CHAPTER 5 Pathogen Evolution athogens have their own agendas: they evolve rapidly in response P both to changes in their individual hosts and to human interven- tions. The most important evolutionary responses of pathogens concern virulence, their role in the microbiota (which can switch from symbiotic to pathogenic), evasion and suppression of the im- mune system, resistance to antibiotics, and reactions to antipatho- gen interventions designed to minimize evolutionary responses. We now discuss these responses in sequence. Virulence caused by pathogens The detrimental effects of infections on hosts are caused both by the direct damage done by pathogens and by the hosts’ responses to infec- tion. Virulence is always an interaction between pathogen infection and host response. We use virulence in this chapter to refer to the portion of the damage that the infection causes the host that is due to proper- ties intrinsic to the pathogen rather than to the host’s reaction to the infection. The properties of the pathogen are determined by its evolu- tionary agenda, which is to maximize its reproductive success over its entire life cycle. That life cycle encompasses everything that happens from infection of a host to transmission into and infection of the next host, including the effects of host responses on pathogen survival and reproduction. Seen from the point of view of the pathogen, five key issues shape its virulence. First, does its impact on the host affect its probability of transmission? If it kills the host too rapidly, it may not be transmitted at all; if it does not exploit the host efficiently, it may lose to competitors that make better use of host resources to produce transmittable progeny. This is the virulence-transmission trade-off. 2 Chapter 5 Second, to what degree is it horizontally transmitted rather than vertically transmitted to offspring of this host? Once it is horizontally transmitted, its reproductive success no longer depends on the continued survival of its original host, whose survival becomes irrelevant, but if it is vertically transmitted, its reproductive success depends on the survival of its host until its host reproduces, which could happen several times. Third, is it the only genetic strain or species of pathogen infecting the host, or are there other strains or species with which it must compete while attempting to reproduce and transmit? If it is alone in the host, it can evolve a level of virulence that maximizes transmission probability, but if it is in a coinfected host, it must scramble to use host resources before its competitors do, even if doing so reduces transmission probability below what it could achieve if it were the only pathogen present. This is the issue of single versus multiple infections. Fourth, is its ability to infect this host a function of its ability to infect other hosts? We expect a jack-of-all-trades to be a master of none: special- ists should outcompete generalists. Evidence supporting that view comes from the production of live attenuated vaccines through serial transfer, which causes the pathogen to increase in virulence on its new host while it loses virulence on its old host, rapidly becoming harmless enough on its old host to be used as a live attenuated vaccine. The ecosystem in which pathogens are evolving during serial transfer is a special one and may not represent natural conditions, in which host genotypes and phenotypes are both more variable. Fifth, how much of this host has it seen in the past? Not all hosts and pathogens are locked in long-term arms races caused by repeated cycles of infection and transmission. Sometimes, pathogens jump into new hosts, producing emerging diseases, situations in which neither the host nor the pathogen has had much, if any, evolutionary experience of the other. Such spillover events are associated with unpredictable levels of virulence, rang- ing from harmless to catastrophic. In general, the precision of adjustment of pathogen to host depends on the frequency with which the two have encountered each other. We now examine each of these five issues in more detail. The virulence-transmission trade-off The paradigmatic example of virulence evolving in a trade-off with transmis- sion is the introduction of the myxoma virus to Australia to control rabbits. Rabbits are not native to Australia; they were introduced by European colonists. The rabbits escaped from their hutches, increased rapidly in an environment that lacked predators that could control them, and grazed the vegetation down to the ground over vast areas, causing devastating damage to farms and ranches. An international search for diseases that could control the rabbits located the myxoma virus in the Americas, where it causes tumors but not immediate death in the indigenous cottontail rabbits (genus Sylvilagus). The myxoma virus, a member of the poxvirus family and a relative of cowpox, monkeypox, and variola, is transmitted by anthropods, including mosquitoes, fleas, lice, ticks, and mites. In European uncorrected page proofs © 2015 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. Pathogen Evolution 3 rabbits (those introduced to Australia), it causes myxomatosis, an acute disease with an initial 100% mortality rate; this spillover event causes initial host mortality well above the optimum for the virus. When the virus was introduced to Australia in 1950, the authorities wisely preserved control samples of virus and rabbits that did not then coevolve with each other. Later, they would use comparisons with the coevolved viruses and rabbits to determine to what degree the evolution of virulence was caused by changes in each (Fenner 1983). The initial introduction was a single, highly virulent strain that soon mutated into a diversity of com- peting, less virulent strains. These strains were classified into virulence grades ranging from I to V, with I being the most virulent, causing a case fatality rate greater than 99%, and V being the least virulent, causing a case fatality rate of less than 50%. Strain III with intermediate virulence rapidly outcompeted both the highly virulent initial strain I and the least virulent mutant strain V (Table 5.1). Although the extrinsic virulence of the virus did decline from its initial catastrophic level, the disease remained deadly after it stabilized at virulence level III, where it has a case fatality rate of 70%–95% and continues to function well in rabbit controls. Comparisons with unevolved strains demonstrated that the evolved level of virulence was the result of evolutionary changes both in the intrinsic virulence of the virus and in the ability of the rabbits to resist or tolerate infection. If the rabbits die quickly, there is little opportunity for the arthropod vectors to transmit the disease. Less virulent strains then outcompete more virulent strains because of their superior transmission. Although they may do worse in a single host, they do better in the population as a whole. The process continues until a stable level of intrinsic virulence in the virus and of resistance/tolerance in the host population evolves (Figure 5.1A). When that level of virulence is achieved, the disease is still very serious. TABLE 5.1 The virulence of strains of myxoma virus in Australia from 1951 to 1981 Virulence grade: I II III IV V Case fatality rate (%): >99 95–99 70–95 50–70 <50 Mean survival Number of time (days): <13 14–16 17–28 29–50 — samples 1950–1951 100 1 1952–1955 13.3 20.0 53.3 13.3 0 60 1955–1958 0.7 5.3 54.6 24.1 15.5 432 1959–1963 1.7 11.1 60.6 21.8 4.7 449 1964–1966 0.7 0.3 63.7 34.0 1.3 306 1967–1969 0 0 62.4 35.8 1.7 229 1970–1974 0.6 4.6 74.1 20.7 0 174 1975–1981 1.9 3.3 67.0 27.8 0 212 Source: After Fenner 1983, Table 4, p. 265. Note: Data are expressed as percentage of samples recovered. uncorrected page proofs © 2015 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 4 Chapter 5 (A) (B) (C) 15 ) 0 Measles R VZV R maximum Mumps 0 Poliovirus Variola major Transmission rate Transmission rate Transmission Pathogen Pathogen tness ( 0 Mortality 1 30 100 Recovery Mortality Pathogen-induced mortality (%) rate Figure 5.1 Trade-offs in virulence evolution. (A) A trade-off between transmis- sion rate and host mortality; the pathogen will evolve upward to the boundary. (B) Parasite fitness (R0) is then proportional to the sum of the recovery rate and the mortality rate; maximum fitness is achieved where the line through the origin is tangent to the trade-off curve, where the host suffers some mortality. (C) Data on R0 and prevaccination mortality rates, however, show that some viral diseases AU: Caption needs toresult identify/explain in negligible red circle host inmortality. (A)* VZV, varicella zoster virus. (After Bull and Laur- ing 2014.) * per original article - “characteristic of pathogen...underneath trhe trade-off curve” simply label it “Pathogen” in art? See above. The virulence-transmission trade-off has been demonstrated with experi- mental evolution in beetles infected with microsporidians, where pathogen virulence decreases to an intermediate level and host genetic resistance increases (Berenos, Schmid-Hempel, and Wegner 2009). It has also been invoked to explain the decrease in virulence of syphilis in Europe following its introduction to Naples from the New World in 1495 (Harper et al. 2011). It is clear, however, that the simple virulence-transmission trade-off does not apply to all cases of host-pathogen interaction because at the evolutionary optimum, there should be some measurable level of host mortality (Figure 5.1B).