Virusphere: What doesn’t kill you makes you stronger

Rubella, or the so-called ‘German measles’, is not a German contagion at all but rather a globally distributed infection. The illness just happened to be first described by two German doctors back in the eighteenth century. No more does it have anything to do with measles. The causative virus is in fact a ‘togavirus’, and an interesting example of this family of viruses since it is the only togavirus that isn’t spread by biting insects. Rubella is a contagious, generally mild, viral infection that mostly afflicts children and young adults. But if the virus infects women in early pregnancy, at a key time when major embryological development is taking place in the foetus, it can cause foetal death or a range of severe congenital defects known as ‘congenital rubella syndrome’ (CRS). These include hearing impairment, eye and heart defects, autism, diabetes mellitus and thyroid malfunction.

The key fact here is that rubella, like measles and mumps, is exclusive to humans. It means that we are the only reservoir or host of all three viruses – in the symbiological lexicon, we are the exclusive partner. That means that if the reservoir were to be closed down, for example through vaccination, the diseases would disappear.

The risk of all three of these viruses – measles, mumps and rubella – has been greatly reduced in developed countries by preventive vaccination, which, in the UK, the US and many other countries, is achieved using the combined MMR vaccine. It is important, given various misinformation scares, that we grasp the purpose of such a vaccine, and indeed the way in which vaccination works.

Vaccines use either a live, but harmless, variant of a live virus, or a killed virus – or even antigens extracted from parts of a virus – to protect children from the suffering and potential complications of virus infection. The MMR triple vaccine, which employs all three live attenuated viruses – measles, mumps and rubella – has greatly reduced the prevalence of all three viral diseases in the countries where it has been introduced. Unfortunately, a scientifically disproven claim that the MMR vaccine increases the risk of autism has persuaded some parents to forgo vaccinating their children.

People really do need to sit up and take notice of the advice of doctors and health authorities and ignore the misinformation coming from unreliable sources. Not doing so has the potential for unpleasant consequences. In a recent case involving the Somali-American community in the state of Minnesota, the local population, being misguided into believing that the vaccine had increased the frequency of autism in their children, stopped vaccinating their children with MMR. The real truth was exposed by a joint study by the University of Minnesota, the Centers for Disease Control in Atlanta, and the US National Institutes of Health, which showed that the incidence of autism in the Somali-Americans was no different from the vaccinated city’s white population. Alas, in May 2017 Minnesota saw the biggest outbreak of measles in the state for 27 years. State officials recommended that the Somali children be protected as soon as possible with vaccination booster shots.

America is far from alone in the resurgence of this dangerous and highly infectious disease of childhood. In May 2018, the British newspaper, the Daily Telegraph, reported a resurgence of measles throughout the continent of Europe, with the disease increasing in Belgium, Portugal, France and Germany. Once again, the efficacy of MMR vaccination was being undermined by the same baseless linking of the measles vaccine to autism, which had resulted in a rise from a record low incidence of measles Europe-wide, with 300 per cent rise in cases from 2017 to an estimated 21,000 cases in 2018, and some 35 reported deaths. In the UK, following years of similar misinformation about a link between the MMR and autism, many people of late teenage years to early twenties had not been vaccinated in their childhood years, making them now susceptible to this unpleasant and potentially dangerous viral infection. In July 2018 The Times reported a national alert being sounded out to family doctors throughout the UK, warning them to be on the alert for the disease in families returning from holidays in Italy. In England alone some 729 cases had already been reported in the first half of the year, when compared to 274 in the whole of the previous year.

Parents with any due concerns should seek the advice of their knowledgeable family doctors.

5 (#ulink_d1eacde7-e84e-5e79-b527-de2917df4af7)

A Bug Versus a Virus (#u05bbd12e-fc53-5e94-91fc-1b07bdd2ba3c)

One of the commonest errors people make in relation to microbes is to confuse viruses with bacteria. It is important that we recognise the differences since this is the first step towards understanding the vital role of the interactions between the two very different organisms – bacteria and viruses – in the great ecological cycles that are central to life on the planet. One of the commonest of bacterial species found in the healthy colon of mammals is Escherichia coli, usually diminished to E. coli. The most widely studied bacterium in laboratory experiments, E. coli is also an important member of the symbiotic gut bacteria, helping in the production of vitamin K and the digestive uptake of vitamin B12, meanwhile also helping to reduce the threat of invading pathogenic bacteria. E. coli colonises the baby’s gut within 40 hours of birth, gaining access through hand-to-mouth human contact – most likely the mother during her fondling and feeding of the child. This, of course, is no threat, but rather the beginning of an important symbiotic interaction between human and bacterium.

The E. coli species is divided into a number of serotypes, most of which are either harmless or symbiotic to humans. This is why contamination of the skin with human waste is a question of hygiene rather than a cause for alarm. However, there are pathogenic serotypes of E. coli that can cause gastroenteritis, and these serotypes may be involved in food scares and product withdrawal from food outlets. More virulent strains of the pathological serotypes can cause urinary tract infections and, rarer still, life-threatening bowel necrosis, peritonitis, septicaemia and fatal cases of haemolytic-uraemic syndrome. Thankfully these serotypes are very rare, so that, under normal circumstances, E. coli is a beneficial contributor to the human gut flora.

Under the light microscope, the bacterium is visible as a single-celled sausage-shaped bacterium roughly 2.0 micrometres long. A micrometre, or μm, is one-millionth of a metre. E. coli has no nucleus and so it is an example of a prokaryote, which translates from the Greek to mean ‘before nucleated life forms’. The bacterial body is enclosed in a membrane, or cell wall, which contains the protein antigens that separate it into different serotypes. The cell wall does not take up the commonly used dye for testing bacterial types, known as a Gram stain, so it is classified as Gram-negative. This same cell wall is capable of acting as a barrier to certain antibiotics, so for example E. coli is resistant to the action of penicillin. Many strains of the bug have flagella and so they can be seen to wriggle about in search of nourishment. The bug is attuned to living in the anaerobic environment of the human intestine, where it sticks on tight to the microvilli of the intestinal wall. When passed out of the body, in faeces, the bug is capable of surviving for some time even when exposed to the oxygenated environment. This is why pathological serotypes can cause food contamination in the home and in food-processing environments.

We are somewhat inclined to see all microbes as potential pathogens. But outside the medical world, microbiologists have long been aware that microbes play much wider roles in nature. For example, the bacteria in soil are essential to the normal cycles of life, helping to break down organic matter to its elemental components, which are then made available for recycling to supply the basic requirements of other living beings. So essential are these soil bacteria that if they were to disappear, the vast majority of life on Earth would follow their example. Such living interdependency is known as symbiosis. We humans are apt to confuse symbiosis with notions of ‘friendliness’ or ‘togetherness’, thereby grafting human attributes onto situations where such human notions do not apply. Perhaps it might be a good idea to clarify what the concept of symbiosis actually means to the biological sciences.

Bugs, such as bacteria and viruses, do not think. No more do they have feelings. Their behaviour among themselves, and in relation to their hosts, is driven by a mixture of happenstance and the fundamental mechanisms of evolution. Symbiosis is not about Mr Friendly Guy who shakes the hand of Ms Friendly Lady and everything is hunky-dory from then on. It is about survival in what Darwin called ‘the struggle for existence’. In 1878 a professor of botany in Berlin, called Anton de Bary, defined symbiosis as ‘the living together of differently named organisms’. A modern interpretation might rephrase his definition as ‘living interactions between different species of organisms’. The interacting partner species are called ‘symbionts’ and the interaction as a whole is called the ‘holobiont’.

While symbiosis includes parasitism, which is defined as a symbiotic interaction in which one or more of the partners benefits from the partnership at the expense of another, symbiosis also includes commensalism, where one or more partners gains without detriment to the others; and it also includes mutualism, where two or more of the interacting partners gain from the partnership without harm to the other partner, or partners. It is important to grasp that mutualism often begins as parasitism – indeed in nature many relationships involve situations somewhere between the extremes of parasitism and mutualism. This broader umbrella of living interactions offers the necessary scope for understanding the enormous variety of living interactions, involving microbes and their hosts, in nature. It allows us to compare and contrast a bacterium, E. coli, with a virus that also has a predilection for the human gut: the so-called winter vomiting bug, known as the norovirus.

The norovirus is the commonest cause of gastroenteritis in the world, familiar to most of us with its unpleasant manifestations of diarrhoea, vomiting and stomach cramps. It is extremely contagious by the faecal-oral route, whether through contaminated food or water, or direct contact contamination from another sufferer. Once again, we humans appear to be the only host. This, in turn, means that we are the natural reservoir in nature of the virus. Symptoms usually develop some 12 to 48 hours after exposure to infection, often with a low fever and headache. The gut irritation is rarely severe enough to provoke the bloody diarrhoea that is sometimes seen in dysentery, and recovery usually follows within a few days. Since the condition is usually self-limiting, diagnosis tends to be made on the basis of symptoms alone, especially when it occurs during a local recognised outbreak. No specific treatment is usually necessary, although sufferers may be helped by increasing fluid intake to avoid dehydration, together with non-specific anti-fever and anti-diarrhoeal medication. Laboratory confirmation is not usually necessary although public health authorities may sometimes make use of it for contact tracing purposes.

Prevention is the judicious policy, through careful hand-washing and disinfection of potentially contaminated surfaces. Unfortunately, alcohol-based hand sanitisers of the sort dispensed in hospitals are, reportedly, ineffective.

Noroviruses comprise a genus within the family of calciviruses, so-called because they have cup-like depressions in their capsids and so were named after the Greek word calyx, which means a cup or goblet. Since they cannot currently be cultured in the usual laboratory media, the single species is divided into six genetically distinct ‘genogroups’, which infect mice, cows, pigs and humans. The human genotypes are extremely infectious even from minute numbers of the virus, so much so that it has been calculated that a single tablespoonful of diarrhoeal effluent from an infected individual would contain enough viruses to infect everyone in the world many times over. But this is no cause for alarm. Thankfully there is rather more to infectious spread than such theoretical extrapolations. A more practical consideration is the fact that affected individuals can remain infectious for several days after the symptoms have settled. This means that they might feel well enough to return to normal life, including work premises, when they are still capable of passing on the virus. It might also contribute to the tendency for outbreaks to occur in closed communities, such as hospitals, cruise ships, schools and residential care homes, where communal food preparation, and common dining areas, make transmission of the virus more likely. Readers may be surprised to learn that, in spite of the relatively mild nature of the illness, the ease of transmission, combined with the prostration of the vomiting and diarrhoea, has led to the norovirus being classed as a Category B bio-warfare agent.

Globally it is estimated that norovirus infects some 685 million people a year, most of whom go on to make a full and speedy recovery. Unfortunately, in a small minority, it can result in a life-threatening illness, with some 200,000 or so deaths worldwide each year. Children under the age of five years are most susceptible, especially in developing countries, where it causes as many as 50,000 paediatric deaths annually. It is worrying that the number of reported outbreaks has been rising since 2002, warning health authorities, if they weren’t sufficiently alarmed already, that we need to treat the norovirus as a dangerous ‘emerging infection’, and one that may be evolving even more highly infectious strains.

The causative virus is globular in shape and between 20 and 40 nanometres in diameter. This means that the norovirus is somewhere between a hundredth and a fiftieth the size of the E. coli bacterium. Viruses lack the enclosing cell wall seen in bacterial, or indeed human, cells. But under the powerful magnification of the electron microscope we see that the norovirus possesses an icosahedral capsid, which encloses and protects the viral RNA-based genome. E. coli, like all bacteria, and indeed all cellular forms of life, has a DNA-based genome.

If we compare and contrast the bacterial and viral genomes, we come across gargantuan differences between bacteria and viruses at every level of their structure and organisation. The E. coli genome is coiled into a single, very lengthy circle of DNA that is attached to the inner aspect of the bacterial cell wall at a single point. This bacterial genome contains roughly 4,288 protein-coding genes, as well as coding sequences for other key metabolic functions involved with the handling of gene expression. This is comprehensive enough for the bacterium to store the memory of its genetic heredity as well as to allow it to carry out numerous internal metabolic functions involved in its internal physiology and biochemistry. One such key function is the control of the processes involved in its budding pattern of reproduction, to produce daughter bacteria.

When compared to the bacterial genome, the norovirus counterpart is frugal in the extreme. The viral genome comprises regulatory regions at either end of a compact linear string of RNA, which codes for a minimum of eight proteins, two of which code for the protein structures of the viral capsid, and six concerned with viral replication. A key difference between the bacterium and the virus is that the bacterium has all it needs to reproduce itself, but the virus can only replicate to produce daughter viruses by making use of the genetic and biochemical properties of its cellular host. In the case of the human strain of norovirus, these genetic and biochemical properties are those of the human target cell.

The norovirus genome codes for a singular aggressive viral protein known as the ‘protein virulence factor’, or VF1. This menacing entity localises to the human mitochondria during infection with the virus, where it antagonises the infected person’s innate immune response to the virus. While some viruses are capable of commensalism or even mutualistic interactions with their hosts, we see little evidence for this in the norovirus. Its symbiotic interaction with humans appears to be exclusively parasitic. Unlike the bacterium, it has no genes devoted to nutrition, or to internal metabolic pathways, since, unlike the bacterium, it has no internal metabolic pathways. Its genome is designed to take advantage of the physiology, metabolic pathways, genetic pathways, and even the very locomotion and life-style patterns of human behaviour in order to replicate itself and transmit its contagion as widely as possible.

So now we see that viruses are not fluids or poisons. They are organisms that follow a wide range of symbiotic interactions, each virus usually associated with a highly specific host, a tiny minority of which happen to be human. They are clearly very different in size, genomic organisation and life-cycle patterns to bacteria. The fact that most viruses do not possess their own internal metabolic processes does not imply that viruses do not utilise metabolic processes. On the contrary, viruses take advantage of their host’s metabolic pathways. This is why it is a mistake to think of viruses in isolation from their hosts. Outside their hosts viruses are biologically inactive: but this does not mean that they are inorganic chemicals.

Outside the target cells of their hosts, viruses have evolved stages that are somewhat equivalent to suspended animation. This stage is well-suited to being ejected in the aerosol created by a cough or a sneeze, or excreted in faeces, or in sexual secretions, or surviving being transferred by a secondary carrier, such as a biting insect or a rabid dog; or in the case of plant viruses, being carried to new hosts on the wind, or through water, or through a miscellany of other avenues of transmission, to find new hosts. Only when they enter into their obligate symbiotic partnership with the new host do we witness viruses behaving with the genetic and biochemical subtlety and efficiency we might expect of biological organisms.

The norovirus is no exception to such symbiotic evolutionary behaviour. So specific is the virus in its symbiotic interaction with its human host that different human-associated viral genotypes have affinities for specific ABO blood group proteins on cell membranes, these protein ‘receptors’ binding with one of the two proteins of the viral capsid as an integral step in the infectious process. On passing into the bowel, the virus has a predilection for the upper small bowel, or jejunum. How, exactly, the virus then penetrates the intestinal wall is not fully understood, but it would appear that it preferentially infects the immune lymphoid follicles in the gut wall, which are known as Peyer’s patches, while also searching out a type of intestinal cell, known as H-cells. After making its way through the gut wall, the virus is identified as alien by the innate immune defences of the gut, which might be just fine as far as the virus is concerned, since these may be its target cells. Whatever the target cells, we can anticipate that the virus will hijack their genetic and metabolic pathways in order to replicate itself, thus establishing its cycle of infection and multiplication, generation after generation.

Since we don’t yet have suitable tissue cultures or animal models to study the norovirus, we are not in a position to examine the ways in which it provokes the vomiting and diarrhoea, which play a key role in spreading the virus far and wide throughout the world. Currently there is no preventative vaccine, but trials of an oral vaccine are taking place as I write. Let us cross our fingers and hope that these trials are rewarded with an early success!

6 (#ulink_4c443cbf-6dc4-52b3-ac71-429186fb4445)

A Coincidental Paralysis (#u05bbd12e-fc53-5e94-91fc-1b07bdd2ba3c)

In the summer of 1921 the 39-year-old Franklin D. Roosevelt fell overboard from his yacht on the Bay of Fundy, a beautiful if freezing inlet between the eastern Canadian provinces of New Brunswick and Nova Scotia. The following day he was tormented by pain in his lower back and then, as the day progressed, he felt his legs grow increasingly weak until they could no longer sustain his body weight. This was the onset of Roosevelt’s poliomyelitis, at this time known as ‘infantile paralysis’. Poliomyelitis is caused by a virus that goes by the same name. In 1921 doctors were limited in their knowledge of the poliovirus, or indeed viruses as such. They might, however, have known that the virus did not infect Roosevelt while he was struggling in the cold water – the only infectious source of poliomyelitis virus is another person who has already contracted it. Once again, we are looking at an exclusively human reservoir. Moreover, the paralytic disease has an ancient pedigree.

Infantile paralysis was familiar to physicians in the time of the pharaohs of Egypt, since the effects of the disease were painted, with stunning accuracy, on the walls of their tombs. In 1921, as indeed today, there was no cure for the paralytic effects of the virus once it had afflicted a victim. Fortunately, Roosevelt was gifted with an extraordinary vitality and courage, enabling him to overcome the lifetime of paralysis that would result from his illness. It is to his credit that despite this handicap he became the 32nd President of the United States and he continued to serve the American people for an unprecedented four terms in office.

Viruses do not follow our human notions of rules and so they are apt to surprise us. One such surprise is that those viruses that replicate primarily in the gut – the so-called ‘enteroviruses’ – do not cause the usual symptoms of gastroenteritis. Instead, the viruses that do cause gastroenteritis are a miscellaneous group with members coming from widely different viral families. Of course, these include the genus of noroviruses within the family of calciviruses. Another group of gastroenteritis-associated viruses are the rotaviruses, a genus within the family of reoviruses, which cause vomiting, diarrhoea and fever in babies under the age of two years. Other similar offenders include adenoviruses, coronaviruses and astroviruses. We are sometimes inclined to joke about the clinical effects of gastroenteritis, but the truth is that this is a distressing condition in people of any age. Moreover, in less developed countries, gastroenteritis is one of the commonest causes of death in children, a tragic situation complicating poor hygiene and contaminated water supplies. As we might anticipate, these illnesses are transmitted by the faecal-oral route.

The ‘enteroviruses’ are also transmitted by the faecal-oral route and the viruses also replicate within the intestine, but curiously they do not present with the typical fever, vomiting and diarrhoea that typifies gastroenteritis. Instead they cause less predictable and often complex patterns of illness that affect various organs and tissues, for example, the brain and meninges, or the heart, skeletal muscles, skin and mucous membranes, the pancreas, and so on. The most familiar of this strange gamut of enterovirus-linked illnesses is poliomyelitis. All three ‘serotypes’ of the poliovirus, which have slight differences in their capsid proteins, are ‘enteroviruses’ within the family known as the picornaviruses. We might recall that these belong to the family of very small RNA-based viruses that includes the rhinoviruses. A cardinal feature of enteroviruses is that they are resistant to acid, so they can pass through the human stomach to replicate further down the alimentary tract. The poliovirus was the first of the enteroviruses to be discovered, earning its finders – Enders, Weller and Robbins – a Nobel Prize in 1954.

We should not be too surprised to discover that humans are the exclusive host of the poliovirus. The individual virion is a mere 18 to 30 nanometres in diameter. Under the electron microscope it has a capsid with the familiar icosahedral symmetry, which encloses a relatively simple RNA-based genome. In the small intestine, the virus binds to a specific receptor molecule in the lymphoid tissues of the pharynx and the ‘Peyer’s patches’ of the gut. Here the virus hacks its way into the interior of the cells, where it takes over the genetic processes to convert the cell into a factory for manufacturing daughter viruses. The daughter viruses are released through rupture of the infected cell, after which they re-invade neighbouring cells and repeat the process.

All of this sounds a trifle horrific and even potentially deadly. But in reality the great majority of individuals infected by poliovirus show little or no signs of disease other than, perhaps, a mild looseness of the bowels. But the stools of an infected individual will now be swarming with virus, which will be passed on to contacts through the faecal-oral route. Polio characteristically moves through populations in epidemic waves, with most of the infected unaware that they have encountered the virus. Only in a tiny minority does the virus make its way to the anterior horn nerve cells in the spinal cord, where infection and subsequent death of the nerve cells gives rise to the paralysis we saw in President Roosevelt. Bizarre as it might seem, the infection of the nerve cells appears to serve no purpose as far as virus transmission or evolutionary pathways are concerned. Indeed, this most dreaded complication of poliomyelitis appears to be coincidental.

The incubation period of poliovirus infection is usually a week to two weeks and, in the minority that show symptoms of infection, this involves a minor malaise, fever and a sore throat. These reflect the virus entering the bloodstream and will usually resolve without requiring any treatment and with no long-term consequences. Only in a small minority of those infected does polio give rise to a more severe illness. The onset is usually abrupt with headache, fever, vomiting – in some this may be accompanied by the neck stiffness typical of meningitis. Even still, the majority of symptomatic cases will go on to make a good recovery. But in the tiny but highly significant minority the paralysis of poliomyelitis sets in.

Paralytic poliomyelitis gets its name from the Greek polios for ‘grey’ and muelos, for marrow. This derives from the fact that the paralysis results from destruction of the grey marrow of the anterior horns of the spinal cord, which contain the cell bodies of the nerves that supply the muscles of arms, legs, chest and remainder of the trunk. The death of those cell bodies in the spinal cord causes a floppy style paralysis of the affected muscles, which is usually apparent within two or three days of the onset of the disease. In children affected by paralysis, this will have secondary long-term effects on limb growth and development. Bulbar poliomyelitis, a similar infection, causes damage to the nerve bodies of the cranial nerves, which results in paralysis of the pharynx and possibly accompanying difficulty with the muscles involved in breathing. This dreadful complication is why, before the advent of vaccination, some unfortunate patients ended up having to be supported by ‘iron lungs’.

We do not know why this unfortunate minority of infected individuals develop serious disease, including paralysis, from the poliovirus. There is some evidence that the virus gets into the central nervous system more commonly than is suggested by clinical signs. Indeed, as we shall see, this pattern of unwanted penetration into the central nervous system can feature in illnesses caused by other enteroviruses. One wonders if some genetic propensity might perhaps play some role, but it may be no more than bad luck. As we saw above, this pattern of paralysis in children, with its effects on limb growth, was recognised in the wall paintings of the tombs of pharaohs from Ancient Egypt. How puzzling then that such an ancient and easily recognisable disease was unfamiliar to European doctors until the latter years of the nineteenth century, when the first epidemics began in the cooler climates of industrialised Europe and the United States!

Such has been the dramatic success of vaccination programmes, using live attenuated viral vaccines taken by mouth, that polio has been largely eliminated from developed countries. In 2018, according to the Global Polio Eradication Initiative, the disease is now endemic in just three countries: Afghanistan, Nigeria and Pakistan. But, given the ease and extent of modern travel, we cannot rest assured until this historic and maiming disease is completely eradicated in these remaining pockets of potential contagion.

While poliomyelitis is now approaching global control, it is not the only enterovirus to afflict humanity. Other members of this virus family are still commonly encountered in developed countries, including viruses that can be baffling in their presentations and clinically unpredictable in the course of their illnesses. Perhaps the best known of these are the Coxsackie B viruses, which sometimes present with a condition known to doctors as epidemic pleurodynia. Also known as ‘Bornholm disease’, after the Danish island where it was first recognised, this can present as severe chest pain arising from inflammation in the intercostal muscles of the chest wall. Popularly known as ‘the devil’s grip’, the sudden onset and severity of the pain can mimic a heart attack. Coxsackie B viruses can occasionally cause inflammation of the brain, presenting as the condition known as myalgic encephalomyelitis, or ‘Royal Free disease’, named after the London teaching hospital where it first presented. The same enterovirus may also present with inflammation of the heart muscle, or myocarditis, coupled with inflammation of the membrane surrounding the heart, known as pericarditis, a combination that presents in both children and adults and can very occasionally prove fatal. Other enteroviruses, including the echoviruses and types 70 and 71 enteroviruses, can cause chest infections and various patterns of muscle, meningeal and brain infections, where the diagnosis of the causative virus may be exceedingly difficult to pin down.

Viruses and their associated illnesses can be very puzzling. Ever since we first discovered their enigmatic presence among us, questions have inevitably arisen as to the evolutionary purpose behind their behaviours. When faced with the unpleasant, sometimes life-threatening, effects of virus infections, we are inclined to wonder what possible benefit such behaviour might confer on the virus. In the case of the poliovirus we saw how it appears to be mere happenstance that the virus causes serious illness in a tiny minority of those it infects. But there are other viruses that sweep through the human population and inflict dreadful patterns of illnesses in the majority of those infected, sometimes accompanied by a high mortality. This is all the more baffling since all that matters to the virus is its survival and successful replication. Survival of the virus must surely be threatened by killing its host. When one views the same question from a medical perspective, we are inclined to question: why are some viruses so deadly?

7 (#ulink_9a05595f-2bcc-50cc-84a2-be8f09c32e27)

Deadly Viruses (#u05bbd12e-fc53-5e94-91fc-1b07bdd2ba3c)

The Four Horsemen of the Apocalypse feature in the biblical Book of Revelation, where, having been released by the opening of seven seals, they ride out on red, white, black and pale horses. Theologians differ in their interpretations of what these riders might signify, but one of the four is commonly interpreted as pestilence, which, in modern terminology, would be interpreted as plague. While the common childhood infections, caused by viruses, are usually self-limiting, some viruses are truly dreadful in their capacity for death and suffering. In the recorded pages of history, two plagues of humanity would justify the term ‘apocalyptic’: these are the bacterial pandemics known as bubonic plague, as seen in the Black Death in the Middle Ages, and its viral counterpart, the plague of smallpox. Both have tormented humanity from ancient times, bequeathing a grim legacy in historical records and grave pits.

The Black Death was named after the festering swellings, or ‘buboes’, where lymph glands in the groin or armpit became swollen with pus and erupted onto the skin of victims. The causative bacterium, Pasturella pestis, is transmitted by the bite of an infected rat flea. Although the public commonly assumes that bubonic plague has gone away, in fact a milder form of the illness is still endemic in rural parts of the United States, South America, Asia and Africa. The viral apocalypse, smallpox, was named after the rash that accompanied the disease, which resulted from pustular blistering in the skin that healed with deep circular scars, or ‘pocks’.

It is comforting to use the past tense here since, mercifully, smallpox has been eradicated as a plague. The clinical term for smallpox was ‘variola’, and the disease followed two very different patterns of virulence, depending on the causative virus. Variola major and Variola minor are species within the family of poxviruses. The poxviruses infect a wide variety of animals, but only three species infect humans: namely the two variola viruses and a related species, Molluscum contagiosum, which causes minor blisters on the skin of children. We shall confine our attentions to the variola viruses, which have a number of unusual features.

Humans are the only hosts for smallpox, so we are the exclusive reservoir of the two variola viruses in nature. The individual ‘brick-shaped’ virions are relatively large, measuring 302 to 350 by 244 to 270 nanometres. Before being displaced by the discovery of the ‘Megaviruses’, poxviruses were the giants among the viruses, being big enough to be seen as tiny cytoplasmic inclusions under high magnification of the light microscope. This feature alone alerts us to the fact that we are dealing with a relatively complex virus. The variola genome is predictably large and DNA-based. Unusually for a virus, it contains the genetic wherewithal for the manufacture of its own virus messenger, RNA, which takes care of the manufacture of viral proteins. This virus also has its own coded enzymes and transcriptional factors which control the manufacture of daughter viruses within the cytoplasm of infected host cells.

Smallpox viruses are extremely contagious, spreading by that most infectious route of all, aerosol inhalation. The viruses are also capable of spread through skin contact with the blistering rash, or through contaminated clothing, bed linen, utensils or dust. Infection usually begins with the arrival of the virus into the air passages of the throat and lungs of a susceptible individual, where they penetrate the superficial lining cells to be ‘discovered’ by the tissue macrophages, the first line of the human immunological defences. The stage of infection within the macrophages is asymptomatic, but accompanied by stealthy advance of the virus towards its ultimate goal. By about the third day after infection, the ‘virus-factories’ within the macrophages journey on to the lymphatic stream and local lymph glands, from where the viruses spread to the other key elements of the ‘reticuloendothelial system’, in particular the bone marrow, spleen and circulating blood. This triggers a massive immune counter-attack on the virus, including cytotoxic T-cells and interferons. But, as the history, and the grave pits, suggests, this counter-attack is unsuccessful in the majority of sufferers. Symptoms begin with a severe sore throat at much the same time that blood-borne spread carries the viruses to the skin, where they produce the blistering and scarring rash, with its predilection for the face and limbs. The blisters are the result of direct viral invasion of the skin and they teem with viruses.

Historically it is thought that smallpox first arrived among humans about 10,000 years ago in the agricultural settlements in northeast Africa, spreading to India through trade with Ancient Egypt. It grieves one to imagine such a disease spreading through such populations of naïve people, and impossible to imagine exactly what they thought was among them. No doubt they had some simple rules for dealing with contagion, and, equally likely, they would have blamed some occult cause. We discover the pathognomonic pocks in the mummified skin of Ancient Egyptian mummies, such as the Pharaoh Rameses V, who died in 1156 BCE.

Smallpox, or the ‘small pocks’, was a clinical term that came into usage in the sixteenth and seventeenth centuries to differentiate it from the inch-or-more-diameter ‘great pocks’ that medical historians assume were pathognomonic of tertiary syphilis, a bacterial plague that may have been imported into Europe from the Americas. The viral plague of smallpox arrived into Europe much earlier, sometime between the fifth and seventh centuries CE, where it persisted as an infection, giving rise to repeated epidemics during the Middle Ages. Estimates suggest that it killed some 400,000 Europeans annually in the late 1700s, affecting all levels of society, including five reigning monarchs, and was responsible for a third of all cases of blindness. The same plague played a key role in the Conquistador subjugation of the Aztecs and Incas of South America, during the sixteenth and seventeenth centuries, when it may have dominated the history of encounters between Eurasian adventurers and the stricken native and hitherto ‘virgin’ peoples.