Infectivity and virulence relationship quotes

Virulence evolution in a host–parasite system in the absence of viral evolution

infectivity and virulence relationship quotes

pathologists and bacteriologists, to regard the host-parasite relationships of the . exalting the virulence of pathogenic bacteria is rapid passage through the . of common antigens by otherwise unrelated organisms, but to quote Topley. Researchers have found positive relationships between titre and virulence, or between Maternal transmission is likely the major route of infection by DMelSV in . While we quote results from the model with all random effects (line and line . to further infection (R); the dynamics of the parasites is described simply as the . (), a trade-off between contact rate β and virulence α, i.e. a relation that some of which I wish to quote here, together with some references to see for.

That is, natural selection would favor highly transmissibleincurablecommensalsor symbionts. In accord with the epidemiologic perspective implicit in the R0 equation, an understanding of the evolution of virulence in microparasites comes down to elucidating the relationship between the rate at which the microparasite is transmitted between hosts and the rate of parasite-mediated mortality in individual infected hosts.

If that relationship is positive, then some level of virulence may be favored. And, since the first statements of this new view of parasite-host coevolution 122627much of the research on the evolution of virulence has focused on the association between these two components of parasite fitness. Within a relatively short time after the release of highly virulent myxoma, the viruses recovered from the then decimated and sometimes more resistant wild rabbitpopulations were less virulent and had lower rates of disease-induced mortality on control laboratory rabbits than those initially released.

However, the extent to which myxoma virus from the wild became attenuated was substantially less than that which could be achieved experimentally This was interpreted as evidence for a positive coupling between the rates of infectious transmission and rates of virus-induced mortality, a trade-off between virulence and transmission. Highly virulent forms of the virus had a disadvantage because they killed the rabbits too quickly and thus reduced the time available for them to be picked up by the insect mosquito or flea vectors required for their infectious transmission.

Viruses that were too attenuated had a disadvantage because they generated fewer skin lesions and had lower densities of circulating virions, which presumably would reduce the rate at which they would be bitten by these insect vectors, the likelihood of biting vectors picking up myxoma, and the number of virions picked up at any given bite.

Thus, in contrast to conventional wisdom and in accord with the enlightened interpretation, natural selection could favor and maintain the virulence of microparasites.


The myxoma story is particularly compelling because the quantitative relationship between virulence and transmissibility inferred from the epidemiologic data and models was independently tested and demonstrated experimentally 30 The myxoma story remains the only one for the microparasites of eukaryotic hosts where the predictions about transmission and virulence made from an interpretation of epidemiologic observations were tested experimentally.

In some cases, these inferences are reasonably strong, e. The latter study is particularly convincing because it includes independent, experimental evidence of a positive correlation between the density of spores in infected hosts and the virulence and transmissibility of this protozoan parasite.

infectivity and virulence relationship quotes

However, increased virulence in a passage experiment is not sufficient evidence for that trade-off. I know of no experiments that demonstrate that the increase in virulence generated during a passage experiment is also reflected as increased—transmissibility, as is necessary for the trade-off interpretation.

infectivity and virulence relationship quotes

Indeed, it may well be that an increase in the case-mortality rate or a reduction in the LD50 of a microparasite will be reflected as a reduction in its natural transmissibility. For example, Ewald has postulated that the virulence of HIV observed in contemporary human populations, AIDS, is in large part due to evolution in this retrovirus responding to the increases in human-human transmission rate resulting from more promiscuous sexual behavior.

The relative contributions of transmission and virulence as measured by the time before the onset of AIDS to the fitness of HIV in the population of hosts depends on whether the disease is in an epidemic or endemic phase.

Moreover, as I consider later, there are other, very different, hypotheses for the evolution of the virulence of this retrovirus and other pathogenic microbes that do not require the necessarily positive association between infectious transmission and virulence upon which Ewald has based his arguments for the evolution and maintenance of virulence in microparasites. A corollary of the hypothesis of a positive trade-off between transmissibility and virulence is that if all else were equal, increases in the degree of vertical e.

There is compelling, experimental evidence to support this corollary. However, the evidence is restricted to experiments with E. Within-Host Population Dynamics and Virulence of Microparasites There is a dearth of experimental investigations of the quantitative relationship between the transmission and virulence of microparasites. In the simplest models developed in these theoretical studies of the within-host population dynamics of microparasites, the virulence of the microparasite, as measured by either the rate at which it kills its host or its LD50, is assumed to be directly proportional to its rate of proliferation in that host, and its rate of infectious transmission is directly proportional to its within-host density Under these conditions, in the absence of superinfection or mutation, selection favors microparasites with intermediate rates of within-host replication, i.

More complex situations, like the coexistence of microparasite lineages with different levels of virulence, result when virulence is proportional to the within-host growth rate of the parasite and single hosts can be infected with parasites of different growth rates 43 or when there are high rates of mutation to different levels of virulence within a host The Convergence of Theories The predictions that can be made on the basis of the current view of the evolution of virulence differ from predictions that might follow conventional wisdom because the new view allows for natural selection in the parasite population to favor the evolution and maintenance of some level of virulence.

If the density of the sensitive host population is regulated by the parasite, an extension of the enlightened theory predicts that natural selection in the microparasite population can lead to continuous declines in the level of virulence, possibly to immeasurable values During the epidemic phase of a microparasitic infection, when the host population is composed primarily of susceptible hosts, selection favors parasites with high transmission rates and thus high virulence.

As the epidemic spreads, the proportion of infected and immune hosts increases and the density of susceptible hosts declines. Selection now favors less virulent parasites that take longer to kill their host and, for that reason, are maintained in the host population for more extensive periods. Analogous arguments have been made for the latent period of a bacteriophage infection 47the evolution of lysogeny 48the tradeoff between vertical and horizontal transmission 4950and the advantages of microparasite latency in general Alternative Models for the Evolution of Microparasite Virulence For any microparasite, the rate of transmission between hosts will always be a significant component of fitness, and, if all else is equal, parasites transmitted at higher rates in the host population have a selective advantage over less transmissible forms.

Moreover, even when there is no relationship or a negative relationship between transmission and virulence, there are at least two ways by which natural selection can lead to the evolution and maintenance of virulence, coincidental evolution 24 and short-sighted within-host selection Coincidental Evolution According to the coincidental evolution hypothesis, parasite-mediated morbidity andmortality are what Gould and Lewontin 52 likened to the spandrels of gothic churches.

While these structural necessities may frame the frescos and paintings within, that is not the reason for their existence. They are architectural constraints.

infectivity and virulence relationship quotes

Analogously, the factors responsible for the virulence of a microparasite in an infected host may have evolved for some purpose other than to provide the parasite an advantage within a host or its transmission to other hosts. It would be difficult to account for the evolution of botulism toxin by selection favoring Clostridium botulinum that kill people who eat improperly canned food.

The same argument could be made for the toxins of C. Although these organisms may proliferate in humans, they are soil bacteria, and the effects of the toxin may not contribute to their capacity to colonize, proliferate, and be maintained in humans or to their capacity to be transmitted between human hosts. How many other microparasite-induced symptoms, and the resulting host morbidity and mortality, provide no advantage to that microbe in or on a host or its transmission between hosts?

Do the toxins confer an advantage on E. An earlier paper on this subject 24 argued that the adhesins produced by the E. The painful symptoms of urinary tract infections generated by an inflammatory response to these adhesins may confer no advantage for the E.

This certainly sounds reasonable for many virulence determinants, e. On the other hand, it is necessary to formally test this hypothesis that these symptoms have that effect and reject the alternative, that the morbidity and mortality generated by the expression of a specific virulence determinant provides neither a within- or between-host infectious transmission advantage to the parasite. Short-Sighted Evolution Natural selection is a local phenomenon.

Characters that confer a survival or replication advantage on the individual organisms that express them at a given time or in a given habitat will be favored and evolve at that time and in that habitat. Whether the expression of those temporally or locally favored characters will increase or reduce the fitness of that organism at other times or in other habitats is irrelevant.

Also irrelevant is whether a locally favored character makes the population better or less adapted to its environment at large or augments the likelihood of its survival in the future. This myopia is a fundamental premise of the theory of evolution by natural selection and the basis of theshort-sighted evolution hypothesis for microparasite virulence Within an infected vertebrate host, microparasite populations go through many replication cycles and may achieve very high densities.

They may also reside and proliferate in many different subhabitats tissues and cells and confront a variety of different and ever-changing constitutive and inducible host defenses which may, sequester, kill, or in other ways inhibit their proliferation. As a consequence of classic mutation, transposition, and recombination, genetic variability will be continually generated in the populations of infecting microbes.

This would occur even when the expression of the characters responsible for that local advantage reduces likelihood of the transmission to other hosts.

Stated another way, the morbidity or mortality caused by a microparasite infection could be the result of the within-host evolution that is short-sighted because that virulence actually reduces the rate at which that parasite is transmitted to other hosts.

Three examples of microparasite virulence that could be products of this mode of evolution can be considered For two of these examples, bacterial meningitis and poliomyelitis, many human hosts are infected by the responsible microparasites, primarily Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae for meningitis and poliovirus for poliomyelitis, but very few manifest the symptoms of these infections.

In the case of meningitis, the neurologically debilitating and sometimes fatal symptoms of the infection are a consequence of an inflammatory response against the bacteria entering and proliferating in the cerebral spinal fluid. These meningitis-causing bacteria normally reside in the nasopharyngeal passages and are transmitted by droplet infection.

The cerebrospinal fluid is, at least with respect to their infectious transmission, a dead end. On the other hand, bacteria capable of invading and proliferating in that habitat could have a local advantage as there are no other competing populations and only modest defenses. An analogous argument can be put forth for poliovirus. Symptomatic infections with this virus are caused by their invasion of, and proliferation in, the neurologic tissue of the central nervous system.

Poliovirus normally replicates in the mucosal cells of the mouth, throat, and intestines and is transmitted by the oral-fecal route. Poliovirus virions proliferating in the central nervous system would almost certainly not be transmitted. The evidence in support of short-sighted evolution for the virulence of these specific microparasites is mostly circumstantial On the other hand, short-sighted evolution for the virulence of specific microparasites is a hypothesis that can be tested.

If the hypothesis is valid, the microparasites responsible for the symptoms would be genetically different from their ancestors that infected the host and better adapted for proliferation in the site of the symptoms than the ancestors themselves.

The third example of short-sighted evolution of virulence considered, HIV, is different from the other two in that virtually every human infected with this retrovirus that does not die of other causes, eventually manifests and succumbs to AIDS.

However, although the case mortality of HIV infection may approach unity, as measured by the rate of mortality deaths per unit of timefrom an epidemiologic perspective, HIV is not a very virulent virus. There is substantial variation in the time between infection and the onset of AIDS.

On average in industrialized countries, the term of this infection is 8 to 10 years During the early phase of an HIV epidemic, most transmission of the virus occursduring the initial viremia, probably before seroconversion and certainly before the onset of AIDS 37 It is not at all clear how the transmissibility of HIV virions during this early phase of the infection is related to the time of onset of AIDS.

If this is the case and all else were equal, increasing opportunities for transmission during the epidemic phase would favor increases in HIV virulence 36 Researchers have found positive relationships between titre and virulence, or between transmission and virulence, in a variety of host—parasite systems, providing support for some of the posited relationships between virulence, load, and transmission Alizon et al.

Evidence of the evolvability of parasite load, a critical component of these two theories of virulence evolution, is even more rare. Although such evolvability has been supported by observational studies of myxomatosis in European rabbits Dwyer et al.

DMelSV has been studied for decades, since it was first identified in wild populations of D. The virus is often virulent, with deleterious effects on multiple components of host fitness, including increased development time Seecof, ; Fleuriet,decreased egg-to-adult viability Wayne et al. Maternal transmission is likely the major route of infection by DMelSV in natural populations.

Maternal transmission is more efficient than paternal transmission i. Moreover, offspring infected by sires rarely pass the virus onto the next generation Fleuriet, ; Wayne et al. Current data suggest that infected males enjoy higher reproductive success than uninfected males with uninfected females, and there is no indication that uninfected females are biased against infected males Fleuriet, ; Rittschof et al.

However, data on preferences of infected females are not available. In general, data for matings where both parents are infected are sparse.

For example, we do not know if there is any difference in transmission between offspring particularly sons infected by both parents, and offspring infected solely by dam or sire.

We subjected infected flies to artificial selection on carcass viral titre and tested for a correlated response in virulence. Lines from the maternal selection regime failed to respond after six generations, so we abandoned this regime but continued the biparental regime for five additional generations.

In generation 12, we assayed the biparentally selected lines for virulence and sequenced the genomes of the derived viruses. The resulting supernatant was kept on ice and used to inject healthy female D.

PCR analysis verified that this line is free of Wolbachia data not shown. For details of injection procedure, see Rittschof et al. Infection success was determined by exposing half the offspring of each injected female to CO2 for 5 min. A fly was scored as CO2 sensitive, and hence infected, if it failed to recuperate from CO2 knockdown.

Selection was used to increase transmission rates by setting up 10 full sibling pairs and testing half the offspring from each pair for CO2 sensitivity. The other half of the offspring from the pair with the highest transmission rate were used to set up the next generation, again using 10 single brother and sister pairs per line, following Rittschof et al.

2. Epidemiology: some basic concepts and definitions

Artificial selection protocol Two selection regimes were tested: We expect that maternal transmission is the major route of infection in natural populations, as noted above.

However, biparental transmission is interesting because it potentially allows for superinfection and thus different within-host dynamics from maternal transmission. Because infection with DMelSV confers CO2 sensitivity, all flies were anaesthetized by cold knockdown immersing vials in a slurry of water and ice, and manipulating anaesthetized flies on a frozen block.

The maternal regime involved collection of a virgin female fly from the selected vial, who was then paired with an uninfected male from an independently maintained, uninfected stock of line 27 i. The uninfected stock was maintained at a constant population size of five males and five females per generation throughout the experiment. For biparental transmission regime, one brother and non-virgin sister from the same vial were used as parents for the next generation.

At the onset of selection for both regimes, the offspring from the females with the highest and lowest viral titres out of a sample of 10 individuals per line were selected for the next generation.

These two females were used to start the high titre high treatment and the low titre low treatment selection lines, respectively.

After this first quantification round, the lines for the high and low treatments from the two selection regimes were propagated independently. RNA extraction and virus titre quantification were conducted simultaneously for both treatments.

The seven independently generated infected lines were used for both selection regimes biparental and maternal treatments, for both treatments high and low titre. Each subsequent generation began by setting up 10 pairs of flies using the first 10 females and males, for the biparental regime to eclose, each in its own vial of fresh food occasionally there were fewer flies and hence fewer vials; see Table S1 at evolutionary-ecology.

Because the QPCR assay requires sacrificing the females, the 10 pairs were allowed to lay eggs for 5 days prior to assay. The fixed laying time, with only a single pair of animals per vial, gave rise to similarly low densities across regimes and treatments; there were no obvious differences in fecundity for regime or treatment, though eggs were not counted at every generation. Following the laying period, the 10 females were sacrificed and assayed for virus titre.

For the low treatment in both selection regimes, the vial containing eggs laid by the female with the lowest titre was retained to give rise to the next generation and the other nine vials were discarded. The same procedure was followed for the high treatment, except that the vial for the female with the highest titre was retained.

After six generations of selection, we ended the maternal selection regime in part because of practical constraints virgin collection made this regime particularly laboriousand in part because we felt that the selection response was more consistent in the biparental regime. Selection for the biparental regime continued for 12 total generations, though one line from the low treatment was lost L at generation 4.

All lines had lost CO2 sensitivity by generation 4, the first generation it was assayed in after initiating selection G0. To create the control lines, one of the eight vials remaining from the original 10 measured at the onset of selection i. For each subsequent generation, the control line was propagated by setting up eight pairs of non-virgin flies in individual vials, allowing them to lay for 5 days, and then haphazardly selecting a single vial to give rise to the next generation.

All eight females were measured for viral titre at every generation. Each extraction product was then diluted to yield ng of total RNA per reverse transcription RT reaction. The forward primer matched the tag sequence from the RT primer [tag: By using the tag, we could count viral genomes, as opposed to replication intermediates. Absolute quantification was used, with a five-point fold serial dilution standard curve, ranging from to Initial concentration of the purified amplicon was estimated using a NanoDrop Spectrophotometer Thermo Scientific.

Selection was conducted using viral copy number estimated from the standard curve. However, because of the poor quality of the standard curve used at generation 8, the raw CT value was used to select flies for this generation only.