TRANSMISSION MODES AND THE EVOLUTION OF VIRULENCE With Special Reference to Cholera, Influenza, and AIDS
Paul W. Ewald Amherst College
Application of evolutionary principles to epidemiological problems indicates that cultural characteristics influence the evolution of parasite virulence by influencing the success of disease transmission from immobilized, infected hosts. This hypothesis is supported by positive correlations between virulence and transmission by biological vectors, water, and institutional attendants. The general evolutionary argument is then applied to the causes and consequences of increased virulence for three diseases: cholera, influenza and AIDS. KEYWORDS:Virulence; Evolution; Acquired Immune Deficiency Syndrome (AIDS); Cholera; Influenza; Human Immunodeficiency Virus (HIV); Disease vectors; Pathogenicity
Received July 13, 1990; accepted September 5, 1990. Address all correspondence to Paul W. Ewald, Department of Biology, Amherst College, Amherst, MA 01002.
Copyright 9 1991 by Walter de Gruyter, Inc. New York Human Nature, Vol. 2, No. 1, pp. 1-30.
1045-6767/91/$1.00+.10
2
Human Nature, Vol. 2, No. 1, 1991
A N EVOLUTIONARY APPROACH TO VIRULENCE
Why are infectious diseases like cholera and typhus severe, whereas others like the common cold are relatively mild? Why are still others, like influenza, highly lethal in some outbreaks and relatively benign in others? For most of the century since acceptance of the germ theory, scientists have made steady progress in answering these questions at the proximate level, that is, by understanding the physiological, cellular, biochemical, and genetic mechanisms of virulence. A complete understanding of any biological phenomenon, however, requires ultimate as well as proximate explanations. Ultimate answers to the preceding questions explain the evolutionary processes through which the various levels of virulence have come into being. For most of the past century, ultimate explanations have been ambiguous and contradictory. The generally accepted viewpoint was that commensalism or very benign disease is the eventual evolutionary end product of host-parasite associations because harm to the host decreases the parasite's chances for long-term survival (Dubos 1965; Hoeprich 1977; Smith 1934; Thomas 1972; Zinsser 1935; I define "parasite" as an organism that lives in or on another organism and has a negative effect on the fitness of that organism and "pathogen" as a subcellular or unicellular parasite). Although there have been a few dissenters over the past half-century (Ball 1943; Coatney et al. 1971; Cockburn 1963), evolution to benignness is still the view generally espoused in medical texts and by health science researchers unfamiliar with current thinking in evolutionary biology (e.g., Doyle and Lee 1986; Essex and Kanki 1988; Steinhauer and Holland 1987). This view is inadequate because it is based on benefits to the species or to large subgroups of the species rather than changes in allele frequencies within parasite species. During the past decade, our understanding of natural selection has been more rigorously applied in studies of the evolution of virulence. Part of this application has involved mathematical models, which demonstrate how evolution can favor intermediate or high levels of virulence (Anderson and May 1982; Levin 1983; Levin and Pimentel 1981; May and Anderson 1983). These models indicate that increased virulence can be favored when correlates of increased virulence, such as increased parasite multiplication, increase transmission rate. A complementary comparative approach (sensu Williams 1985) has been to determine what modes of transmission favor the more virulent parasite genotypes by analyzing relationships between virulence and the parasites' ability to contribute genetic instructions for virulence into succeeding generations--that is, the parasites' fitness costs and bene-
Transmission Modes and the Evolution of Virulence
3
fits. This paper will analyze the potential of this cost-benefit approach for explaining the ultimate causes of virulence across and within species of human pathogens. This approach assumes that virulence per se generally does not benefit the pathogen; rather it is an inevitable side-effect of selective pressures favoring increased reproduction of pathogens within hosts and increased densities of pathogens transmitted from hosts. As an infection proceeds, rapidly reproducing genotypes should comprise a progressively greater percentage of the total population of pathogens within the host than less rapidly reproducing genotypes, and they should also be increasingly represented in the groups of pathogens that disperse from a host. By shedding higher densities of pathogens, the former may also infect susceptibles earlier and trigger an i m m u n e response that precludes the latter's entry. These mechanisms of competition leading to increased virulence involve an association between increased reproduction within hosts and an increased probability of infecting a contacted host. Countering this selective pressure is the negative effect of virulence on the number of hosts contacted. A severely ill host, being less mobile, generally can be expected to contact fewer susceptible individuals than would a relatively healthy host. Predictions can be generated from this theoretical framework by specifying situations in which extensive use of host resources should provide the pathogen with exceptionally great fitness benefits or small fitness costs. These predictions can then be tested by comparing them with the actual relationships derived from the literature. As described below, several tests have supported the general hypothesis that changes in human culture can alter the evolution of pathogen virulence. This support provides a basis for understanding evolutionary changes of virulence throughout our history and into our future.
VECTOR-BORNE TRANSMISSION AND VIRULENCE: COMPARATIVE STUDIES
Transmission by Arthropod Vectors The first study using a comparative approach to test the cost-benefit theory of virulence predicted that parasites transmitted by biting arthropod vectors (e.g., ticks and insects) should evolve to higher levels of virulence than directly transmitted parasites (Ewald 1983). The logic is as follows. Transmission of arthropod-borne parasites is not as ad-
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Human Nature, Voi. 2, No. 1, 1991
versely affected by host immobilization as transmission of most other parasites; in fact, experimental studies in rodents, rabbits, and sheep (Day and Edman 1983; Day et al. 1983; Turrell et al. 1984; Waage and Nondo 1982) indicate that severely ill hosts are bitten by mosquitos more frequently than uninfected hosts, largely as a result of reduced effectiveness of behavioral defenses. The benefits to the pathogen from increased multiplication should therefore outweigh the costs of decreased transmission at a higher level of multiplication (and hence virulence) for vector-borne pathogens than for nonvector-borne pathogens. The data on human pathogens confirm the predicted positive association between transmission by arthropod vectors and virulence (Ewald 1983). These data also indicate that this association results from evolutionary adaptation: the lethality of vector-borne pathogens in humans is positively correlated with their degree of previous association with h u m a n hosts (Ewald 1983). The cost-benefit theory predicts that vector-borne pathogens should evolve in the opposite direction in the vector host. A high level of virulence in vectors should impose high fitness costs on vector-borne parasites because an immobilized vector generally cannot transmit the parasite. Parasites transmitted by arthropod vectors should use their vectors as dispersal agents and their vertebrate hosts as resource bases. The high virulence in vertebrate hosts should therefore be coupled with low virulence in vectors (Ewald 1987). Testing this prediction is complicated because vector-borne pathogens are also frequently vertically transmitted from female vectors to offspring, and vertical transmission, like vector-borne transmission, should favor benignness in the vector (Ewald 1987; Ewald and Schubert 1989). An analysis of the literature on vector-borne and nonvector-borne pathogens of mosquitos confirms this prediction. Vector-borne viruses are less lethal to mosquitos than nonvector-borne pathogens when effects of vertical transmission are taken into account, and virulence among vector-borne viruses and among nonvector-borne protozoal parasites decreases as frequencies of vertical transmission increase (Ewald and Schubert 1989). The greater benignness of vertically transmitted vector-borne parasites could be interpreted as a consequence of a weaker selective pressure toward commensalism among the less vertically transmitted vectorborne parasites. That is, the eventual evolution to commensalism in vectors may not yet have had enough time to take place or might be countered by nonselective processes, such as genetic drift. Evidence against this hypothesis comes from examples in which m o d e r a t e virulence in vectors improves chances of p a t h o g e n transmission. Malaria organisms, for example, destroy specific parts of the salivary glands
Transmission Modes and the Evolution of Virulence
5
of mosquitos. This destruction increases the duration of probing, and hence the probability of vertebrate infection (Rossignol et al. 1984).
Waterborne Transmission
Like pathogens transmitted by arthropod vectors, waterborne pathogens should incur relatively small fitness costs and large benefits from extensive reproduction inside hosts and shedding of progeny from hosts. A person immobilized with a severe case of diarrhea will release pathogens into bedding, clothing, and other objects that will probably be washed, or fecal material may be disposed of directly into water (e.g., in canals or toilets) by attendants. When the water contaminated with this fecal material mixes with unprotected drinking water, large numbers of susceptible people could become infected from the pathogens released from an immobilized host (Ewald 1988, 1990). Analogous to the transmission of pathogens by arthropod vectors, this process can be considered an example of transmission by cultural vectors. The term cultural vector denotes a set of characteristics that allow transmission from immobilized hosts to susceptibles when at least one of the characteristics is some aspect of human culture (Ewald 1988). The cultural vector could transport the pathogen from the infected individual to susceptibles, or it could transport the infected individual to susceptibles or susceptibles to the infected individual. In waterborne transmission, the cultural vector transports the pathogens from the infected to the susceptibles and includes the materials contaminated by the immobilized host, the person removing this material, the contaminated waters that flow into the drinking water, and agents contributing to this flow or delivering the contaminated water to susceptible people. From this argument regarding cultural vectors it follows that the virulence of gastrointestinal tract pathogens should be positively correlated with their tendencies for waterborne transmission. The confirmation of this prediction is presented in Figure 1. These data points represent all pathogenic bacteria of the gastrointestinal tract that are regularly transmitted between humans in community settings and for which both waterborne transmission and mortality could be quantified. Each data point represents the lowest taxonomic subdivision for which differences in waterborne transmission and mortality could be distinguished. The data base consists of approximately 1000 outbreaks referenced in Ewald (1990) as well as data from one additional study (Black et al. 1982). The strong positive correlation between waterborne transmission and mortality cannot be explained by possible correlates of these two variables,
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Human Nature, Vol. 2, No. 1, 1991
O
o
O O
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O
0
0
00 25
i
50
-
-
-
-
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I
75
100
W a t e r b o r n e O u t b r e a k s (%)
Figure 1. Deaths per infection as a function of degree of waterborne transmission. Pathogens listed from most to least waterborne are the classical biotype of Vibrio cholerae, Shigella dysenteriae type 1, Salmonella typhi, the El Tor biotype of V. cholerae, Shigella flexneri, Shigella sonnei, enterotoxigenic Escherichia coli, Campylobacter jejuni, and nontyphoid Salmonella. (Spearman rs= 0.98, p
Paul W. Ewald Amherst College
Application of evolutionary principles to epidemiological problems indicates that cultural characteristics influence the evolution of parasite virulence by influencing the success of disease transmission from immobilized, infected hosts. This hypothesis is supported by positive correlations between virulence and transmission by biological vectors, water, and institutional attendants. The general evolutionary argument is then applied to the causes and consequences of increased virulence for three diseases: cholera, influenza and AIDS. KEYWORDS:Virulence; Evolution; Acquired Immune Deficiency Syndrome (AIDS); Cholera; Influenza; Human Immunodeficiency Virus (HIV); Disease vectors; Pathogenicity
Received July 13, 1990; accepted September 5, 1990. Address all correspondence to Paul W. Ewald, Department of Biology, Amherst College, Amherst, MA 01002.
Copyright 9 1991 by Walter de Gruyter, Inc. New York Human Nature, Vol. 2, No. 1, pp. 1-30.
1045-6767/91/$1.00+.10
2
Human Nature, Vol. 2, No. 1, 1991
A N EVOLUTIONARY APPROACH TO VIRULENCE
Why are infectious diseases like cholera and typhus severe, whereas others like the common cold are relatively mild? Why are still others, like influenza, highly lethal in some outbreaks and relatively benign in others? For most of the century since acceptance of the germ theory, scientists have made steady progress in answering these questions at the proximate level, that is, by understanding the physiological, cellular, biochemical, and genetic mechanisms of virulence. A complete understanding of any biological phenomenon, however, requires ultimate as well as proximate explanations. Ultimate answers to the preceding questions explain the evolutionary processes through which the various levels of virulence have come into being. For most of the past century, ultimate explanations have been ambiguous and contradictory. The generally accepted viewpoint was that commensalism or very benign disease is the eventual evolutionary end product of host-parasite associations because harm to the host decreases the parasite's chances for long-term survival (Dubos 1965; Hoeprich 1977; Smith 1934; Thomas 1972; Zinsser 1935; I define "parasite" as an organism that lives in or on another organism and has a negative effect on the fitness of that organism and "pathogen" as a subcellular or unicellular parasite). Although there have been a few dissenters over the past half-century (Ball 1943; Coatney et al. 1971; Cockburn 1963), evolution to benignness is still the view generally espoused in medical texts and by health science researchers unfamiliar with current thinking in evolutionary biology (e.g., Doyle and Lee 1986; Essex and Kanki 1988; Steinhauer and Holland 1987). This view is inadequate because it is based on benefits to the species or to large subgroups of the species rather than changes in allele frequencies within parasite species. During the past decade, our understanding of natural selection has been more rigorously applied in studies of the evolution of virulence. Part of this application has involved mathematical models, which demonstrate how evolution can favor intermediate or high levels of virulence (Anderson and May 1982; Levin 1983; Levin and Pimentel 1981; May and Anderson 1983). These models indicate that increased virulence can be favored when correlates of increased virulence, such as increased parasite multiplication, increase transmission rate. A complementary comparative approach (sensu Williams 1985) has been to determine what modes of transmission favor the more virulent parasite genotypes by analyzing relationships between virulence and the parasites' ability to contribute genetic instructions for virulence into succeeding generations--that is, the parasites' fitness costs and bene-
Transmission Modes and the Evolution of Virulence
3
fits. This paper will analyze the potential of this cost-benefit approach for explaining the ultimate causes of virulence across and within species of human pathogens. This approach assumes that virulence per se generally does not benefit the pathogen; rather it is an inevitable side-effect of selective pressures favoring increased reproduction of pathogens within hosts and increased densities of pathogens transmitted from hosts. As an infection proceeds, rapidly reproducing genotypes should comprise a progressively greater percentage of the total population of pathogens within the host than less rapidly reproducing genotypes, and they should also be increasingly represented in the groups of pathogens that disperse from a host. By shedding higher densities of pathogens, the former may also infect susceptibles earlier and trigger an i m m u n e response that precludes the latter's entry. These mechanisms of competition leading to increased virulence involve an association between increased reproduction within hosts and an increased probability of infecting a contacted host. Countering this selective pressure is the negative effect of virulence on the number of hosts contacted. A severely ill host, being less mobile, generally can be expected to contact fewer susceptible individuals than would a relatively healthy host. Predictions can be generated from this theoretical framework by specifying situations in which extensive use of host resources should provide the pathogen with exceptionally great fitness benefits or small fitness costs. These predictions can then be tested by comparing them with the actual relationships derived from the literature. As described below, several tests have supported the general hypothesis that changes in human culture can alter the evolution of pathogen virulence. This support provides a basis for understanding evolutionary changes of virulence throughout our history and into our future.
VECTOR-BORNE TRANSMISSION AND VIRULENCE: COMPARATIVE STUDIES
Transmission by Arthropod Vectors The first study using a comparative approach to test the cost-benefit theory of virulence predicted that parasites transmitted by biting arthropod vectors (e.g., ticks and insects) should evolve to higher levels of virulence than directly transmitted parasites (Ewald 1983). The logic is as follows. Transmission of arthropod-borne parasites is not as ad-
4
Human Nature, Voi. 2, No. 1, 1991
versely affected by host immobilization as transmission of most other parasites; in fact, experimental studies in rodents, rabbits, and sheep (Day and Edman 1983; Day et al. 1983; Turrell et al. 1984; Waage and Nondo 1982) indicate that severely ill hosts are bitten by mosquitos more frequently than uninfected hosts, largely as a result of reduced effectiveness of behavioral defenses. The benefits to the pathogen from increased multiplication should therefore outweigh the costs of decreased transmission at a higher level of multiplication (and hence virulence) for vector-borne pathogens than for nonvector-borne pathogens. The data on human pathogens confirm the predicted positive association between transmission by arthropod vectors and virulence (Ewald 1983). These data also indicate that this association results from evolutionary adaptation: the lethality of vector-borne pathogens in humans is positively correlated with their degree of previous association with h u m a n hosts (Ewald 1983). The cost-benefit theory predicts that vector-borne pathogens should evolve in the opposite direction in the vector host. A high level of virulence in vectors should impose high fitness costs on vector-borne parasites because an immobilized vector generally cannot transmit the parasite. Parasites transmitted by arthropod vectors should use their vectors as dispersal agents and their vertebrate hosts as resource bases. The high virulence in vertebrate hosts should therefore be coupled with low virulence in vectors (Ewald 1987). Testing this prediction is complicated because vector-borne pathogens are also frequently vertically transmitted from female vectors to offspring, and vertical transmission, like vector-borne transmission, should favor benignness in the vector (Ewald 1987; Ewald and Schubert 1989). An analysis of the literature on vector-borne and nonvector-borne pathogens of mosquitos confirms this prediction. Vector-borne viruses are less lethal to mosquitos than nonvector-borne pathogens when effects of vertical transmission are taken into account, and virulence among vector-borne viruses and among nonvector-borne protozoal parasites decreases as frequencies of vertical transmission increase (Ewald and Schubert 1989). The greater benignness of vertically transmitted vector-borne parasites could be interpreted as a consequence of a weaker selective pressure toward commensalism among the less vertically transmitted vectorborne parasites. That is, the eventual evolution to commensalism in vectors may not yet have had enough time to take place or might be countered by nonselective processes, such as genetic drift. Evidence against this hypothesis comes from examples in which m o d e r a t e virulence in vectors improves chances of p a t h o g e n transmission. Malaria organisms, for example, destroy specific parts of the salivary glands
Transmission Modes and the Evolution of Virulence
5
of mosquitos. This destruction increases the duration of probing, and hence the probability of vertebrate infection (Rossignol et al. 1984).
Waterborne Transmission
Like pathogens transmitted by arthropod vectors, waterborne pathogens should incur relatively small fitness costs and large benefits from extensive reproduction inside hosts and shedding of progeny from hosts. A person immobilized with a severe case of diarrhea will release pathogens into bedding, clothing, and other objects that will probably be washed, or fecal material may be disposed of directly into water (e.g., in canals or toilets) by attendants. When the water contaminated with this fecal material mixes with unprotected drinking water, large numbers of susceptible people could become infected from the pathogens released from an immobilized host (Ewald 1988, 1990). Analogous to the transmission of pathogens by arthropod vectors, this process can be considered an example of transmission by cultural vectors. The term cultural vector denotes a set of characteristics that allow transmission from immobilized hosts to susceptibles when at least one of the characteristics is some aspect of human culture (Ewald 1988). The cultural vector could transport the pathogen from the infected individual to susceptibles, or it could transport the infected individual to susceptibles or susceptibles to the infected individual. In waterborne transmission, the cultural vector transports the pathogens from the infected to the susceptibles and includes the materials contaminated by the immobilized host, the person removing this material, the contaminated waters that flow into the drinking water, and agents contributing to this flow or delivering the contaminated water to susceptible people. From this argument regarding cultural vectors it follows that the virulence of gastrointestinal tract pathogens should be positively correlated with their tendencies for waterborne transmission. The confirmation of this prediction is presented in Figure 1. These data points represent all pathogenic bacteria of the gastrointestinal tract that are regularly transmitted between humans in community settings and for which both waterborne transmission and mortality could be quantified. Each data point represents the lowest taxonomic subdivision for which differences in waterborne transmission and mortality could be distinguished. The data base consists of approximately 1000 outbreaks referenced in Ewald (1990) as well as data from one additional study (Black et al. 1982). The strong positive correlation between waterborne transmission and mortality cannot be explained by possible correlates of these two variables,
6
Human Nature, Vol. 2, No. 1, 1991
O
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-
-
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100
W a t e r b o r n e O u t b r e a k s (%)
Figure 1. Deaths per infection as a function of degree of waterborne transmission. Pathogens listed from most to least waterborne are the classical biotype of Vibrio cholerae, Shigella dysenteriae type 1, Salmonella typhi, the El Tor biotype of V. cholerae, Shigella flexneri, Shigella sonnei, enterotoxigenic Escherichia coli, Campylobacter jejuni, and nontyphoid Salmonella. (Spearman rs= 0.98, p
