The basic trends in virulence evolution can be summed up as towards increased parasitism or instead towards decreased parasitism. By increased parasitism I mean increased parasite virulence. Increased parasite virulence may be associated with increased parasite expedience, such as in terms of within-host rates of population growth, or instead a consequence of mechanisms of parasite transmission. Decreased parasitism can be viewed as tendencies instead towards commensalism, that is, decreased parasite virulence. Reductions in parasite virulence can be associated with decreased parasite expedience, potentially resulting in increased parasite economy during within-host population growth, though also could result from decreased host damage in the course of transmission. In this section we consider these basic ideas of parasite evolution towards what essentially is greater or lesser restraint in terms of negative parasite impact on the host environment: evolution towards commensalism versus parasitism, including towards economy versus expediency.

Parasite Expedience versus Economy

When new-host availability is low, and new-host availability cannot be increased through increases in pathogen virulence, then selection may favor instead a reduction in parasite virulence. This would be especially true if reduced virulence allows for longer spans over which transmission is possible. There is at least one general hurdle, however, that must be overcome to achieve the within-host, parasite population-wide restraint on, especially, parasite reproduction that is necessary to allow for such increased opportunities for transmission. That is, a strategy of reproductive restraint is one of cooperation between parasite individuals infecting a single host and therefore is ripe for exploitation by defectors. Defectors here would be parasite individuals that gain a within-population growth advantage by not displaying growth restraint. In other words, the body can be viewed as a "Commons" and a failure to display restraint, by a population, gives rise to a "Tragedy", one which can be measured in terms of host fitness (decreased), parasite virulence (increased), or transmission opportunity particularly as measured in terms of duration over which transmission is possible (reduced).

There are two mechanisms, in general, that can give rise to this Tragedy of the Commons, with virulence in both cases assumed to be directly proportional to parasite load. Thus, parasite genotypes that display more rapid or greater overall levels of replication may result in reduced transmission opportunities and this should occur to the extent that virulence increases as a function of parasite number while transmission opportunities decrease as virulence increases. The second possibility is that greater parasite replication ability may come with a per-parasite-individual increase in displayed virulence. That is, not only can anti-host virulence increase as parasites increase in number but so too can levels of damage increase if parasites are especially rapacious. In either case, though slightly different from our previous usage, we can view the reduced-restraint parasite as displaying a greater expedience versus an overall lower-virulence genotype's greater economy (here, a.k.a., restraint). The usage of "expedience" here refers to impact on host fitness and therefore to the overall virulence of the parasite because of its expedient replication at greater host-environment expense (i.e., essentially a parasite exceeding its host's ability to sustain the parasite's population density, or equivalently the parasite exceeding its carrying capacity). By displaying greater restraint on its own replication, a parasite population may be able to avoid exceeding the body's carrying capacity for that parasite, thereby potentially allowing for greater spans of time over which parasite transmission to new hosts might occur.

A reasonable default assumption would be that any parasite population that displays less than maximal with-host population growth rates may be invaded by faster replicating parasite variants. Furthermore, this increase in parasite replication rates, their within-host fitness, could come at the expense of between-host transmission ability: Even if this excess replication has the consequence of reducing absolute rates of pathogen transmission, those genotypes that have come to predominate within a host should still display the greatest frequencies of transmission among those parasites present from that host. That is, expedient parasites may come to dominate within individual hosts though potentially at the expense of overall transmission ability of the parasite population out of the host. This, is a Prisoner's Dilemma-type situation where T > R > P > S and T represents the temptation to expediently outcompete otherwise cooperative competitors, within hosts, while P represents an overall decreased parasite transmission ability given that expedient defectors have come to dominate the parasite population within a host.

What, then, keeps parasites from evolving ever higher levels of virulence, that is, greater rates of replication within a given host? The first and obvious answer to the question of why parasites might display restraint on their virulence is that those parasites, as a population within hosts, that display too great virulence could be at a selective disadvantage owing to any reductions in transmission rates that result. Because virulence is a global (to the host) phenomenon, however, this reduced-transmission-with-higher-virulence explanation is inherently a group selectionist argument; that is, it assumes that those parasites which display reduced virulence as a group – such as while infecting a single host – should come to predominate over those groups that instead display excessive virulence. Given selection among parasites for greater within-host competitive ability, just as selection for cancerous growth occurs among the cells making up our own tissues, and the potential for this mechanism to result in increased levels of virulence along with reduced rates of transmission, then the crucial question is what are the individual selection mechanisms that might slow the evolution of ever greater virulence among parasites? The answers to this question are multiple, but basically come down to a few now-familiar concepts: bottlenecking, resulting clonality, and antagonistic pleiotropy.

Evolution of Parasite Restraint

As has been discussed, bottlenecking in organisms that are not obligately sexual can occur as the passage of only a single individual, which automatically initiates a population that is clonal. It may very well be that infectious diseases are often initiated with just a single individual, and this is one way of viewing the common notion of an infectious dose-50 (ID50). An ID50 is that number of organisms that individuals must be exposed to for half of those individuals to become infected, and this is a concept that can be equivalent to the most probable number (MPN) method of organism quantification, in microbiology. The basis of MPN determinations is that dilutions that reduce inoculations to about one organism per culture, on average, is approximately the inverse of the starting organism density: That is, a 10,000-fold dilution of a culture containing 10,000 organisms (per unit volume) will produce a culture which, on average, contains one organisms per unit volume (e.g., ml). Presumably people are typically exposed to less than an ID50 of pathogens (that is, somewhat fewer than half individuals become sick) meaning that successful inoculations might indeed often consist of only a single surviving and then infecting pathogen individual. Alternatively, inoculations that are substantially greater than the ID50, or in which synergistic interactions between multiple pathogen individuals are required to effect a mass initiation of infection, may be viewed as equivalent to serial passage (below).

Inclusive Fitness and Restraint on Virulence Evolution

With clonal organisms there exists a greater potential for the evolution of restraint through mechanisms of inclusive fitness. That is, if restraint on virulence, e.g., restraint on excessive pathogen replication, should result in increased pathogen-population fitness, then clonal infections that display this restraint will be fitter than infections that do not display such restraint. Yes, this takes us back to the group selection argument presented two paragraphs previous. The difference, however, is that now the group is assumed to be clonal, with inclusive fitness therefore operating to enhance cooperation. Again restating, but from a somewhat different perspective, a parasite mutant that defects will be well off within the infection in which it arises, and thereby potentially more likely to be transmitted among those parasite individuals found within that infection (that is, the payoff for this unilateral defection in a parasite Prisoner's Dilemma can be relatively greater transmission opportunity, essentially T for unilateral defection). Once the parasite has been transmitted, assuming severe bottlenecking in the course of acquisition of each new host, then the mutant parasite defector will be among only its own genotype within the resulting new infection (or infections) and therefore mutual defection will ensue (i.e., P). We've previously made similar arguments with regard to the evolution of cooperation (see "Cooperation: Achieving Mutual Cooperation").

Of course this is not a problem if in fact a pathogen population displays a level of virulence that is lower than optimal. That is, if the defector is defecting by displaying greater virulence and greater virulence in this case is actually adaptive (rather than maladaptive), then this mechanism actually could give rise to an acceptable, for the parasite population's average fitness, directional selection. Thus, again, there are two levels at which selection operates, within the host and between hosts, or within infections versus between infections. When selection is operating in both cases in the same direction, that is, towards increased virulence, then selection presumably should carry the parasite population in that direction with reasonable efficiency. Alternatively, and the point under consideration in this section, if selection operating in both cases is not in the same direction, that is, towards reduced virulence, then obtaining an optimal end point requires more constrained circumstances, e.g., as one sees as well in various scenarios for the evolution of within-population cooperation, such as selection for economy over expediency.

Recall that attainment and maintenance of clonality are not the same processes. Bottlenecking down to a single, transmitted individual is a mechanism of clonality establishment. It is reduced mutation rates, lack of attainment of very larger population sizes, and protection from invasion by other, non-clonal individuals, however, that is required to prevent invasion of populations by non-cooperative genotypes, at least over relatively short spans (more active mechanisms may be necessary over longer spans, e.g., such as policing against defectors). Organisms with very high mutation rates or very high population sizes thus would be expected to display higher levels of cheating and, therefore, higher levels of virulence that is caused by within parasite-population selection for more rapid replication. These qualities are relative ones, though, since given the existence of such qualities we would expect cheating to evolve to the point where it becomes limited instead by the parasite's biology. This is another way of saying that given sufficient opportunity for defection it may no longer be inclusive fitness that limits the evolution of ever higher virulence but instead antagonistic pleiotropy, that is, selection against higher virulence particularly because of counter selection, either on the individual or on the population, for more effective transmission.

Antagonistic Pleiotropy and Restraint on Virulence Evolution

The evolution of greater restraint because of the negative impact of increased virulence on subsequent transmission of parasite individuals can, in particular, be viewed as an example of antagonistic pleiotropy. So far, though, we've only considered a direct antagonism between virulence and transmission, e.g., greater parasite loads may reduce the duration of opportunities for parasite transmission. Alternatively, there can be antagonism between the mechanism of increased expediency, i.e., of pathogen growth rates, and parasite-mediated mechanisms of transmission. That is, faster parasite population growth can reduce transmission opportunities because of the negative impact on host health but also can reduce transmission opportunities because the parasite individuals display properties that result in their becoming individually less effective transmitters. Especially this latter point can be viewed in terms of conflicts between life stages, with an enhancement of effectiveness in one stage resulting in a reduction in effectiveness in another. These, of course, are concepts we considered under the heading of serial passage experiments (see specifically "Passage Through Time: Serial Passage: Transmission Impact").

A straightforward example of conflicts between life stages is seen when the transmission stage is a non-growing stage. For example, if the transmission stage is a spore, then a lineage must devote at least part of its reproduction to spore formation in order to successfully transmit. The larger the proportion of its reproduction so devoted then the more transmittable progeny it produces, at least in the near term. So too the fewer vegetative cells that will be available to produce these spores, however. Thus, a lineage could optimize its reproductive output, within a single host, by reducing spore production, but this occurs with a direct transmission cost. Alternatively, a lineage could devote a large fraction of its reproduction to the production of spores, but by doing so it may be a poorer within-host competitor and as a consequence it may end up producing fewer spores over the long term. A similar but non-spore, non-bacterial example is seen with Plasmodium, the etiology of malaria, where the disseminating stage is generated by meiosis whereas intra-host replication occurs instead via mitosis and (p. 869) "For every gametocyte produced, an asexual lineage has to sacrifice its future asexual reproduction and hence future transmission potential" (Mackinnon and Marsh, 2010) .

Evolution of Parasite Restraint: Conclusions

In summary, we can expect pathogen virulence evolution to result in reduced replication rates and/or increased host-exploitation economy so long as increased pathogen loads negatively impact transmission opportunities for the overall within-host pathogen population. Alternatively, though towards the same ends, we can expect pathogens to display reduced replication rates to the extent that increased replication ability negatively impacts transmission opportunities for pathogen individuals. For the latter, individual selection operates by default, i.e., as a consequence of antagonistic pleiotropy and resulting conflicts between life stages (reproduction versus transmission). In other words, defectors in this case do not gain transmission opportunities, relative to the rest of the group, from their more-rapid replication. For the former, population case, however, individual selection does not by default give rise to reductions in parasite virulence. Instead we must invoke inclusive fitness as a driving force behind the evolution of restraint (i.e., pathogen economy) and this mutual cooperation is much more likely to the extent that pathogen clonality, per infected host, can be established and subsequently maintained.

Note as a reminder that even if selection overall favors reduced virulence for a parasite, that virulence itself can be defined in relative terms. Thus, a parasite can display reduced virulence, but still kill its host, perhaps just not as quickly. Alternatively, a parasite can display what we would view as extremely high virulence (i.e., the host dies) but still evolve even higher virulence (such as the host is killed even faster). It is this potential for selection to give rise to higher levels of virulence that we take on next.

Table: Impact of Various Factors on Evolution of Parasite Virulence

MechanismGreater VirulenceReduced Virulence
Bottlenecking of parasite populations during transmission No Yes
Lower parasite mutation rates No Yes
Antagonistic pleiotropy between parasite life stages No Yes
Smaller within-host parasite population sizes No Yes
Reduced host availability (impacting transmission potential) No Yes
Antagonism between virulence and transmission opportunity No Yes
Requirement for greater host health to achieve transmission No Yes
Reduced environmental durability during transmission No Yes

Selection for Increased Virulence

Transmission likelihood can be a function of parasite numbers that are available for transmission, individual parasite properties (i.e., those directly impacting parasite transmission potential), and group parasite properties such as the overall virulent impact of parasite load on the host. Generally, if all other factors are otherwise held constant (i.e., ignoring potential for antagonistic pleiotropy), then greater parasite numbers as well as greater individual-parasite ability to be transmitted (of course) should result in greater transmission likelihood. The group property of virulence, however, is a more variable concern. This is in part due to tradeoffs between nearer-term and longer-term transmission opportunities. It also is a consequence, however, of the impact on parasite transmissibility of host health, which can range from negative, to benign, to even positive. Especially it is those mechanisms that directly increase rates of parasite movement out of the host that will tend to be selected for, in the parasite population, including such things as coughing or diarrhea. There may be limits, though, on the degree to which these mechanisms may be exploited since too-great declines in host health can result in declines in the efficacy of these transmission mechanisms, e.g., by interfering with parasite replication; by reducing host potential to interact with other, potential hosts; or by outright killing the infected host.

Transmission typically occurs starting from parasite-specific portals of exit from infected bodies. Some of these portals do not display reduced abilities to support parasite transmission even given increasing negative impacts on host health, e.g., such as the host-tissue dissolution seen with baculovirus. In these cases, what serves to limit virulence, evolutionarily, is host availability. To some degree this availability, however, is under parasite control via parasite extra-host durability. Thus, a parasite that shows extreme durability outside of the host, for example, may be better able to afford to display high levels of virulence during infection, potentially even that resulting in host death, because eventually the resulting progeny may still find another host, since they can afford, due to their high durability, to wait a long time. Musings such as this represent guiding principles, but ultimately it is the details of individual host-parasite interactions, both within individual hosts and within host populations (and their environments) that will determine what virulence intensity would optimize parasite fitness.

Serial Passage and Increased Virulence

The worst plagues of history have been acute infectious diseases that spread swiftly and lethally through human populations. The most damaging examples generally have been well adapted to transmission through human populations, either directly from person to person or indirectly through a biologic vector, such as a mosquito, or a nonbiologic vehicle, such as water. These diseases as a rule were long adapted to humans and caused their harm when they spread through previously unexposed human populations. Measles and smallpox decimated native populations in the Americas when they were introduced during the early colonial period… Syphilis probably caused large amounts of death in previously unexposed populations in Europe as a result of a reciprocal introduction into Europe from the New World… These outbreaks were devastating largely because they were introduced from human populations with which they had been in evolutionary arms races into populations that had no acquired immunity and little if any evolved resistance. — Paul W. Ewald (2004)

Note the similarity in these arguments to the ideas we considered in terms of serial passage experiments (see "Passage Through Time: Serial Passage"). That is, in the course of the evolution of pathogens to a single host, there can be a tendency for that pathogen to display greater virulence due to a specialization on the particular physiology of that host. In the case of the spread of disease with na&iauml;ve populations, we must also consider that the host availability can be high due to low rates of resistance. The result, given invasion of pathogens into new populations, can be a combination of specialization and increased transmission opportunity, both of which can result in the evolution of greater pathogen virulence.