VECTORBORNE TRANSMISSION
Evolutionary theory identifies vectorborne transmission as a second factor favoring evolution toward relatively high levels of virulence. If a disease organism is transmitted by a biting arthropod vector such as a mosquito or reduviid bug, then it can still be transmitted even if a person is entirely immobilized with illness because such biting arthropods come to feed at immobile people. In fact, experimental studies indicate that mosquitoes are better able to bite a laboratory animal when it is sick with a vectorborne disease such as malaria than when it is healthy, and reduviid bugs (which are vectors for Chagas' disease) typically feed on sleeping individuals. As a consequence, natural selection should favor relatively high levels of host exploitation by vectorborne pathogens, and we should therefore see a particularly high virulence among vectorborne diseases.
The mortality associated with untreated infections is highly variable among both vectorborne and directly transmitted pathogens, but it is greater for vectorborne pathogens than for directly transmitted pathogens (Ewald 1983, 1994). Just as reduction of waterborne transmission should favor evolutionary decreases in virulence, reduction in the potential for arthropodborne transmission from immobilized humans should favor decreases in virulence. This effect can occur through two mechanisms. One mechanism is the direct analog of the argument for waterborne transmission, namely that reduction of transmission from immobilized humans causes a greater reliance on human mobility for transmission. Much as provisioning of uncontaminated drinking water is an intervention that should cause evolutionary reductions in the virulence of diarrheal pathogens, mosquito-proofing of houses is an intervention that should cause an evolutionary reduction in the virulence of vectorborne pathogens such as the agents of malaria or dengue. If a person ill with malaria or dengue stays in bed in a vector-proof house (or hospital), then the transmission of any pathogens in that person will be blocked during that period. To the extent that those variants tend to be inherently more virulent than variants that allow infectious people to be feeling well enough to move around outside of their homes, the composition of the pathogen population will shift toward a greater representation of the milder variants. That is, the pathogen population will have evolved toward mildness. This prediction has not yet been tested, but the information available in the literature, both supports the key steps in logic and suggests that the next stage of large-scale testing is warranted and would be beneficial even if the hypothesis is incorrect.
First, illness tend to be associated with infectiousness. For vectorborne viral diseases, such as dengue, the evidence is straight-forward: viremia occurs during the symptomatic period (e.g., Vaughn et al. 1977). In parasites with more complicated life histories, such as plasmodia, the evidence is more complex because the critical variable is the timing of infectious life history stages (i.e., the gametocytes) is the critical variable. In this case the evidence still supports the idea that much of the transmissibility will be associated with the period of reduced host mobility (e.g., see Ewald 1994).
Geographic variation indicates that parasites have the potential to cause largely mild infections where opportunities for vectorborne transmission are limited. P. vivax strains, for example, tend to be more mild in geographic areas associated with low and sporadic mosquito transmission (Ewald 1994). The variation in P. vivax's distribution appears to be largely a result of differences in the parasite's tendency to generate dormant resting stages (i.e., "hypnozoites").
P. falciparum infections are often similarly mild where the potential for vectorborne transmission is low, for example, in low transmission areas in the Sudan and Columbia (Elhassan et al 1995, Gonzalez et al. 1997). This tendency also occurs in Mali and more generally along the northern edge of P. falciparum's range in subsaharan Africa (D. S. Peterson, pers. comm.), where the parasite's distribution may be limited by the restricted abundance of mosquitoes. The relative importance of host and parasite characteristics in determining the mildness of P. falciparum infections has not been determined in any of these areas, however. If the mildness of such P. falciparum infections results at least in part from the mildness of the P. falciparum variants, evolution toward reduced virulence would seem particularly feasible. With pre-existing mild strains, detectable evolutionary shifts toward mildness could occur relatively quickly if mosquito-proofing programs were enacted at the edges of P. falciparum's distribution. If these programs proved successful the interventions could progress toward the center of the ranges, because the mild strains that would be needed to replace the more severe strains would already be present in the P. falciparum gene pool. Although such a progression might facilitate a rapid evolutionary shift toward benignity, it may not be necessary, as variations in pathogen virulence appear to be present even in areas with intense transmission (e.g., Kun et al. 1988).
Influences of exposure to infection on host resistance is a potential confounding variable in any efforts to control malaria through reduction in frequencies of transmission. One hypothesis attracting recent attention proposes that reductions in entomological inoculation rates (EIRs) will have little effect on overall mortality and morbidity in areas with moderate to high bite frequencies, where the benefits of reduced EIRs might be offset by reductions in acquired resistance (Snow & Marsh 1995). With regard to evolutionary effects, this concern is applicable primarily to areas with moderate EIR. In areas with low EIR, mosquito-proofing should lower frequencies of infections to the point of eradication (Watson 1949). In areas with high EIRs, one would expect that mosquito-proofing would cause an evolutionary shift toward benignity with relatively little effect on frequency of infection, and hence with little effect on benefits of acquired immunity. If the evolutionary hypothesis is incorrect, great epidemiological benefits can be expected at least in areas with low EIRs; such nonevolutionary benefits at higher EIRs are uncertain. If the evolutionary hypothesis is correct this benefit at low EIRs will be supplemented with reduced virulence of infections across the spectrum of EIRs.
As is the case with waterborne transmission, vectorproofing of houses can be expected to provide evolutionary reductions in virulence across a spectrum of vectorborne diseases. Different strains of dengue, for example, vary in virulence, with the more virulent strains being more productive in cell culture (Morens et al. 1991). Vector-proofing of houses against dengue's vector, Aedes aegypti, should similarly favor the milder less exploitative variants, driving the dengue population to a more benign state. When more than one vectorborne disease is occurring in an area, the overall cost effectiveness may increase in proportion to the number of diseases, because the same intervention should have similar evolutionary effects for each.
The next stage of testing of these ideas will be feasible only if those who control the sources of funds consider the effort worthwhile. The chances of such a positive assessment would be improved if vector-proofing of houses could be shown to have traditional nonevolutionary epidemiological benefits (i.e., reduction in the frequency of infection) in addition to the hypothesized evolutionary epidemiological benefits (i.e., reduction in the harmfulness of the causative organisms). The available evidence indicates that traditional benefits do occur. The effectiveness of mosquito-proof housing against transmission of dengue, for example, is suggested by the resistance to invasion when such housing is generally present. Over the past two decades thousands of cases of dengue fever have occurred on the Mexican side of the US/Mexico border along the Gulf of Mexico. Dengue has been introduced repeatedly into Texas there but has failed to spread in spite of the ubiquitous presence of Aedes vectors. For every reported case acquired on the Texas side of the border there are about 1000 reported cases on the Mexican side (CDC 1996). The pervasiveness of mosquito-proof on the Texas side appears to be responsible for this difference. Similarly, malaria has been introduced on numerous occasions in recent years to areas in the US where it had previously been endemic. Appropriate vectors are abundant, yet little secondary transmission occurs; when it does, it has been self-limited and localized (Wyler 1993, Dawson et al. 1997; for an analogous example involving severe diarrheal disease, see Weissman 1974 ).
The most thorough experimental test of the effectiveness of mosquito-proof housing on malaria transmission was conducted from 1939 through the 1940s in a large section of northern Alabama, by the Tennessee Valley Authority (TVA), which was overseeing the construction dams in the area (Watson 1949). The TVA was concerned about malaria because the construction of dams in the region had previously contributed to the malaria problem there (Ackerman 1956, Derryberry 1956).
During the 1930s about half of the people in the area tested positive. In 1939, the TVA began a campaign to mosquito-proof all houses in the area and accomplished this goal within seven years. They divided the area into 11 zones and completed the mosquito-proofing of each zone at different times. The results of their study show that mosquito-proofing virtually eradicated malaria from the area, with the decline occurring earlier in those zones in which mosquito-proofing was completed earlier (Fig. 4). No other intervention was enacted prior to the decline (Watson 1949).
These results do not represent a test of the idea that malaria pathogens evolve to lower levels of virulence in response to mosquito-proofing of houses. The results do, however, demonstrate several important points.
First, the results show that Plasmodium populations are influenced by mosquito-proofing. If the population as a whole declines so strongly in response to screening, it seems probable that certain variants within the population will be more substantially reduced by screening than others, leading to an evolutionary change in the Plasmodium gene pool.
Second, the results demonstrate nonevolution-ary benefits necessary to justify the large-scale evolutionary experiment that would be needed to assess virulence management through mosquito-proofing. To justify the experiments from both ethical and economic perspectives, new areas for experimentation could be selected on the basis of having a slightly more difficult control problem than those for which nonevolutionary success has been demonstrated (e.g., a slightly higher prevalence of infection than occurred in northern Alabama just prior to the mosquito-proofing).
Third, the results show that the experiment is feasible logistically and financially even with the limitations of 1940s technology. The costs of mosquito-proofing (in 1944 dollars) was about $100 per house for the area with the poorest quality of housing; the costs of maintaining the mosquito-proofing was about $12 per house per year (Watson 1949). Modern technology has generated materials that are more effective, more durable, easier to apply and maintain, and more pleasant to live with than those used in the TVA study. Costs should therefore not be as greatly increased as would be indicated by a simple adjustment of the TVA costs for inflation. The actual costs may be influenced up or down depending on the details of a particular area such as the quality of existing houses, the degree to which materials could be generated locally and the costs of local labor.
Finally, the results of the TVA study demonstrate that mosquito-proofing worked even though this geographic area can be stiflingly hot and humid during the malaria season. Skeptics could have argued that people would not stay inside of houses sufficiently under such conditions for the antimalarial effects of mosquito-proof housing to work. Or, skeptics could have argued that people would deliberately destroy screens to increase air-flow through houses, but such vandalism was rare in the Alabama study (Watson 1949).
These ideas should be generally applicable across the spectrum of vectorborne diseases, although the particular details of the application will depend on the details of the vectorborne disease. Chagas disease offers an informative illustration of one variation on the theme. The agent of Chagas disease, Trypanosoma cruzi, is transmitted by reduviid bugs that bite sleeping individuals. It is therefore transmitted largely while people are immobilized in their houses. The frequencies of infection should therefore be reduced by vector-proofing of houses.
The details of T. cruzi transmission indicate that this intervention could reduce the virulence of T. cruzi through two evolutionary processes. The first process is analogous to that proposed above for malaria and dengue. To the extent that transmission does sometimes occur from mobile hosts outside of houses, virulence could be reduced.
The second evolutionary process concerns the effects of alternative vertebrate hosts on virulence in humans. The extent of human-bug-human transmission varies substantially geographically; substantial human-bug-human transmission occurring throughout most of T. cruzi's range but is virtually if not entirely absent in the US. Theory and comparative data indicate that vectorborne pathogens should tend to be relatively mild in humans when they rarely cycle in humans (Ewald 1983). About 5-25% of nonhuman vertebrate hosts (racoons and oppossums) in the southern US are infected with T. cruzi (Burkholder et al. 1980, Karsten et al. 1992, Pung et al. 1995), and a comparison of such strains with strains from humans in Brazil that they are genetically distinct (Clark & Pung 1994). In the US humans rarely acquire T. cruzi via vectors, and appear to be dead-end hosts, probably because of the vector proof housing and low vector densities (Burkholder et al. 1980, Kirchhoff 1993, Barrett et al. 1997). In accordance with theory about the evolution of virulence, such infections appear to be particularly mild in humans, so much so that only three cases of acute Chagas' disease from bug bites had been reported in the US as of 1993 (Woody et al. 1961a, b, Kirchhoff 1993).
This situation is of importance to evolutionary control of T. cruzi in countries with endemic Chagas disease because by making houses vector-proof, the importance of human-bug-human cycling relative to enzootic cycling should become greatly reduced, thus causing the evolution of increased specialization of T. cruzi on nonhuman vertebrates, reduced specialization on humans, and consequently, reduced virulence in humans. As in the case of malaria, the presence of benign strains could be beneficial through protection against severe strains like a free live vaccine, because benign strains of T. cruzi can protect against highly virulent clones (Lauria Pires & Teixeira 1997).
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