Great American Diseases: Their Effects on the course of North American History

By Ian R Tizard and Jeffrey MB Musser

Great American Diseases: Their Effects on the Course of North American History presents medical history as it pertains to the major infectious diseases of North America. The book is designed to provide an interesting and engaging introduction to microbiology, immunology and epidemiology. With the advent of COVID-19, this book will serve as a reference on the history of previous epidemics. The book presents pandemics in an easy-to-read volume and provides concise chapters on the history of a disease, progression of understanding on the pathogen (agent of the disease), and their social ramifications through the history of North America.

• 2023 PROSE Awards - Winner: Finalist: Reference Works – Biological and Life Sciences: Association of American Publishers
• Focuses on the major infectious and parasitic diseases of North America
• Provides historical and scientific information in an easy-to-digest volume
• Includes an introduction to the basic science of bacteriology, virology, immunology and epidemiology

• Language: English
• Publisher: Academic Press
• Release date: Jan 11, 2022
• ISBN: 9780323989268

Ian R Tizard

Ian Tizard, BVMS, BSc, PhD, DSc (Hons), DACVM, is a Diplomate of the American College of Veterinary Microbiologists and a University Distinguished Professor Emeritus of Immunology, Department of Veterinary Pathobiology, The Texas Veterinary Medical Center at Texas A &M University (TAMU), College Station, Texas, USA. Dr. Tizard earned his Bachelor of Veterinary Medicine and Surgery from the University of Edinburgh, Scotland in 1965. He then completed a Bachelor of Science in Pathology and a PhD in Immunology. After completing his studies, Dr. Tizard became a Post-Doctoral Fellow at the University of Guelph, where he remained on as a professor until 1982 when he moved to TAMU. Dr. Tizard wrote the first standardized textbook on Veterinary Immunology in 1977. This text, now in its 10th edition, is used worldwide, and has played a major role in establishing Immunology among the key disciplines of Veterinary Science.

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Introduction: How infectious diseases have shaped American History

Ian R. Tizard; Jeffrey M.B. Musser, Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX, United States

It is now more than 100 years since the great influenza pandemic of 1918 killed more than 600,000 Americans. It has been more than 50 years since Jonas Salk’s polio vaccine began to eliminate that scourge from the continent. Diseases that had killed thousands and caused widespread despair and death have been largely eliminated or controlled. Therefore, the emergence of the coronavirus that causes COVID-19 came as an ugly reminder that infectious diseases have not been eliminated. They have simply been controlled temporarily. Infectious diseases will continue to return and kill because they are an integral part of life on earth. In this microbial world, humans and other animals are merely a resource to be exploited by microbes.

The history of the Americas has been defined by infectious diseases: from the depopulation of Native Americans by European smallpox, to diseases that determined the course of the War of Independence, and to the major engineering projects designed to provide citizens with clean water and sewage treatment. Disease has defined and in a large part controlled our history. The Americas are not unique in this respect. Other countries and continents have also been profoundly affected by infectious disease outbreaks.

That said, there has been a perception that those diseases were behind us. Infectious diseases were no longer considered a threat. Many believed that if more arrived, they could be handled. Certainly, the history of the 20th century suggests a progressive and inexorable improvement in our health. On the face of it, we appeared to have won; we beat the microbes.

This of course was an illusion. First, we must not extrapolate the situation in the developed world to the less developed areas of the world. Second, we are beginning to see cracks appearing in our own medical defenses, ranging from antibiotic resistance in bacteria to vaccine refusal by large segments of the population. Most importantly, the results of overpopulation, encroachment on wilderness areas, and climate change have increased disease instability and transmissibility and provided bacteria and viruses with hitherto unexpected opportunities to spread.

In rich countries such as the United States, life expectancy, which had hovered around 30–40 years for hundreds of years, began to increase; by 1900, it had reached 50, and by 2010, it had reached 80. We long outlive the lifespan of our grandparent’s generation. This increase is predominantly due to the control of infectious diseases. Antibiotics, water chlorination, pasteurization, adequate sewage treatment, and above all, vaccination have profoundly changed the human condition. This has occurred not only in the United States but also worldwide. The great diseases described in this book are largely features of a distant past.

Prior to the development of microbiology, most disease treatments were useless or worse. The introduction of variolation at the beginning of the 18th century was the first occasion where a medical treatment was shown to be effective. Even up to WWII and the discovery of antibiotics, doctors had few effective cures for infections.

Notwithstanding the massive increase in life expectancy and an effective doubling of our lifespan, what we have seen over the past 75 years has been no more than a temporary lull in hostilities, a pause where we hopefully shored up our defenses and waited for the war to recommence. Victory has not been total. As with real human wars, we appear to be entering a period of asymmetric warfare where our major weapons may be circumvented by more subtle forms of microbial invasion.

Another feature of our current expectations of prolonged good health is an intolerance of massive casualties. Recent disease outbreaks such as SARS or Zika virus have killed only a few thousands, a far cry from the massive pandemics of the past. Nevertheless, they resulted in a panic that subsided once the threat was removed. This panic-and-forget pattern was a feature of American responses to infectious diseases for many years until COVID arrived. Therefore, it is appropriate to remind ourselves of that overused adage that those who do not remember history are doomed to repeat it. If we are to maintain our improved status with respect to infectious diseases, we need to remember another cliché: The price of freedom (from disease) is also eternal vigilance.

The diseases that we have chosen to explore in this text are those we consider the most historically significant. After all, many of the outbreaks we describe have been covered previously with entire texts dedicated to individual diseases or epidemics. Nevertheless, we believe that a holistic approach serves to place the North American infectious disease history in perspective.

This book follows, in part, the curriculum of our introductory microbiology course at Texas A&M University titled Great Diseases of the World. That course was conceived as an introductory course in microbiology. Rather than teach the rather dry topics of biochemical reactions and microbial diseases, we chose to focus on the cool bits of microbiology and the lurid history of many infectious diseases. Therefore, this book is not designed to be a comprehensive list of all the major infectious and parasitic diseases that have affected Americans over the years. Rather, it is a look at the most important and, in our opinion, the most interesting. We hope that you will agree.

This book does not need to, nor is it intended to be read in a linear manner from the first to the last page. The reader or instructor is free to pick and choose the disease of interest and topics within each chapter. Most aspects of biology and history are not linear but convoluted and often times circular. However, the order of the disease chapters in this book is chronological based on when they were first identified and began to cause problems in North and Central America.

One consistent feature of the history of medicine is an ongoing debate regarding specific diagnoses prior to the modern era. Until about 150 years ago, diagnosis was a subjective art. Disease diagnosis was a matter of physician opinion rather than science. For this reason, it is appropriate to retain some skepticism regarding the specific causes of many historic epidemics: was it smallpox or really measles; was it typhus or typhoid; was it influenza or coronavirus? This intrinsic uncertainty has given rise to a minor academic industry of those seeking to second guess widely accepted disease attributions. Some of these claims are wildly speculative. Many have been dismissed by recent discoveries as, for example, the unequivocal identification of Yersinia pestis as the cause of the early plague pandemics. On the other hand, some early pandemics attributed to influenza may really have been due to coronaviruses! The cause of some historic outbreaks will likely never be established unless molecular evidence can be adduced by new studies. It is also abundantly clear that many epidemics were likely a result of multiple diseases occurring at the same time. However, experience has shown that in most cases the original diagnoses were correct. Therefore, we have tried to resist the temptation to ascribe new causes to old epidemics. That said, science and history advance hand in hand and no doubt some surprises still remain in store.

In January 2020, news emerged of yet another coronavirus outbreak in Wuhan, China. Within a remarkably short time, it became apparent that the world was in for a pandemic, the likes of which had not been seen since the great influenza pandemic in the fall of 1918. The disease caused by this coronavirus, COVID-19, is likely to be with us for a long time and the story has scarcely begun. We have sought to place COVID-19 in its historical context. The pandemic has many features in common with epidemics of the past. Technology may change but human behavior does not. Likewise, neither history nor science stop when we send our manuscript to the publisher. If it was not COVID, it would have been some other disease. But that is another story.

In memory of Dr. Mohamed Tawfik Omran—scholar, teacher, colleague, and friend.

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Chapter One: Infectious diseases and their causes

Abstract

We live in a world dominated by microbes, bacteria, viruses, molds, and protozoan parasites. Only a few are pathogens that cause infectious diseases. The most important are bacteria and viruses. Bacteria are single-celled organisms. There are many species that differ in size, shape, and metabolism. Many are normal inhabitants of body surfaces. Some can invade the body and cause tissue destruction. Viruses are small molecular constructs consisting of nucleic acids, packaged in a protein shell. Viruses can only replicate within living cells. Some important human diseases such as malaria are caused by protozoan parasites. Infectious diseases may be acquired from other humans or domestic/wild animals—so-called zoonoses. Some of these organisms can cause disease in healthy individuals while others may only attack individuals whose immune defenses are weakened. When infectious disease outbreaks do occur, they may be localized or develop into epidemics and pandemics.

Keywords

Bacteria; Viruses; Protozoa; Epidemic; Pandemic; Immunity; Pathogen; Virulence; Opportunistic; Zoonoses

Infectious diseases have had, and continue to have, profound effects on the course of American history. Historically they killed millions, caused untold suffering, and played a key role in the colonization and development of both the United States and Canada. And they have not ceased. In 2020 the SARS-2 coronavirus, the cause of COVID-19, escaped from China and spread around the world. It killed millions of people and caused enormous social disruption.

In addition to social factors, the impact of infectious disease outbreaks, epidemics, and pandemics is determined largely by two key factors. One is the ability of an organism to cause serious disease—its virulence. The other is the ability of humans to combat these infections, in other words, their immunity. The outcome of such diseases is determined by the balance between virulence and immunity. The decline in the apparent importance of infectious diseases over the past 100 years has been a direct result of improved sanitation practices as well as our growing ability to prevent and treat these infections through the use of vaccines and drugs such as antibiotics. In the absence of vaccines and drugs, organisms may spread unchecked, especially in large, dense populations [1]. That is the case in our present outbreak of COVID-19. It was certainly the case in the past before modern medicine achieved its successes and it will remain the case in the future.

While the idea that some diseases were caused by invisible microorganisms was floated from time to time, this was mere speculation until Antonie van Leuwenhoek in the Netherlands learned how to make lenses capable of magnifying up to 275 times or greater. He used these in single-lens microscopes to examine a diverse mixture of biological specimens. As a result, he was the first to observe bacteria and protozoa [2]. When he examined the gunk from between his teeth, he saw all sorts of small organisms that he called kleine diertjens— Dutch for small animals. This word was translated into English as animalcules. These creatures were swimming around and he drew and described their shapes. He also examined his own feces and found a parasitic protozoan that we now call Giardia. Van Leuwenhoek reported this finding of oral bacteria in a letter to the Royal Society in London in September 1683.

The significance of these microscopic animalcules was not readily apparent at the time and while other thoughtful individuals such as Cotton Mather in Boston, made statements speculating that invisible organisms were the cause of disease, it was not until the science of microbiology developed in the mid-19th century that specific organisms were recognized as causes of specific diseases. In 1838, Gottfried Ehrenberg in Germany called these animalcules bacteria, from the Greek bakteria, meaning a little stick since they were rod-shaped.

Robert Koch in Germany was the first to link a specific bacterium with a disease when he identified the anthrax bacillus [3]. Koch was a physician working in practice in Wöllstein, in eastern Germany. As the district medical officer, he was confronted by an ongoing outbreak of anthrax. A disease that had killed hundreds of people and thousands of cattle. On examining the blood of dead animals under a very primitive microscope, Koch observed rod-shaped structures. He also showed that blood from a sheep that had just died of anthrax, when injected into a mouse, would kill the mouse within 24 h. Then he found the rod-shaped structures in the blood and tissues of the mouse! Spleen tissue from the dead mouse, when injected into another mouse would give the same result—rapid death. Koch determined that the rod-shaped structures were bacteria. He eventually developed a method of growing the bacteria in culture and was thus the first to link a specific bacterium to a specific disease. His paper demonstrating that anthrax was caused by the bacterium, Bacillus anthracis was published in 1876.

As a result of his growing reputation, Koch moved to Berlin and joined the Imperial Health College. Here he made more significant advances. He found that he could fix bacteria to a glass microscope slide by drying them from a liquid solution; he could stain them with aniline dyes; he worked on improving microscopes; and was the first to publish photographs of bacteria. Others in his laboratory also made significant advances. For example, the plate technique of growing bacteria in pure culture was developed in his laboratory. Two of his assistants, Walter and Fannie Hess discovered that agar, a gel obtained from seaweed, could be used to make a nutrient medium on which bacteria could be cultured. Another of his assistants, Julius Petri designed a shallow dish (now called a Petri dish) to hold the agar-based medium and permit bacteria to grow without contamination. Subsequently, Robert Koch went on to describe other disease-causing bacteria such as Mycobacterium tuberculosis in 1882 and Vibrio cholerae in 1883. Koch, as the founder of the science of bacteriology, received the Nobel Prize for Medicine in 1905.

From the point of view of history, it is important to emphasize the dates of Koch’s discoveries. Any disease diagnosis prior to the 1870s must be considered speculative. Physicians could diagnose some very obvious diseases such as smallpox or yellow fever but in many other disease outbreaks reported prior to the 1870s, their causes must remain speculative. This is especially true of diseases with nonspecific clinical signs such as fever or diarrhea.

As a result of Koch’s discoveries, bacteriology rapidly developed as a discipline, and competing scientists sought to be the first to identify the cause of specific diseases. It was not until the end of the 19th century that protozoan parasites, also visible under the microscope with suitable stains, were detected and associated with specific diseases such as malaria and Texas Fever. Fungi were also identified as a cause of some diseases around the same time.

Bacteria are not the only organisms that can cause disease. Viruses can invade and destroy cells and cause many serious infections. Viruses are small molecular complexes that cannot be seen under a light microscope. It was not until 1938 when the first virus was observed by electron microscopy. Prior to that time however their existence had been inferred by filtering body fluids to remove bacteria and demonstrating that the filtered material was still infectious. Thus, the first report of a filterable virus was in 1892 when it was found to be the cause of a disease of tobacco plants.

A world of microbes

While we are largely unaware of it, we live in a world dominated by microbes, especially bacteria. Half the Earth’s biomass consists of microorganisms. (Plants account for 35% of the biomass and animals only about 15%.) Microbes live everywhere, including inside and on our bodies. All our body surfaces carry a dense microbial population collectively called the microbiota. The densest population of bacteria on this planet lives within our large intestine. The soil we stand on has a huge microbial population as do the oceans. With every breath, we inhale about a million bacteria. We have about the same numbers of bacteria in our body as we have human cells. Almost all of these organisms have evolved to make use of the sources of energy in their environment. A few of them, very much in a minority, have evolved to obtain their energy from the human body. It is these select few that can invade and cause disease under appropriate circumstances.

Bacteria

As noted earlier, enormous populations of bacteria live on our body surfaces. They live on the skin where they are responsible for body odor. They live in our respiratory tract. They live in our mouth where they are responsible for, among other things, tooth decay and bad breath. They live in the genital tract. The greatest population of bacteria lives within our intestinal tract. They share our food with us. They send chemical signals to the body ensuring that its defenses stay in tip-top shape, and when we die, they make our bodies decompose.

Properties and classification

The early microbiologists learnt to recognize bacteria under the microscope and grow them in nutrient-rich culture media. Thus, the first method of classifying what they saw was simply by their shape [4]. The round grape-like bacteria they called cocci and the rod-shaped bacteria they called bacilli (Fig. 1.1). The cocci were subdivided into those that formed chains, like the streptococci and those that formed clusters, like the staphylococci. Those that formed pairs they called diplococci. Some bacilli are consistently curved into a comma shape and vibrated as they moved so they were called vibrios. Some bacteria possess long filamentous processes called flagellae (Fig. 1.2). When flagellae are waved around, they enable the bacteria to move, in other words, some bacteria are motile. The precise arrangement and numbers of these flagellae are also an aid to bacterial classification.

Fig. 1.1

Fig. 1.1 The major bacteria and their shapes. Gram-positive bacteria stain strongly with the dye, methylene blue when stained by Gram’s method. Gram-negative bacteria do not retain the blue dye so that it can be washed out and they can then be stained by a red counterstain.

Fig. 1.2

Fig. 1.2 Pili are cell surface structures by which bacteria can attach to cells.

The next step in the discovery process involved the staining of bacteria by chemical dyes. The most useful and important staining technique turned out to be one developed by Hans Christian Gram, a Danish microbiologist in 1884. He was examining stained tissue sections from the lungs of patients autopsied after dying from pneumonia and noticed that his dye stained the bacteria very strongly but not the lung tissue. Upon investigation Gram found that he could stain some bacteria with a dye called crystal violet. More importantly he found that in some bacteria, after staining, the crystal violet was easily washed out by alcohol, while in others it persisted. Those bacteria that stain strongly with crystal violet are classified as Gram-positive while those that readily lose the dye are classified as Gram-negative. Gram-positive bacteria stain blue while Gram-negative bacteria can be counterstained by, for example, the red dye safranin. These differences between Gram-positive and negative bacteria are significant since they reflect major structural and biochemical differences between their cell walls. The cell walls of Gram-positive bacteria are significantly thicker than those of Gram-negative organisms. Some bacteria such as the treponemes that cause syphilis do not stain strongly with Gram’s stain. Thus, confirming their distant relationship to other bacteria.

A second staining procedure was developed by the German chemist and pathologist, Paul Ehrlich and modified by Franz Ziehl and Friedrich Neelsen in 1882. This involves the use of a dye called carbol fuchsin to stain the bacteria. Once stained, certain lipid-rich bacteria can retain the stain after washing with hydrochloric acid in alcohol because it binds to lipids called mycolic acids. In those bacteria that lack mycolic acids, the carbol fuchsin is readily washed out and the bacteria are decolorized. Those that retain the dye are stained red and are classified as acid-fast bacteria. Acid-fastness is characteristic of the group of bacteria called Mycobacteria. These are the cause of diseases such as tuberculosis and leprosy. The lipids in the cell walls of these bacteria tend to make them impermeable to Gram’s stain. These lipids also protect them from destruction once they invade the body.

In addition to their physical properties, bacteria may be classified according to their metabolic needs. For example, some require lots of oxygen and are called aerobes while others only grow in the absence of oxygen and are called anaerobes. It should come as no surprise therefore that an aerobe such as M. tuberculosis prefers to grow in well-oxygenated tissues like the lung. On the other hand, Clostridium tetani, a strict anaerobe that causes tetanus, prefers to grow in dead tissue such as in deep wounds where oxygen tension is low. Some bacteria such as V. cholerae prefer a low oxygen tension and are therefore considered microaerophilic.

Bacteria, with relatively simple metabolic systems, can readily use sugars as an energy source. They differ however, in which sugars they can use. This too can be used to classify them. For example, two bacteria that cause diarrhea are Escherichia coli and Salmonella enterica. They look exactly the same, both are Gram-negative bacilli, but Salmonella cannot use lactose as a food source while E. coli can.

It has long been convention to give bacteria a Latin name using two words (binomial). The first name denotes the genus while the second denotes the species. For example, the organism that causes syphilis is called Treponema pallidum, while the bacterium that causes the related disease yaws, is called Treponema pertenue. Other examples are the organisms of the genus Brucella. All cause undulant fever but Brucella abortus infects cattle, Brucella melitensis infects goats, Brucella suis, as its name implies, infects pigs, and Brucella canis infects dogs. All can cause disease in humans (Table 1.1).

Table 1.1

These bacterial names may also change as more information accumulates about the organism and its properties. For example, when Alexandre Yersin first identified the bacillus that caused the plague, he called it Bacillus pestis. Several years later it became clear that the organism did not really belong in the genus Bacillus, so it was renamed Pasteurella pestis. Finally, in 1970, another reassessment moved it to another genus, and it is now called Yersinia pestis.

As more is learnt about bacteria, this binomial system appears to be increasingly inadequate. For example, there are over 2500 distinct varieties of S. enterica. These varieties are designated serovars or subspecies because they can be distinguished by the use of specific antibodies made in immunized animals. These antibodies are found in blood serum, hence the term serovar.

The normal microbiota

As mentioned earlier, animal bodies are not sterile. We have enormous populations of bacteria living in our intestine, in our upper airways, and on our skin. These bacteria benefit us in several ways. Thus, they help us digest food. They generate metabolites that serve as essential nutrients. They release otherwise unavailable energy from foods and they stimulate the development of our immune system. If the microbiota is disrupted by, for example, excessive antibiotic use, the resulting dysbiosis can lead to changes in the immune system that can provoke allergies. The intestinal microbiota also serve a protective function insofar as they are well adapted in the intestinal environment. They can therefore out-compete and so exclude poorly adapted organisms that should not be there. The intestinal microbiota are considered to be commensals, with mutually beneficial interactions between them and their host [5].

How bacteria cause disease

Bacteria that cause disease are said to be pathogenic. Obviously, there are degrees of pathogenicity and this is measured by virulence. Thus, a highly virulent pathogen is one that causes severe disease. Less virulent bacteria can cause mild disease while avirulent bacteria do not cause disease. In all the major bacterial diseases described in this book, the causal agents were highly virulent.

There are many reasons why a bacterium will act as a virulent pathogen. These may be directly related to the organism’s mode of growth or the lack of resistance in its host. Bacteria that invade the body in effect, seek to feed on it. If they are successful, they may grow rapidly, and the disease will progress. For example, Y. pestis, the cause of the plague possesses enzymes and toxins that kill the white blood cells defending the body. These toxins also destroy blood vessel walls so that blood leaks into tissues such as the lungs. The organism multiplies explosively, and death occurs within days. Other bacteria such as M. tuberculosis grow much more slowly. The host immune system keeps most such infections under control so that the majority of individuals infected with M. tuberculosis usually remain healthy. Only if the host’s immunity fails does disease develop.

A few bacteria can secrete potent protein toxins that kill their hosts. For example, strict anaerobes such as B. anthracis, the cause of anthrax, and C. tetani, the cause of tetanus, benefit by killing their hosts. Inside the dead animal, there is an anaerobic environment where they can thrive. On the other hand, most bacteria do not benefit from killing their animal host. If they lose their host, they too may die. Thus, an organism such as V. cholerae, the cause of cholera, simply causes severe diarrhea that spreads the bacterium throughout the environment. M. tuberculosis causes lung infection. The resulting coughing by the victim results in the spread of tuberculosis. Many bacteria, especially Gram-negative ones possess a cell-surface coat of lipopolysaccharide molecules. This lipopolysaccharide coat is recognized by the host and triggers a defensive response. The response triggers behaviors including fever, malaise, and all the other uncomfortable signs we associate with sickness. Thus, these lipopolysaccharides are also called endotoxins.

Resistance to bacterial infections is inherited. When a pathogenic bacterium invades a population there is great variation between individuals in their defensive responses. Some individuals are highly resistant while others are very susceptible. Most of the population lies somewhere in-between. Over time, repeated infections will kill the most susceptible and as a result the population as a whole will become more resistant. If however a completely new infectious disease appears to which nobody has resistance, then a lethal epidemic can ensue. This is what happened in the Black death due to Y. pestis where the population of Europe had never previously experienced the disease. Nobody was resistant and as a result, mortality was very high. In general, high death rates in an epidemic reflect the invasion of a completely new microorganism.

Resistance to an infection changes in a predictable way during a disease epidemic. Thus, at the onset of the epidemic the most virulent organisms will kill their victims and the most susceptible victims will die. However, the organisms also die when their victims die, especially in viral diseases. As a result of the preferential elimination of the most virulent agents and the death of most susceptible victims, the severity of the epidemic will gradually decline. This was seen well in the smallpox epidemics in the Americas following the European invasions and in the 1918 influenza pandemic. The longer the infection persisted, the less severe it became.

Antibiotics

There were no really effective drugs that worked against bacterial diseases until the beginning of the 20th century. At that time, the German chemist Paul Ehrlich developed sulfonamides and salvarsan, chemicals that could selectively kill bacteria without harming the patient. The situation was further transformed when Alexander Fleming discovered penicillin, the first antibiotic. Antibiotics are chemicals produced by fungi and bacteria. Within their natural environment, organisms use these antibiotics to remove competing microbes and so enhance their own chances of success. Following the discovery of penicillin, a massive search was conducted for other antibiotics. Many new and different antibiotics were discovered. As a result, most significant bacterial diseases were rapidly brought under control and in some circles, bacterial infections were no longer regarded as a threat, especially in developed countries. But, just as some human victims may survive infections, so too can some bacteria survive antibiotics. If used inappropriately in small doses, or for too brief a time, those resistant bacteria preferentially survive—a classic example of survival of the fittest. As a result of the growth of antibiotic resistance, their effectiveness has dropped significantly, and bacterial diseases have become a significant threat once again [6].

Viruses

Viruses are totally unrelated to bacteria. The two are not synonymous. Unlike bacteria that consist of complex single cells, viruses are simple molecular constructs. They consist of one or two nucleic acid chains packaged within a protein coat—the capsid. In some viruses the capsid may also be covered by a lipid layer—the envelope. Viruses vary in both size and shape. Some, such as poliovirus are very small indeed. Others such as the poxviruses are 10–20 times larger and correspondingly more complex (Fig. 1.3). They come in various shapes but the commonest are spheres or icosahedrons. Some may have spikes over their surface like coronaviruses. Others may be long curved rods while, yet others are bullet-shaped.

Fig. 1.3

Fig. 1.3 The relative size of a typical bacterium ( E. coli ) and some important viruses. Bacteria can, but viruses cannot be observed under a conventional light microscope.

Viruses do not use metabolic pathways; they do not move, and they depend totally on living host cells for their replication. Outside living cells, they are in effect inert particles. They can however bind, enter, and infect prokaryote cells such as bacteria as well as eukaryotes such as animal and plant cells.

Viruses are very small so that they cannot be seen under a conventional light microscope. All the photographs of viruses you see were made using an electron microscope. (The wavelength of visible light is too long to interact with viruses. Thus, a short wavelength source such as electrons must be used. Electrons have a wavelength up to 100,000 times shorter than the photons of visible light.) The first viruses were not therefore observed until 1938. Before that, their existence had to be inferred by passing fluids through ultrafilters that excluded bacteria.

In 1884, Charles Chamberland working in Louis Pasteur’s laboratory developed a porcelain filter. The pores in the filter were small enough to stop any bacteria from getting through. Chamberlain envisioned his filter being used to purify drinking water in the home. The first virus, a plant virus called tobacco mosaic virus, was detected in 1892. It was found by passing a tissue suspension from an infected plant through a Chamberland filter and transmitting disease with the filtrate. This filterable virus was clearly smaller than a bacterium and could not be seen under the microscopes of that time. The first animal viral pathogen to be identified, foot-and-mouth disease virus from cattle, was found by Friedrich Loeffler and Paul Frosch using a similar filtering method in 1898.

Properties and classification

Viruses are classified on the basis of their nucleic acid content [7]. Some contain DNA and others contain RNA. Unlike other organisms, viruses consist of few proteins and hence require very few genes. The simplest viruses such as yellow fever virus or poliovirus have less than 10 genes. On the other hand, the pox viruses such as smallpox or cowpox may contain over a hundred genes. When they enter cells, viruses force the cell to make new viruses. You may recall that the genetic information in cells is normally encoded in the DNA chain. This information is then transcribed into RNA and the RNA translated into the proteins needed for cell growth. Thus, when a cell is infected with a DNA-containing virus, the viral DNA is transcribed to RNA and the RNA then encodes the viral proteins. Most DNA viruses replicate within the nucleus of the host cell although poxviruses are an exception, they replicate in the cell cytoplasm. Poxviruses, herpesviruses, and parvoviruses are examples of DNA viruses.

Viruses that contain RNA have a choice of pathways by which proteins can be made. The simplest viruses contain positive-stranded RNA that is simply translated into viral protein. For example, coronaviruses are positive-stranded RNA viruses. Some important animal viruses contain negative-stranded RNA. (RNA comes with two chains that have complementary sequences and so bind to each other. One, the positive strand, is used for translation, the other, the negative strand, serves as a template for making more positive-stranded RNA.) Thus, a negative-stranded RNA virus must first produce a positive strand before proteins can be made. Examples of negative-stranded RNA viruses include measles, rabies virus, and influenza viruses. A third way that an RNA virus can make its proteins is by reversely transcribing its RNA to generate DNA. This DNA is then transcribed to RNA and translated to protein. Viruses that undergo reverse transcription are called retroviruses. The most important example of a retrovirus is HIV, Human Immunodeficiency Virus, the cause of AIDS.

Some DNA viruses may have a very large genome and consist of many different proteins. One such example is smallpox virus (variola). Its double-stranded DNA encodes many different enzymes and nucleoproteins. An important feature of DNA viruses in general is that they replicate their DNA faithfully. Any accidental mutations that occur during replication are identified and repaired. As a result, smallpox virus does not change significantly as it passes through humans. Immunity to smallpox lasts for a very long time. The smallpox vaccine has not changed for many years. It therefore became possible to eradicate the disease simply by vaccinating everyone once.

The influenza viruses are RNA viruses. Their genome consists of eight single-stranded segments of negative-stranded RNA. As a result, they must be copied into positive strands before they can be translated into protein. These 8 RNA segments encode 10–14 proteins depending on the strain. In order to make positive-stranded RNA the virus uses enzymes called RNA polymerases. However, these enzymes are prone to make mistakes. The changed (or mutated) RNA sequences result in changes in the amino acid sequences of the resulting viral protein. As a result, over a few years, influenza viral proteins may change to such an extent that the immune system can no longer recognize them, and immune individuals become susceptible again. Thus, influenza undergoes antigenic drift. As a result, if an individual needs to be protected they must receive a current influenza vaccine every year. Under some circumstances the influenza gene segments from two different flu viruses may recombine to create a completely new virus. This antigenic shift generates a virus to which no one is immune and if it is transmitted between humans a pandemic may result.

The Human Immunodeficiency Virus (HIV), the cause of AIDS is a retrovirus. Retroviruses use reverse transcriptase to reversely transcribe their RNA to DNA. This enzyme is highly inaccurate so that the proteins that make up HIV are constantly changing. When an individual is infected with HIV, within a few weeks there will be large numbers of virus variants circulating in their bloodstream. The immune system can recognize and respond to most of these variants—but not all. As a result, it is constantly playing catch-up. Importantly, how can we select a virus strain to make a vaccine? We can protect against one, but not against hundreds of variants. This is why there is currently no vaccine available against AIDS.

Because viruses are so simple and are metabolically inactive, it has proven to be very difficult to produce effective antiviral drugs. Antibiotics have no effect on them. Some drugs are available to control influenza and many are available to fight HIV. For most of the rest, we must rely on vaccination, good nursing, and bed rest.

How viruses cause disease

Viruses, when they enter the body first attach to their target cells. They usually bind to preexisting cell surface receptors for this purpose. Once they bind, the cell takes them in using a process called endocytosis. Once inside the cell, the viruses shed their protein coat. They then use their genes to compel the cell to produce copies of the viral genome. These genes are translated into new viral proteins. The nucleic acids and the proteins are then assembled into new virions. Once assembled, newly formed viral particles may bud off from the infected cell taking some cell membrane with them to form a structure called an envelope. Alternatively, they may simply rupture the cell as they make their escape. A few viruses such as the herpesviruses may hide inside cells and only break out when the host is immunosuppressed. Some viruses cause their target cells to become cancerous. Once they escape from cells, viruses proceed to invade other nearby normal cells until the host can mount an immune response that blocks further viral replication and spread. The clinical effects of a viral infection depend upon the cells attacked. Thus, influenza and human coronaviruses mainly attack cells in the respiratory system resulting in respiratory disease. Poliovirus attacks selected cells in the nervous system and so causes paralysis; while yellow fever virus attacks liver cells resulting in their destruction and the development of