Virulence

Virulence • • • • • • • • • • • • • • • • • • • • • • • • Darwin and his Victorian contemporaries came to view nature as a battleground Tennyson called it “nature red, in tooth and claw” Darwin himself lamented what his theory revealed, the “dreadful but quiet war of organic beings going on in peaceful woods and smiling fields” Reality of the natural world is a little less gloomy… Most organisms eventually coevolve to adjust to one another Cooperation and coexistence often prevail in natural competition So why do so many infectious diseases, like cholera or malaria, continue to be so virulent, so powerful? Why have we never reached an evolutionary truce with our worst microbial foes? Why are some diseases so highly infectious and dangerous, while others seem to become scarcer and milder over time? That‟s what happened to syphilis… Used to be a raging destroyer of nations, now (relatively speaking) it‟s pretty wimpy It‟s hard for us to imagine how dreadful this disease must have been when it first emerged It was extremely rare in Europe before ~ 1500, may even have originated in the New World First major epidemic was 1495, in Naples Victorious army of Charles VIII of France carried it into Naples Came to be called the “French disease” or “Neapolitan disease” Unbelievably savage disease, it covered the body from head to knees in horrible open pustules Skin so badly damaged it would fall off in pieces Victims were so horrendous that even the lepers avoided them!! Those few who survived took several years to recover, and were horribly scarred Within 50 years of this dramatic emergence, it was already evolving toward a more benign form, in which we know it today Whatever happened to scarlet fever? Characteristic rash that appears first, rapidly spreads all over the body Followed sore throat, headache, fever, tummy pains, vomiting, • • • • • • • • • • • • • • • • • • • • • Caused by streptococcus A strain Used to be a major child killer! Most common in children between 5-15 yrs. Chicago, 1877- 819 deaths per 100,000 Death rate started to drop in the late 19th Century, no deaths since 1960 Most common in schoolchildren, when it occurs at all, but now so mild it is known as “scarletina” My sister had it when she was little! Bubonic plague is another historic killer that now seems to have faded into the background Disease is still around, endemic in the US Southwest! Several cases of plague reported every year, but it never spreads very far Part of the explanation for the ebbing of the plague may lie in its vector, the rat flea Rats are scarcer that they used to be, even in poor countries Rats originally came to Europe from the Orient… Rats first appeared in European cities around 400-1100 AD Rattus rattus, black house rat or ship rat was the first Followed by hordes of brown rats, Rattus norvegicus, the Norway rat (misnomer, really an Asian species) Norway rats are highly competitive, displace all other rat species They are known to carry a wide variety of nasty surprises, like the plague, typhus, trichinella, a type of jaundice, even a form of equine flu… Rat populations built up to frightening levels after their successful invasion Mass seasonal migrations through cities and countryside were common, blankets of rats covering the streets and meadows Helped spread the plague rapidly over a wide area • • • • • • • • • • • • • • • • • • • • • • • • • • Modern rat populations are much smaller, even in poor nations Much more “domesticated”, tend to stay in a house or neighborhood, less likely to spread out Disease never builds up to a dangerous level in the broader rodent population Some diseases come out of nowhere, ravage the world, and disappear forever, as mysteriously as they arose Take the case of the “English sweats”… English sweating sickness was unknown prior to 1485 Appeared after the Battle of Bosworth, when King Henry VII won the English throne Victorious troops fell ill, carried the disease throughout England when they dispersed Disease started with chills, tremors, led to fever, headaches, chest pains, rash, very profuse sweating Death often came within a few hours of the first symptoms, most died within a day!! Those who survived it did not get immunity - could catch it over and over again Many towns in England lost 1/2 to 2/3d‟s of their population Reached Calais, but never spread beyond into Europe Second outbreak began in London in 1529 Even worse than the first, total disruption of society, agriculture, led to famine This time it crossed the Channel… Deaths in Gottingen were so high, and gravediggers so scarce, victims were buried 5-8 to a grave Fifth and final outbreak started in Shrewsbury in 1551, burnt itself out overseas By 1552 it had vanished, never reappeared What was this mysterious malady? We haven‟t a clue… Perhaps it was a mutant so virulent that it literally ate its way through the world then went extinct after exhausting its sole prey Diseases ebb and flow for many reasons But there are larger patterns that we can tease from the history of epidemic diseases Patterns reveal some basic evolutionary strategies of pathogens and their hosts After years of teaching about peaceful coexistence in nature, I feel I‟ve been lulled into a false • • • • • • • • • • • • • • • • • • • sense of security Bacteria demonstrate that sometimes the evolutionary arms race can get downright ugly! A successful organism should achieve a balance over time with its competitors and predators or prey And this is often what we find Remember the lynx and the hare? These two species of mites, one herbivorous, the other preying upon it, show the same fragile balance In the wild, the herbivorous mite can often escape when finally cornered by the predatory mite It spins a slender thread of silk and uses it to balloon away to safety However, when it is prevented from escaping, it is rapidly eaten up by the predator, which then starves to death So a new species of bacteria might be extremely deadly But this should not work for a long-term evolutionary strategy There might be such a thing as too virulent… Virulence - disease that causes especially severe symptoms, and a high mortality rate, measured by % fatalities among victims A virulent organism like plague or smallpox in their heyday would roar through a population like a runaway freight train Few survived… It stands to reason that any organism that punches its own lunch ticket prematurely will not last long So shouldn‟t evolution put a premium on pathogens evolving into a benign strain, that can spread itself indefinitely?? Over time, pathogens should evolve to become more benign And with many diseases, like syphilis and scarlet fever, that is exactly what we see More benign pathogens are a double blessing for humanity > Require fewer or no antibiotics > Evolution of resistant strains is OK, if they no longer do any serious damage • • • • • • • • How can we force pathogens to relent? As we will see, it is in the matter of virulence that Darwinian medicine has met with greatest success From the bacterial standpoint, we‟re like one great big refrigerator, stuffed full of food Whoever is best at raiding the fridge without getting caught will win the battle for survival Even if it means the death of the host… Exploiting the host to the point of death might even be in the bacterium‟s best interests Might give that species competitive superiority over another, if it is more effective at converting host tissue into bacterium babies before the host expires From the standpoint of microbes, we are > A lunch ticket > A baby factory > A baby dispersal system Microbes evolved to feed upon us, and to disperse themselves over a wide area to continue feeding on others Natural selection will always favor the microbe that does this most efficiently The key to rapid dispersal might be high virulence Severe symptoms may quickly kill the host, but they effectively broadcast the pathogen far and wide As long as you succeed in getting into a handful of new victims, your species will survive If the host dies in the process, tough break…for the host! We can consider the evolution of virulence from two perspectives > Selection within hosts > Selection between hosts Each form of selection has a very different outcome Within-host selection is tough for us to consider After all, we ARE the host, hard to be objective! Bacteria are fighting other species of bacteria (and fungi etc.) for the privilege of eating us!! Within-host selection, therefore, is a no-holds barred Texas Death Match! Over time, the pathogens‟s productivity will increase, at the expense of the host‟s tissues and • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • resources Pathogen will rapidly kill the host In the case of malaria, knocking your host off his feet is a very good idea The semi-comatose victim of malaria is ill-prepared to wave off the swarms of mosquitoes eager to feed on him Like a mosquito country picnic…. One important evolutionary consideration in understanding the evolution of pathogens is how a pathogen is dispersed If dispersal requires physical contact, a mobile sick person is ideal If dispersal doesn‟t depend on mobility, it‟s OK to knock „em dead! On the other hand, if selection is acting between hosts, then long-term survival of the host is beneficial for the pathogen Here the strategy is to move slowly from host to host over a long period of time Such pathogens cannot be highly virulent This implies that, from an evolutionary viewpoint, vector-borne diseases should be much more virulent than diseases that rely solely on physical contact As Paul Ewald has demonstrated, that is exactly what happens Diseases that are spread by contact often evolve to become much less virulent Diseases relying on vector transmission can evolve and maintain a high level of virulence Two basic strategies of pathogen dispersal have evolved > Direct transmission > Vector transmission Both have evolutionary advantages and disadvantages Direct transmission does not rely on intermediate hosts, their fate is unimportant Direct transmission does not expose the microbe to additional risks, like getting from the vector to the host and back again Direct transmission benefits directly from dense human populations • • • • • • • • • • • • • • • • • • • • • • • • Vector transmission faces additional risks in vector/host and host/vector journeys Vector transmission relies on intermediate hosts, greater long-term risk (more links in chain) So why does this strategy work so well? Big advantage of vector diseases is that as long as vector population is stable or expanding, the pathogen will do well Human hosts are useful, but not essential Disease can be highly virulent and still succeed, OK to immobilize or kill the host Ewald has shown that vector-borne diseases are significantly more virulent than those relying on direct transmission Pathogens carried by arthropods evolve higher virulence, because the host can be immobilized and the vector can still spread the disease In some cases, a vector is not needed to spread pathogens from immobilized hosts Ewald reviewed a number of different species of bacteria that are spread through water Such diseases rely on fluids like diarrhea to enter the water supply (non-vector) Transmission can occur from immobile victims through waste disposal and contaminated bedding and clothes Each point on the following graph shows a different bacterial species Notice that the more likely they are to be spread by water, the more virulent they are Hospital infections are another interesting example of the relationship between virulence and mode of transmission Infections often spread from immobile patients through direct contact with nurses, doctors, other patients, etc… Hospital-acquired infections are often called “nosocomial” infections Hosts can be immobile (usually are), because the hospital staff themselves are the vectors!! Hospital strains can be deadly, especially if people forget to wash their hands.… E. coli and other intestinal diseases are hard to control in hospitals, where contact is frequent with patients, equipment Nurse will touch each baby in a hospital about 20 times a day The longer such infections last, the higher the mortality (virulence) Scientists frame their hypotheses as a statement about the world that can be tested If Ewald‟s evolutionary hypothesis about between-host versus within-host selection is true, it should make a testable prediction • • • • • • • • • • If Ewald‟s hypotheses are correct, then a pathogen spread by direct contact should tend to become more benign over time, or be replaced by a more benign species In the case of diphtheria, that is exactly what happened Ewald also hypothesizes that pathogens that are more durable can be much more virulent than those that are more mobile Ewald calls it “sit and wait” transmission It‟s the strategy evolved by anthrax… If you can survive long enough outside a host a healthy new one is bound to come along sooner or later… Anthrax can survive 40 years or more in the soil, infect a new host Virulence, therefore, results from an evolutionary trade-off It is to the parasite‟s advantage to convert as much of the host into parasite as possible, in as short a time as possible The trade-off is that doing so > Will make the host less effective in getting more resources for the parasites (host must feed itself etc..) > Will make the host less effective in transmitting the pathogen to new hosts (sick in bed at home, versus dragging yourself to work) Traditional medicine views virulence as maladaptive Ultimately of little or no benefit to either host or pathogen Traditional view would predict that all pathogens should become more benign over time Traditional medicine offers no solutions, continues to put all its efforts into seeking for a new generation of super drugs Darwinian medicine sees virulence as highly adaptive - if you consider the mode of transmission… Darwinian medicine suggests possible ways to gently nudge the evolution of pathogens into gentler channels! • • • • • • • • Ewald has shown in each of these situations, there is a statistically significant relationship between virulence and a particular hypothetical variable Virulence correlates significantly with > Vector-borne transmission > Waterborne transmission > Hospital attendant-borne transmission > Durability Virulence is not maladaptation, it is a most exquisite adaptation The entire diversity of human pathogens can be explained in terms of the evolution of their modes of transmission Malaria, typhus, yellow fever, sleeping sickness, the black death, are virulent because they are carried by animal vectors Cholera, typhoid fever, Shigella are virulent because they are waterborne Enterococci and nosocomial staph and strep infections are virulent because they are carried by hospital attendants Smallpox, tuberculosis, anthrax, and diphtheria are virulent because they are very durable outside the host What therapies or preventive measures can we extract from these hypotheses? For vector-borne diseases, make it more difficult for the vector to reach the host Techniques that isolate immobilized hosts from vectors should alter the competitive balance in favor of more benign strains Make houses and hospitals mosquito proof Money spent on developing an expensive replacement for quinine might be better spent on isolating victims from vectors This hypothesis may explain why the northern strain of malaria, Plasmodium vivax is milder than its more tropical cousins There are fewer hosts out and about and available to bite in more northern latitudes They are more likely to be safely tucked away in mosquito-proof schools ands offices Hosts more steadily available in the tropics P. vivax needs to maximize the potential “up and about” hosts provide to spread the disease make the most out of what you‟ve got… So more northern species of malaria have been selected for milder strains • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Uncontaminated drinking water is the only way to nudge waterborne diseases towards friendlier strains Milder variants relying on direct contact should be selected for, if clean water prevents more virulent (diarrhea) strains from spreading And that is precisely what happened when the industrialized nations cleaned up their water supply Even Shigella is not the killer it used to be As we cleaned up the water supply, Shigella dysenteriae could no longer spread quickly from one victim to the next The less virulent Shigella flexneri became the common species in industrialized nations In countries with very pure water, S. sonnei dominates, very benign Cholera is another ancient killer that can be tamed by manipulating its environment The classic strain of Vibrio cholerae is deadly, and readily spread in contaminated water supplies In Bangladesh, public water supply is a very bad, V. cholerae is the dominant strain In India, water supply was greatly improved in the „50‟s and „60‟s Milder “El Tor” strain replaced the virulent “classic” strain of V. cholerae Researchers in Bangladesh have shown that simple cloth filters can help tame cholera Putting cloth filters over water taps reduced the incidence of cholera by 50%! Getting doctors, nurses, aides to wash their hands more thoroughly would be a huge step toward blunting the edge of hospital-acquired infections Studies show there is still lots of room for improvement Thank you, Ignaz Semmelweis Durable pathogens, like tuberculosis, require a different strategy Enclosed spaces, with poor circulation of air, are ideal environments for this pathogen Better AC systems in old age homes, hospitals etc, to get it outside where UV will quickly kill it Each of these broad measures would significantly control a multitude of similar diseases, like dengue and cholera, and select for milder strains of hospital infections • • • • • • The way we alter the environment of the many microbes that feed on us will shape their future evolution The evolution of bacterial resistance to antibiotics finally brought this lesson home to the medical establishment An evolutionary perspective offers a valuable and useful perspective on the ultimate causes of virulence Conventional medicine has usually ignored this perspective on virulence, or dismissed it as a long-term symbiotic relationship The perspective of Darwinian medicine provides valuable insights into the evolution of virulence We need to continue to look for new ways in which an evolutionary perspective can give us the fighting edge, in our age-old struggle against diseases