reduced the incidence of disease within a year. To this day, mosquito control remains an important method for preventing yellow fever, as well as other viral diseases transmitted by arthropod vectors (Box 1.2).
Other human viruses were identified during the early decades of the 20th century (Fig. 1.2). However, the pace of discovery was slow, in great part because of the dangers and difficulties associated with experimental manipulation of human viruses so vividly illustrated by the experience with yellow fever virus. Consequently, agents of some important human diseases were not identified for many years, and then only with some good luck.
A classic example is the identification of the virus responsible for influenza, a name derived in the mid-1700s from the Italian language because of the belief that the disease resulted from the “influence” of contaminated air and adverse astrological signs. Worldwide epidemics (pandemics) of influenza had been documented in humans for well over 100 years. Such pandemics were typically associated with mortality among the very young and the very old, but the 1918–19 pandemic following the end of World War I was especially devastating. It is estimated that one-fifth of the world’s population was infected, resulting in more than 50 million deaths, far more than were killed in the preceding war. Unlike in previous epidemics, healthy young adults were often victims (Fig. 1.3).
BACKGROUND
Mosquito control measures
In the 1930s, a vaccine was developed for yellow fever virus that dramatically reduced the mortality associated with infection by this virus. Nevertheless, mosquitos remain a primary vector for transmission to humans of viruses for which vaccines do not exist, including Zika and chikungunya viruses, as well as the parasite that causes malaria. Consequently, mosquito control remains a major public health initiative worldwide, but these ubiquitous flying syringes pose a formidable challenge to such efforts.
As mosquitos breed in standing water, reducing the prevalence of seemingly innocuous water traps such as old tires, inflatable pools, birdbaths, clogged gutters, and dis carded soda bottle caps can have a substantial impact on mosquito populations. However, such strategies are likely to be only moderately effective in humid, rainy, or swampy environments. Mosquito netting, with a maximum effective mesh size of 1.2 millimeters, has proven effective when hung over beds or incorporated into tents, and variants of this physical barrier were in effect even in the time of Cleopatra. Similarly, the widespread use of insecticides and repellents has reduced spread of mosquito-borne infections.
Recently, more-creative strategies for mosquito control have been added to the anti-mosquito arsenal, including biocontrol, the use of natural enemies to manage mosquito populations. For example, certain fish, lizards, and other insects, such as dragonflies, feed on mosquito larvae. Their presence may thus help to limit populations naturally, although careless introduction of these species into mosquito-rich environments could de stabilize fragile ecosystems. Genetic manipulation of the mosquitos themselves is an active area of research: studies are ongoing to breed and then release large numbers of sterile male mosquitos; females that mate with a sterile male produce no offspring, thus reducing the next generation’s population size. An even more sophisticated control has been the development of genetically modified strains that require an antibiotic to develop beyond the larval stage. Modified males develop normally when provided with the antibiotic in nurseries. However, when the males are released into the wild and mate with normal females, the genetic vulnerability is transferred to future generations in an environment where the antibiotic is not available. As a result, progeny maturation cannot occur. In April 2014, Brazil’s National Technical Commission for Biosecurity approved the commercial release of a genetically modified mosquito, and the U.S. Food and Drug Administration is considering such measures in the United States.
Other successful, and creative, mosquito control campaigns have been waged. For example, to reduce transmission of dengue virus, a community in Australia released millions of mosquitos infected with a bacterial species, Wolbachia, which prevents transmission of viruses such as dengue. When Wolbachia-infected mosquitos were released, they bred with others, infecting them with the bacteria and, in turn, preventing the infected mosquitos from transmitting viruses.
Figure 1.2 The pace of discovery of new infectious agents in the dawn of virology. Koch’s introduction of efficient bacteriological techniques spawned an explosion of new discoveries of bacterial agents in the early 1880s. Similarly, the discovery of filterable agents launched the field of virology in the early 1900s. Despite an early surge of virus discovery, only 19 distinct human viruses had been reported by 1935. Data from Burdon KL. 1939. Medical Microbiology (MacMillan Co., New York, NY), with permission.
Despite many efforts, a human influenza virus was not isolated until 1933, when Wilson Smith, Christopher Andrewes, and Patrick Laidlaw serendipitously found that the virus could be propagated in an unusual host. Laidlaw and his colleagues at Mill Hill in England were using ferrets in studies of canine distemper virus, a paramyxovirus unrelated to influenza. These ferrets were secluded from the environment and other pathogens (for example, all ferrets were housed separately, and all laboratory personnel had to disinfect themselves before and after entering a room). Despite such precautions, it is thought that an infected lab worker transmitted the influenza virus to a ferret. When this ferret developed a disease very similar to influenza in humans, Laidlaw and colleagues realized its implications. These researchers then infected naïve ferrets with throat washings from sick individuals and isolated the virus now known as influenza A virus. (Note the effective use of Koch’s postulates in this study!) Subsequently, influenza A virus was shown to also infect adult mice and chicken embryos. The latter proved to be an especially valuable host system, as vast quantities of the virus are produced in the allantoic sac. Chicken eggs are still used today to produce most influenza virus vaccines.
New Methods Facilitate the Study of Viruses as Causes of Disease
Technological developments propelled advances in our understanding of how viruses are reproduced (Volume I, Chapter 1) and also paved the way for early insights into viral pathogenesis. The period from approximately 1950 to 1975 was marked by remarkable creativity and productivity, and many experimental procedures developed then are still in use today. With these techniques in hand, scientists performed pioneering studies that revealed how viruses, including mousepox virus, rabies virus, poliovirus, and lymphocytic choriomeningitis virus, caused illness in susceptible hosts.
Revolutionary developments in molecular biology from the mid-1970s to the end of the 20th century and beyond further accelerated the study of viral pathogenesis. Recombinant DNA technology enabled the cloning, sequencing, and manipulation of host and viral genomes. Among other benefits, these techniques allowed investigators to mutate particular viral genes and to determine how specific viral proteins influence cell pathology. The polymerase chain reaction (PCR) was first among the many new offshoots of recombinant DNA technology that transformed the field of virology. PCR can be used to amplify extremely small quantities of viral nucleic acid from infected samples. Once sufficient viral DNA has been obtained and the sequence determined, the virus can be more easily identified, studied, and manipulated experimentally. The ability to sequence and manipulate DNA also led to major advances in the related field of
