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Parasites and hosts remain locked in a continuous struggle for survival. The co-evolutionary interactions between the hosts and parasites influence both the host and parasite. Parasite pathogenesis and host defense act in a concert to shape the evolution of virulence. There are various theories on the evolution of virulence in parasite. Host mortality, host resistance, host recovery, mutation, co infection, super infection, host heterogeneity, and mode of transmission have been described for explaining the virulence in parasite. The evolution of parasite virulence focuses on the tradeoff between costs and benefits of the parasite from the host exploitation and appears to be satisfactory. The interaction between the hosts and parasites is multidimensional, dynamic and exceedingly complex. A number of factors perhaps act to shape the level of parasite virulence. Generally, virulence is not beneficial to most of the parasites. Virulence attains a maximum level due to the mutation which is induced by the changing environment. A thorough understanding of pathogenesis including a complete inventory of spatial and temporal expression of genes by both hosts and parasites, from the time of exposure to the final resolution of infection, would contribute a lot in our understanding of evolution of parasiteâs virulence.
The survival of the parasite depends on the conditions in which parasites grow and multiply1. Death of the host often limits the evolutionary success of the parasite. Successful microbes avoid extinction, multiply, and leave descendants 2. Myxoma virus cause a mild disease in the American rabbit .Simian Immunodeficiency Virus (SIV) does not cause immunodeficiency in its natural hosts 3.Many Orthomyxo-, Arena-, and Hantaviruses cause asymptomatic infection4. Some parasites are extremely virulent in the novel host. The virulence decline in course of time as observed in smallpox, measles, and influenza infections in Indian populations 2. In Australian populations of European rabbits 5, the initially introduced myxoma virus strain was lethal with case mortality of > 99 percent. In subsequent years, the virulence was declined .Later, rabbits developed resistance leading to the development of more virulent virus strains 6,7. Killing the host may be advantageous for parasites which are transmitted only from dead hosts 8. The Probability of producing virulent variants increases with host population size, and crowding and co-mingling of the different host species 9. The parasite-host relations naturally constitute a co-adaptive evolutionary dance along the pathogenecity threshold, which is likely to be crossed due to anthropogenic disturbances 10. With this summary of background of our understanding, the present communication aims to sum up the topic of parasitic virulence in the light of modern evolutionary research.
Virulence is the reduction in hostâs fitness due to parasite infection 11 which is proportional to reduction in the reproductive success of the infected host. This is not in the parasites interest to severely damage or kills its host as this affects the parasiteâs fitness. A weak host is the easier prey for parasites than a strong one. Evolution leads to an increase or decrease in virulence, depending on the circumstances 12.Virulence is indicated by the mortality of the infected hosts, the average life-span of infected hosts, and the lethal dose50, LD50. In avirulent parasite, the infected host does not die. Evolutionary change of parasite occurs due to change in micro-environment provided by the host. Parasites with more opportunities for vertical transmission and reduced opportunities for horizontal transmission often become less virulent 13. The zoonotic transfer of a parasite from one host species to another may be highly virulent in the new host, as observed in 1918 influenza pandemic. Severe virulence kills the host before the parasiteâs transmission to new hosts. Less virulent parasite increases over time14.Â
 The evolution of parasite virulence is   based on a trade-off between the advantage of within-host replication and the disadvantage of such replication on host survival 15,16. Hypotheses on parasite virulence are the conventional wisdom, adaptive theory, and non-adaptive theory. Changes in transmission rate lead to changes in virulence suggesting the existence of underlying trade-off. Strong inhibition of host immunity by the parasite reduces the parasite clearance rate from the host, increase the hostâs death rate and in such case the parasite tend to be relatively more virulent. As the parasite gains the immediate benefit of escaping before the subsequent consequences of immune manipulation 17, immuno-modulatory or escape mechanisms may be favoured in spite of their virulence. Some progress on mechanistic coupling between transmission and virulence has been made 18. For example, transmission may occur through spores after hostâs death. Autographa californica, a nucleopolyhedro virus attacks caterpillars. After ingestion, the virus invades the midgut cells 19, replicates and spreads until more than 1010 polyhedra fill the host. Ultimately, the virus produces chitinase and cathepsin that together breakdown the host cuticle. The host liquefies at death; release the viruses which are taken up by other hosts. Many terminally killing pathogens have similar life histories20. In mammals; anthrax (Bacilus anthracis) is a case of mechanistic coupling 21. In the late infection, bacterial density in the host grows to high levels and the high concentration of anthrax lethal toxin knocks out the immune system by destroying the macrophages. Anthrax oedema toxin causes the production of a high amount of cAMP in host cells, which disrupts the flow of ions and cellular functions leading to host death. Transmission occurs primarily by spores which are released after the death of the host.  B. cereus , although closely related to B. anthracis   does not cause severe virulence 22 .B. cereus transmits through oral-faecal route, colonizes the intestine, and causes diarrhoea 23.From an evolutionary perspective, mechanistic coupling between transmission and extreme virulence strongly shapes the life history of parasites 18. In the first major transmission episode parasite grows to maximum density and maximize the opportunities for successful transmission, consequently severely damages the host, and the chance of subsequent transmission rate is low.
Reproductive success of a parasite is sometimes calculated by the number of newly infected hosts. A long period of infection is beneficial to the parasite. A shorter infection period may be advantageous, if compensated by an increase in the infection rate to new hosts. This trade-off between the infection rate and the duration of infection determine the optimal parasite infectivity and duration of infection. A shorter infection period is associated with high virulence of the parasite.   Parasite evolution with this trade-off is the backbone of the adaptive theory. Anderson and May 15 proposed a theoretical framework for the evolution of parasites.
An increase in the parasite-independent host mortality rate should lead to selection of parasites that kill their hosts rapidly and are more virulent 18. Shorter life-span of the host often leads to a shorter infection period that in turn selects for rapidly replicating parasite.  A long host life-span leads to selection of slower replicating parasites with low virulence. These predictions have been tested with variable success 24.  In multiple infections , high virulence is evolve at low natural host mortality rate 25 as the long duration of infection increases the probability of an already infected host to be super-infected with a more virulent parasite strain forcing the existing  parasites to become more virulent. Reduction in the mortality of transmission stages allows parasites to compensate for increased virulence and maintain infections in population previously too small to sustain them. Importantly, increase in the size of host population usually leads to increase in the incidence of parasite population26.
In plants and invertebrates, host resistance is often defined as inability of the parasite to infect the host 27. In vertebrates, host resistance is often the host ability to mount an effective immune response to clear the infection. An increase in the recovery rate should select for more virulent parasites28 as a higher recovery rate leads to a shorter duration of infection forcing parasites to evolve higher growth rate and virulence. Increased host resistance may select for high or low virulence depending on mechanisms of resistance 29. Imperfect vaccines increase host resistance and allow replication and transmission of parasites leading to evolution of parasites with low or high virulence depending on the vaccine 30
In epidemic infections the number of susceptible hosts is large and parasite strains infecting the hosts rapidly gain selective advantage 31. In endemic diseases there is always dearth of susceptible hosts, so parasites infecting the maximum number of hosts will have selective advantage. Thus, in endemic infections parasites maximize their basic reproductive number in case of directly transmitted diseases. Higher host densities and high rates of parasite transmission cause outbreaks of highly virulent parasites including influenza, cholera and HIV 32,33. Host immunodeficiency due to HIV infection may result from the within host, short-sighted evolution of the virus and may have nothing to do with the rate of virus transmission34. Duration of HIV infection is inversely correlated with the virus density in plasma of infected hosts early in the asymptomatic period of the infection 35. Viral load is positively correlated with the probability of heterosexual transmission of HIV 36. Such relationships indicate a positive correlation between HIV transmissibility and virulence for viral strains with different set points.
Adaptive theory assumes that only one parasite strain can occupy a given host. For example, Daphnia magna can be repeatedly infected with the same microsporidian parasite 37. Humans infected with malaria often harbor several different strains of the parasite 38. Theoretical results suggest that competition between different parasite stains within one host select for increased virulence because of the risk to share the host with a more virulent parasite strain. The increase in the number of parasite strains occupying the same host may result from mutation 39 and co- or super infection 40. Mixed-clone infections of mice with malaria parasite Plasmodium chabaudi result in higher maximum weight loss of the host 38 that correlates well with other measures of virulence in this experimental system 41. Some observations of malaria infection in humans or trypanosome infection of bumblebee suggest that single infections may be as virulent as mixed infections 38.During an acute infection, the probability of super infecting an already infected host is very low because of the short duration of infection. Because of the short duration of infection, mutations are not likely to generate high diversity in the parasite population during the infection unless the mutation rate is extremely high. The presence of different parasite strains in the initial inoculums is the most likely mechanism by which multiple infections may occur in acute infections. During chronic infections co-, super infection and mutation may lead to increased parasite diversity in infected hosts. 38.
Adaptive theory assumes that parasites evolve in populations of identical hosts. Higher levels of host heterogeneity would select for less virulent parasites .Spread of infections in host populations with low genetic diversity often results in high host moralities42. Many parasites when serially pass in new genetically identical hosts evolve to increase their virulence. In accord with this increase, virulence generally decreases when it is measured in the original host. An increase in virulence of serially pass parasites may be simply due to strong selection for more rapid growth and not due to low genetic diversity of hosts 43. Parasites causing acute infections in vertebrates evolve in the hosts that stochastically differ in their susceptibility to infection or their quality of the immune response. In the absence of heterogeneity parasites evolve to an intermediate growth rate but kill no host due to a high loss in total transmission when the parasite kills the host. When the level of host heterogeneity increases, the optimal level of virulence increases This is because in order to obtain the maximum total transmission, the parasite has to compromise between killing âsusceptibleâ hosts and obtaining high transmission from âresistantâ hosts 44. Thus, the analysis suggests that higher levels of stochastic heterogeneity should select for higher optimal level of parasite virulence.
Since host mobility is not required and may be even deleterious for the transmission of vector-borne parasites, such parasites should on average be more virulent than parasites that are transmitted directly and that require host mobility for transmission 45. Similar arguments are applied to water-borne infections causing diarrhea because they can spread from immobilized hosts 46. Assuming a positive correlation between parasite transmissibility and virulence for directly transmitted and water-borne parasites, Ewald and De Leo 47 have found that parasites that can be transmitted directly through contact and indirectly through environment evolve higher virulence than parasites transmitted exclusively directly. Since indirect transmission is not affected by the immobilization, there is no decrease in transmission rate with increasing virulence 47. Ewald has suggested that high longevity of parasites in the environment should select for high virulence, because longer survival in the environment relaxes the parasite need for host and for transmission 33. Parasite longevity does not affect the optimal level of parasite virulence for endemic infections transmitted exclusively indirectly 48. Assuming that there is no trade-off between the parasite longevity in the environment and its virulence, the authors found that parasite longevity affects only the R0 of the infection but not optimal virulence.  However, results suggest that it is very difficult to make any general predictions on whether there is any relationship between the route of transmission and optimal virulence unless specific details of the infection are known. In contrast with parasites, transmitted horizontally, it has been argued that vertically transmitted parasites should be less virulent because in this case transmission of the parasite is linked to the survival of the host 48. Bull and coworkers in a series of elegant experiments have shown that increasing opportunities for horizontal transmission of a bacteriophage lead to selection of more virulent viral stains 13. Finally, a comparative study suggests that vertically transmitted lice are less virulent than horizontally transmitted mites while infecting the same host species, rock doves Columba livia 50While exclusively vertically transmitted parasites should evolve low virulence, even small rates of horizontal transmission may be sufficient for maintenance of highly virulent parasites that are transmitted vertically with high efficiency51., parasites experiencing severe bottlenecks during vertical transmission, may evolve lower virulence because of the reduced strength of intra-host competition 52. Thus the amount of vertical transmission may indicate of how virulent a parasite is but it needs not be the general rule.Limited parasite dispersal favours lower parasite growth rates and, hence, reduced virulence because it decreases the direct benefit of producing offspring, and increases the competition for hosts experienced by both the focal individual and their relatives. This demonstrates that reduced virulence can be understood as an individual level adaptation by the parasite to maximize its inclusive fitness, and clarifies the links with virulence theory more generally 14
Simple theory assumes that parasites evolve much faster than their hosts, but this may not be entirely correct since many host species may increase the rate of their evolution by reproducing sexually 42. Clearly in the presence of parasites, hosts evolve to become more resistant to the infection and this in turn may affect parasite virulence. One good example is the co-evolution of the myxoma virus and rabbits in Australia, where as hostâs evolved high levels of resistance, the virus evolved higher virulence 5. Parasites may evolve to high or low virulence depending on particular properties of transmission and host connectivity 53.
In many cases, parasite virulence is not related to parasiteâs fitness and therefore should be considered as nonadaptive. In some cases, this is because such parasites infect hosts that are not normally transmitting the parasite to other hosts 2. Such accidental infection or âspill-oversâ may sometimes be lethal to the host, although many harmless infections most likely occur unnoticed 43. Infections of this type include soil bacteria Clostridium tetani causing tetanus, and bacteria Clostridium botulinum causing botulism. Both parasites cause disease in humans by accident and toxin production by these bacteria most likely has evolved due to other reasons than to kill humans54. Similarly, hantaviruses, Niphavirus, and rabies may cause serious diseases but yet for neither of the infections there is detectable human to human transmission of the parasite 4.It is possible, that such spill-overs may with time evolve to begin spreading from human to human without the requirement for the original hosts 55. In that case, virulence of such an infection may evolve but how it will evolve would depend on many biological details of the within-host dynamics and epidemiological spread of the parasite. Levin and Bull 34 have suggested that virulence of such infections may be a result of the short-sighted, within-host parasite evolution. Ebert42 argues that within-host evolution of highly virulent parasite strains may be the direct cost of having high mutation rate required, for example, for evasion of the immune response. HIV persists for long periods of time in a given host and during that time it is faced with a constant pressure from the immune system. High mutation rate might be one way of avoiding the recognition by the immune response 56. A high mutation rate may have a cost of generating mutants that are able to end the infection by killing the host 57. An increase in the mutation rate of such parasites should lead to an increased probability of disease occurrence and to an increased total transmission from hosts that have not developed the disease. Decrease of the mutation rate should reduce the total transmission of parasites. Alternative explanation for the N. meningitidis virulence has been suggested in a recent study by Ancel Mayers et al.58. In summary, regardless of forces driving evolution of such parasites, within-host evolution may be an important factor affecting virulence of parasites which, when looked from a between-host viewpoint, may appear to be nonadaptive.
Parasites have short lives and populations in comparisons to hosts. Parasites are probably going to adapt to most prevalent gene complexes of their host, which means that there is, in general, a selective advantage to rare alleles and recombination. This principle states that since every improvement in one species will lead to a selective advantage for that species variation normally continuously lead to increase in fitness, in one species, or another. Since in general different species are co-evolving, improvement in one species implies that it will get a competitive advantage on other species and thus, be able to capture a larger share of resources available to all. This means that fitness increase in one evolutionary system will tend to lead to fitness decrease in another system 12.Evolution of virulence should be viewed from broad biological, epidemiological and clinical perspectives. Man made changes in the environment which facilitates zoonotic transfer of parasites should be urgently addressed.
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