volume Rats, Lice and History may trigger a wry smile (for how, after all, could lice be part of history?), the ideas proposed in this famous history of pathogens and the diseases they cause remain as relevant today as when they were published in 1934. As Zinsser argued, the global impact of pathogens, including viruses, has shaped human history as much as any war, natural disaster, or invention. This view may seem an exaggeration to today’s student of virology, who may perceive most viral infections as annoyances that result in a few missed classes or days of work. But in the context of history, epidemics of smallpox, yellow fever, human immunodeficiency virus, and influenza have caused an incalculable loss of life and have changed entire societies. Smallpox alone killed well over 300 million people in the 20th century, more than twice the number of deaths from all the wars that occurred in the same time period. Huge empires fell to a relatively small number of invaders, in part because the conquerors inadvertently introduced viruses that crippled the empires’ defense forces. Not all such victories were accidental, however: in the 1760s, British traders offered blankets and handkerchiefs from the smallpox hospital at Fort Pitt to American Indians who had never been exposed to this pathogen. As William Trent, one of the traders, noted, “I hope it will have the desired effect.” Smallpox, used in this way, was the first bioweapon.
Although vaccines and antivirals have reduced, and even eliminated, some of these scourges, we are reminded of the challenges we still face by the looming threat of an influenza pandemic, the devastation caused by Ebolaviruses in Africa, the lack of success in developing a human immunodeficiency virus vaccine, and the resurgence of vaccine-preventable infections. We also face the emergence of “new” human viral pathogens, such as the coronavirus that is the cause of the worldwide pandemic in 2019–2020, and Zika virus, which causes gross defects in brain formation. Of equal importance, viruses that cause disease in crops and animals have crippling consequences for the infected species, the farmers who depend on them for their livelihoods, and human populations that may face starvation.
The ways that viruses cause diseases in their hosts, the tug-of-war among viruses and the host’s defenses, and the impact that viral epidemics have had on human, animal, and plant populations are therefore not just interesting academic pursuits, but rather life-and-death issues for all organisms. That said, it is important to bear in mind this critical principle: pathogenesis (the processes that lead to disease) is often a collateral outcome of the parasitic nature of viruses. As is true for humans, selective pressures that control evolution of viruses act only on their abilities to survive and reproduce. From this perspective, one could argue that the most successful viruses are those that cause no apparent disease in their natural host.
In the first chapter of Volume I, we recounted an abbreviated history of virology and described milestones that established the foundation for our current understanding of viral reproduction. In this chapter, we return to history, focusing on watershed events that catalyzed the fields of viral epidemiology and pathogenesis. Subsequent chapters in this volume will consider the impact of viral infections on individual hosts, tissues, and cells. Our goal in Volume II is to build on the principles of viral reproduction that were established in Volume I, providing an integrated view of how viruses cause disease in single cells, discrete hosts, and large populations, as well as the host responses that mitigate or prevent such diseases.
PRINCIPLES Introduction to viral pathogenesis
Diseases associated with viral infections are a collateral outcome of the parasitic nature of these pathogens.
Koch’s postulates helped to identify causal relationships between a microbe and the disease it causes in the host, although these postulates may not be fulfilled when associating some viruses with a particular disease.
Major insights in viral pathogenesis have come from exploitation of technical advances in the fields of molecular biology and immunology.
The increased mobility of human and animal populations on the planet has accelerated the emergence of epidemics.
Many viruses that can infect multiple species establish a reservoir in an animal host in which the virus causes negligible disease. Spread into new human hosts, called a zoonosis, is usually a dead-end infection.
Epidemiology, the study of infections in populations, is the cornerstone of public health research and response.
Individual differences among prospective hosts, group dynamics and behaviors, geography, and climate all influence how efficiently a virus can establish infection within a population.
The regional occurrence of viral infections may be due to the restriction of a vector or animal reservoir to a limited geographical area.
Seasonal differences in the appearances of some viruses may be due to variations in viral particle stability at various temperatures or humidity, changes in the integrity of host barriers (such as the skin or mucosa), or seasonal changes in the life cycles of viral vectors, such as mosquitos.
Susceptibility to infection does not necessarily signify susceptibility to disease.
A Brief History of Viral Pathogenesis
The Relationships among Microbes and the Diseases They Cause
Long before any disease-causing microbes were identified, poisonous air (miasma) was generally presumed to cause epidemics of contagious diseases. The causative association of particular microorganisms, initially bacteria, with specific diseases can be attributed to the work of the German physician Robert Koch. With his colleague Friedrich Loeffler, Koch developed four criteria that, if met, would prove a causal relationship between a given microbe and a particular disease. These criteria, Koch’s postulates, were first published in 1884 and are still used today as a standard by which pathogens are identified. The postulates are as follows:
the microorganism must be associated regularly with the disease and its characteristic lesions but should not be found in healthy individuals;
the microorganism must be isolated from the diseased host and grown in culture;
the disease should be reproduced when a pure preparation of the microorganism is introduced into a healthy, susceptible host; and
the same microorganism must be reisolated from the experimentally infected host.
Guided by these postulates and the methods developed by Pasteur for the sterile culture and isolation of purified preparations of microorganisms, researchers identified and classified many pathogenic bacteria (as well as yeasts and fungi) during the latter part of the 19th century. Identifying a cause-and-effect relationship between a microbe and a pathogenic outcome set the stage for transformative therapeutic advances, including the development of antibiotics to treat bacterial infections.
However, during the last decade of the 19th century, it became clear that not all diseases could be attributed to bacterial or fungal agents. This apparent breakdown of the paradigm led to the identification of a new class of infectious agents: submicroscopic particles that came to be called viruses. Koch’s postulates can often be applied to viruses, but not all virus-disease relationships meet these criteria. While compliance with Koch’s principles will establish that a particular virus is the causative agent of a specific disease, failure to comply does not rule out a possible cause-and-effect relationship (Box 1.1).
