Select Committee on Science and Technology Written Evidence

Memorandum by Edward Purssell, Florence Nightingale School of Nursing and midwifery



  1.1  The consideration of infectious diseases usually involves looking at the incidence or prevalence of a disease, or aspects such as inability to treat because of resistance or other traits. Problems associated with increased travel, changes in climate etc. are well documented in Getting Ahead of the Curve. This very brief paper suggests that the Committee should investigate the effect that modern lifestyles and medical practices are having upon the virulence of human pathogens.

  1.2  Virulence refers to the detrimental effect of parasite exploitation on the host, which may result in morbidity or mortality. It can occur as the result of the effects of the pathogen on an individual, that is killing or damaging the host (for example by preventing mobility or reproduction), or because of the speed at which the pathogen spreads through the population even if the effects on the individual are less severe (Sigmund et al 2002).

  1.3  Within the biological and medical press there is an increasing awareness of the need to consider virulence, and the effect that humans are having upon the evolution of virulence of both pathogenic, and previously non-pathogenic organisms, and what we might do in the future to manage virulence.


  2.1  There are two main evolutionary theories of what makes a successful parasite:

    1.  Parasties which do least harm to their host are best adapted and will be most successful because in doing little harm, they ensure both their hosts, and their own, survival.

    2.  That evolution will result in an intermediate level of harm to the host, because of a trade-off between the need to reproduce (which requires host exploitation), and the effect that this has on host mortality and transmission (Lenski and May 1994).

          For many years it was the former theory that had been accepted as the conventional wisdom (Lenski and May 1994), leading many to assume that most pathogens would eventually evolve towards a virulence as they aim to ensure their hosts, and consequently their own survival. Virulence was therefore seen as the result of a poorly adapted parasite.

  2.2  However, this view does not take account of the fact that for the pathogen, the human host is only of any concern in as much as it is a source of nourishment and a method of growing and transmitting to a new host. For a microorganism, the aim is to maximise its evolutionary fitness, which has been defined as "the individual's success at passing on its genes to future generations through its survival and reproduction" (Ewald 1994 p9). There are a number of circumstances under which it is not at all clear that evolutionary fitness requires avirulence, indeed it is becoming increasingly clear that virulence may, in some situations, be beneficial. Some of these are discussed below.


  3.1  The most important thing that any living organism, including microorganisms, can do is to ensure the survival of their species. In the case of the pathogenic organisms being considered here, this involves transmission from an existing to a new host. If this can be done, it is then of little concern to the microorganism what happens to the original host. Evolution would therefore be expected to favour any trait that increases the likelihood of transmission of the organism from one host to another, whatever the effect of this on the original host.

  3.2  For example, in the case of HIV the likelihood of the virus passing from one person to another is increased by a high viral load (Quinn et al 2000), which occurs during the initial infection and when the person has AIDS. As viral replication is directly linked to immune damage, this link between virulence and transmission means that evolution is likely to ensure that HIV remains a highly pathogenic virus. Of course the period when a person has AIDS is characterised by illness which may reduce the likelihood of sexual transmission (although not necessarily other forms of transmission), but this may be a sufficient trade-off if transmission has been able to occur during previous periods of viraemia.

  3.3  Other pathogens are able to transmit either despite, or because of, increased virulence because their mode of transmission does not require host mobility; in other words, it is of no cost to the pathogen that it is causing severe disease in the host. Such transmission methods include waterborne transmission, vectors (both animal and human), and pathogens that are durable in the environment (Ewald and DeLeo 2002). In each case the method of spread of the microorganism removes the cost of virulence.

  3.4  In some cases extreme virulence actually aids transmission if, for example, it makes the person too ill to defend themselves from insect or other vectors (Ewald et al 1998). Although relatively fortunate in this country that we have few diseases that are truly vector borne, there are situations in which people or inanimate objects can become pseudo-vectors. This might be particularly significant in hospitals where staff can act as vectors for the transfer of pathogens from host to host. Some organisms, such as the spore forming Clostridium difficile and Mycobacterium tuberculosis, commonly found in hospitals are also durable in the environment, which again reduces the cost of increased virulence if this results in widespread shedding of the organism.


  4.1  In natural populations, the density of hosts is important for the spread of any infectious disease. If population density is high, transmission is more likely, but crucially it means that transmission is probable even if the parasite is virulent and causes severe disease or even death in the host, simply because of the availability of new hosts. Under normal conditions there would be a feedback mechanism in place which is that increased virulence would reduce the population density of susceptible hosts, either because susceptible hosts recover and become immune or because of death, this acting as a check against ever increasing virulence (Lenski and May 1994). In hospitals this is not the case, as population density is maintained by very high patient turnover bringing a plentiful supply of new hosts who may be susceptible either because they have no previous exposure to the organism concerned, or because disease or treatment has made them susceptible.


  5.1  Not all virulence can be traced to increased transmission or other obvious benefit. For a number of organisms, the death of a host is effectively a "dead end". This may be "accidental" virulence, for example a major virulence factor of Neisseria meningitidis is the polysaccharide capsule which may increase transmission, and also allow it to evade the immune system and so cause invasive disease. Although the capsule may increase transmission, the bacteria gains no particular fitness benefit from causing invasive disease (Taha et al 2002).

  5.2  Although there may be no fitness benefit from virulence, it may also not necessarily be a negative selective force even in the absence of a link with transmission. A recent study has shown that invasive Staphylococcus aureus infections are more likely to be caused by a relatively limited group of longstanding clones, and that as these clones diversify genetically invasive disease becomes less common. Interestingly, as invasive staphylococcal disease does not increase transmission of the bacteria, this suggests that virulence without the compensation of increased transmission is not necessarily costly for the bacteria (Day et al 2001). Virulence management in such situations may be more complicated than previous examples because this virulence appears to be almost accidental but not costly.


  6.1  The presence of multiple infections may also act to increase virulence because different organisms or clones of the same organism are competing for the resources of the host. In this case they are not only competing for host resources and with the host immune system, but also against each other. This battle between different clones or organisms, known as individual selection, is a much more powerful form of evolution than the group selection that assumes an almost consensual approach to evolution (Lenski and May 1994), as any long-term movement towards avirulence in one organism is pointless if another out-competes the more benign variant (Ewald and DeLeo 2002).

  6.2  Such a situation is referred to as within host competition, and a number of mathematical models suggest that this selects for increased virulence (Gandon and Michalakis 2002). Such a situation may occur in multiple infections, where different pathogens compete for the resources of the host. However, in practice the dynamics of this are more complicated because all humans are constantly exposed to the possibility of multiple infections. Additionally it is not clear how the dynamics of multiple infection applies in vivo.


  7.1  Traditionally we have sought to treat and minimise symptoms of disease. However, it is becoming apparent that a greater understanding of the significance of symptoms in transmission and the evolution of virulence are required if rational decisions are to be made about their treatment.

  7.2  There are a number of conditions where the symptoms of an infection are linked to transmission, for example diarrhoeal diseases, many of which are spread most easily if the host has severe diarrhoea. Another example is respiratory pathogens, which are spread more easily if the host has symptoms such as a cough or sneezes (Johnson 1986).

  7.3  In contrast to this, there are many other conditions where symptoms probably either impede transmission or have a negligible effect (Johnson 1986). The symptoms that we see as the result of an infectious disease may therefore be of benefit to the parasite, that is a manipulation of the host to increase the chance of the organism being transmitted to a new host. Alternatively it may be a host defence mechanism, or a pure side-effect, of benefit to neither host nor pathogen (Ewald 1980).

  7.4  Because of the link between some symptoms and transmission, it might be tempting to suggest that these symptoms (such as diarrhoea) should be suppressed. However, it should be remembered that diarrhoea may also be important to the host in removing toxins or pathogenic organisms from the gastrointestinal tract, while coughing may help in the removal of pathogens and secretions from the lungs.

  7.5  Greater understanding of the evolutionary significance of various symptoms may be helpful in reducing infectious disease because it would be of help in deciding which symptoms should be treated. In practice this means establishing the importance of the role of the symptom in transmission, and how this might equate with host defences. What does appear clear, however, is that in making a person feel ill, the symptoms are giving a message to the person concerned. This is that they should avoid contact with others who may be susceptible, a message that is often lost in the pressure for people to work, study and travel at all costs. The Committee might like to consider the part that employers and others can take in reinforcing this message.


  8.1  Although the concentration so far has been on parasite dynamics, it is important that host factors are not forgotten. Host genotypes are also important, as not everyone within a population will suffer equally from the same parasite. This is because genetic recombination within sexually reproducing organisms such as humans results in genetically unique individuals, not all of whom are equally susceptible to a given parasite. In particular, parasites have to adapt to, and overcome, the host immune system. One particular problem that we face is the increase in those persons who are imunosuppresssed either because of disease (such as AIDS), or treatment (for autoimmune, malignant and other diseases).

  8.2  Even for those who are not immunosuppressed, many modern practices, which are beyond the scope of this evidence, lead to alterations in host factors, some of which are discussed in Getting Ahead of the Curve. I believe the Committee would be wise to consider in detail how our actions and medical interventions may alter our relationship with potential and actual pathogens. For example, what is the future regarding vaccination, and can this be applied to an ever increasing number of organisms, or is there a maximum that is practicable and acceptable to the public? How can we improve our general health? What effect might genetic manipulation of plants, animals, and humans have upon the genetic diversity upon which we depend?


  9.1  The above points lead to the question of whether it is possible to manage virulence? Some evolutionary biologists think that this is the case, and that, for example, by managing transmission less virulent organisms might be favoured because the cost of damaging the host may now exceed the benefits of host exploitation.

  9.2  One example of virulence management that has been discussed in the literature in some detail is that of diarrhoeal disease. Here it is suggested that virulence management by reducing waterborne spread might be effective if there is sufficient genetic variation to allow selection between strains in a reasonable time frame (Ewald 2002). Although waterborne disease is not a big problem in the United Kingdom, it is one of the easier to investigate. Additionally it is a major problem in many parts of the world, and the principles that we could learn from investigating this may be of use in other areas of virulence management. For example, if transmission were to be positively correlated to virulence, and reducing one led to a reduction in the other, this could be helpful in the control of other problems such as antibiotic resistance as there would be fewer serious infections requiring treatment, and those that there were would be with less pathogenic organisms.


  10.1  When constructing a research policy into infectious diseases, it is important that virulence is considered. Because of the increase in the prevalence of antibiotic resistance other methods of controlling infectious diseases must be found. Virulence management, if it were to be possible might be one method of doing this. However, although there is much theoretical literature on the subject, research is limited on how it might be applied in practice. This is partly because virulence management is a young discipline, and some of the research techniques are difficult and rely on good animal models. Nonetheless observational, experimental and comparative methods of research have been suggested (Ebert 1999).

  10.2  The Committee might give some consideration to the investigation of virulence management, and how the different disciplines within and beyond the health service might be bought together. Virulence management has, in some areas, united biologists, doctors and epidemiologists. Much of the literature remains highly theoretical and somewhat speculative however, and more practical research might be of benefit.


  Day N P J, Moore C E, Enright M C, Berendt A R, Maynard Smith J, Murphy M F, Peacock S J, Spratt B G, Feil E J (2001) A link between virulence and ecological abundance in natural populations of Staphylococcus aureus. Science 292 114-116

  Ebert D (1999) The evolution and expression of virulence. In: Stearns S C : (Ed.) Evolution in health and disease. Oxford University Press, Oxford pp.161-172

  Ewald P W (1980) Evolutionary biology and the treatment of signs and symptoms of infectious disease. Journal of Theoretical Biology 86 169-176

  Ewald P W (1994) Evolution of infectious disease. Oxford, Oxford University Press

  Ewald P W (2002) Virulence management in humans. In: Dieckmann U, Metz JAJ, Sabelis M W, Sigmund K (Eds.) Adaptive dynamics of infectious diseases: in pursuit of virulence management. Cambridge, Cambridge University Press pp.399-412

  Ewald PW, DeLeo G (2002) Alternative transmission models and the evolution of virulence. In: Dieckmann U, Metz J A J, Sabelis M W, Sigmund K (Eds.) Adaptive dynamics of infectious diseases: in pursuit of virulence management. Cambridge, Cambridge University Press pp.10-25

  Ewald P W, Sussman J B, Dister M T, Libel C, Chammas W P, Dirita V J, Salles C A, Vicente A C, Heitmann I, Cabello F (1998) Evolutionary control of infectious diseases: prospects for vectorborne and waterborne pathogens. Mem Inst Oswaldo Cruz. 93 (5) 567-576

  Gandon S, Michalakis Y (2002) Multiple infection and its consequence for virulence management. In: Dieckmann U, Metz J A J, Sabelis M W, Sigmund K (Eds.) Adaptive dynamics of infectious diseases: in pursuit of virulence management. Cambridge, Cambridge University Press pp.150-164

  Johnson R B (1986) Human disease and the evolution of pathogen virulence. Journal of Theoretical Biology 122 19-24

  Lenski R E, May R M (1994) The evolution of virulence in parasites and pathogens: reconciliation between two competing hypotheses. Journal of Theoretical Biology 169 253-265

  Quinn T C, Wawer M J, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, Meehan M O, Lutalo T, Gray R H (2000) Viral Load and Heterosexual Transmission of Human Immunodeficiency Virus Type 1. New England Journal of Medicine 342 921-929

  Sigmund K, Sabelis M W, Dieckmann U, Metz J A J (2002) Introduction. In: Dieckmann U, Metz J A J, Sabelis M W, Sigmund K (Eds.) Adaptive dynamics of infectious diseases: in pursuit of virulence management. Cambridge, Cambridge University Press pp.1-9

  Taha M, Deghmane A, Antignac A, Zarantonelli M L, Larribe M, Alonso J (2002) The duality of virulence and transmissibility in Neisseria Meningitidis. Trends in Microbiology 10 376-382

October 2002

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