodies in two waves, rising to a peak by 21 days, by which time a single drop of the now-immune rabbit serum was seen to inactivate a billion viruses in mere minutes. With the help of other colleagues at the university, we obtained pictures of what was actually happening under the electron microscope, which showed the syringe-shaped phage virus being overwhelmed with antibody molecules and gathered up in sticky antibody-wrapped aggregates that would have been readily mopped up and cleared from the system by the ever-vigilant phagocytes.

What I observed in the phage virus experiment is similar to what would be expected to happen in a child suffering from measles. There is an incubation period of one to 12 days after exposure to the virus, during which it is passing through the target cells in the respiratory tract, through the lymph glands and entering the bloodstream. At this stage the illness becomes obvious, with fever, cough, runny nose and inflamed eyes. Two or three days later, the Koplik’s spots appear on the inner lining of the cheeks and the rash appears on the face and spreads over a day or two to be confluent over the skin. Ironically the striking symptoms and signs, including the fever and the rash, are actually produced by the attack of the immune system on the virus. Through the actions of that same immune system, the majority of children go on to make a full recovery – after which the immune system retains its memory of the antigens on the surface of the virus. In most cases, this will ensure that the sufferer is resistant to any future infection with measles. But further complications bedevil the recovery in a tragic minority of infected children, which include diarrhoea, pneumonia, blindness and, most serious of all, the inflammation of the brain called encephalitis.

Readers may be astonished to read that before the introduction of the measles vaccine, in 1963, major epidemics of measles swept through the global population every two to three years, causing some 2.6 million deaths. Even today, measles is still one of the leading causes of death in young children, despite the fact that a safe and cost-effective vaccine is available to prevent the infection. Between the years 2000 to 2016, the World Health Organization estimated that measles vaccination had prevented some 20.4 million deaths; but, tragically, in 2016 some 90,000 people still died needlessly from this preventable infection.

Unlike my generation, in which measles infection was commonplace, most parents in developed countries these days will have little or no experience of dealing with measles in the family. This, thankfully, is through the benefit of the MMR vaccination programmes which are now governmental policy in many countries. MMR vaccines protect children against three different viral illnesses: measles, mumps and rubella. But as a result of so-called ‘MMR misinformation scares’, the triple vaccine has been the subject of controversy in different countries, with some misguided parents withdrawing their children from the vaccination programmes.

I shall return to this important topic later in this chapter, but first I would like to examine the other two viruses involved in the vaccine.

The infection we call ‘the mumps’ probably derives its name from an old word meaning ‘to mope’ – an apt description of the afflicted child, struck down by malaise and fever and, a day after the onset, the painful swelling of one or both parotid glands within the cheeks, a condition known clinically as ‘parotitis’. The causative virus, the mumps virus, is another paramyxovirus, which is also global in distribution. Unlike measles, mumps was familiar to Hippocrates, some two and a half millennia ago. Mumps is also specific to and dependent on the human host, which, in symbiological parlance, is its co-evolving partner, and sole natural reservoir. Once more, the mumps virus is usually spread by the respiratory route, but it can also be spread through contamination with virus-infected saliva.

Fortunately, in most cases the illness is quickly dealt with by the immune system, with the symptoms settling within a few days, so that recovery is usually uneventful. In some cases the illness is so slight that the sufferer doesn’t even realise he or she has encountered the virus. But in 20 per cent of males who contract mumps after the age of puberty, the virus causes inflammation of the testes, clinically known as ‘orchitis’. This manifests as local pain, which can be severe, accompanied by the swelling of one or both testes some four or five days after the onset of the parotitis. Though some testicular atrophy may result, thankfully the orchitis doesn’t usually cause subsequent sterility. Though uncommon, mumps can occasionally cause inflammation in the ovaries in females, and equally rarely cause pancreatitis in either sex. Mumps may also cause a viral, or ‘aseptic’, meningitis and, like measles, it may also cause encephalitis. Meningitis and encephalitis are serious medical complications, which will usually result in hospitalisation and, in some cases, mortality.