cc  >> Nadia Dominguez: All right,  thank you for joining me  for Wednesday Nite at the Lab  at the UW-Madison Biotechnology  Center.  Tonight we welcome Dr. Lindsey  Moser, a postdoctoral  research associate in the  Department of Med Micro,  Medical Microbiology and  Immunology, here at UW-Madison.  Dr. Moser completed her  undergraduate degree in  biology, a BA in fact,  at the University of St. Thomas  in Minnesota, which is also  where I got my degree.  She then obtained a PhD  in microbiology from the  University of Wisconsin-Madison  under the direction  of Stacey Schultz-Cherry,  again in medical microbiology  and immunology.  And again we overlap as well, we  were both PhD students in the  Med Micro Department.  Lindsey's graduate work focused  on the cellular effects and  mechanisms of the  diarrhea-inducing pathogen the  astrovirus.  And following graduate school,  Lindsey did a brief stint as a  postdoctoral fellow in  Dr. Schultz-Cherry's laboratory  examining the cellular responses  to influenza virus before she  accepted another postdoc  position in Dr. Laura Knoll's  lab, again at UW-Madison.  She is currently working to  develop a model to study the  sexual forms of toxoplasma  gondii in the laboratory.  Please join me in welcoming  Dr. Lindsey Moser to Wednesday  Nite at the Lab.  [APPLAUSE]  >> Lindsey Moser: Thank you,  Nadia for that introduction. 

 And thank you everyone  for coming today.  So, how many people here have  actually heard of toxoplasma  gondii?  Wow, I'm very impressed, that's  impressive.  Probably the rest of you have  heard of the saying that  pregnant women shouldn't handle  cat litter because of possible  damage to the fetus.  And toxoplasma is the reason  behind that, and I'm hoping to  give you guys just a background  in toxoplasma, why we study it,  and why it's such a successful  parasite, and hopefully you'll  come to see that it's a pretty  unique and interesting pathogen.  So toxoplasma gondii was  originally discovered about a  hundred years ago.  And it was named toxoplasma  gondii for a couple of reasons.  The first name, toxoplasma,  refers to its shape.  So toxo means bow and plasma  means life.  And you is can see from this  schematic that the parasite is  actually kind of lunar-shaped or  bow-shaped, and gondii actually  is a misspelling of the African  rodent that it was found in.  And so you can see how sometimes  those mistakes stick. 

 Toxo is a eukaryotic pathogen.  So it's fairly complex.  It has a nucleus and various  intracellular organelles, many  of which are very unique and  very different from ours.  Toxoplasma is an obligate  intracellular parasite so that  means that it can only replicate  inside the cells of whatever  host it currently is living in.  I'm going to make the argument,  actually today, that toxoplasma  is one of the most successful  parasites on earth, and  hopefully I can convince you of  that.  In order to be considered a  successful parasite it has to  meet three requirements.  It has to have a broad host  range, a high infection rate and  a benign coexistence within its  host.  So we'll go through my arguments  for each of these starting with  the broad host range.  The host range of toxoplasma is  incredibly extensive and is  actually broken down into two  categories.  The hosts that are known as  intermediate hosts or definitive  hosts. 

 An intermediate host is a host  that only supports asexual  replication.  And for the case of toxoplasma,  this pretty much includes all  warm-blooded animals and birds.  In intermediate hosts, the  parasite lives and is infectious  but the host doesn't actually  shed infectious parasite.  In this hosts, the infection  produces two different types of  asexual parasites.  So typically, during infection,  the host, whatever kind of  animal it is, will usually take  something in that's contaminated  with the parasite, and this  moves into the stomach where the  parasite is released.  In the small intestine, the  first form of the parasite,  known as tachyzoites, arises.  So this happens within a couple  hours of ingestion.  And this first form,  tachyzoites, is the rapidly  replicating form.  So the replication happens  within a couple hours, actually.  It's very fast. 

 But this rapid form is actually  very susceptible to  environmental conditions  including desiccation or stomach  acid or heating.  So this form, actually, is not  orally infectious.  So if you just take some  tachyzoites in or meat  contaminated with tachyzoites,  it's really unlikely that you'll  actually develop a toxoplasma  infection.  However it is the first form  that arises after the parasites  have moved through the stomach.  They begin rapidly replicating  and they disseminate throughout  the body and they really go all  over.  You can pretty much find them in  all the tissues of the body.  Because this form is so rapidly  replicating, it's actually  responsible for the physical  damage that you see during  infection.  And this is because the parasite  actually invades host cells.  You can see that right down  here.  It invades the host cells and it  replicates to very high levels. 

 And you see that this cell is  actually just filled almost to  bursting with parasites.  And this happens, of course, all  over the body and then the cells  actually do burst and the  parasites continue to  disseminate throughout the body.  And you can imagine this would  really not be something that you  want, if this parasite is all  over and it's killing cells.  So that's why it's the  detrimental form of the  parasite.  Because it's this drastic  infection, it's replicating like  crazy, it's slicing cells, it  actually triggers a really  strong immune response from the  body, and the immune response is  amounted within eight to 12 days  after infection.  And you get clearance of this  form of the parasite and  transition to the second form of  the parasite, bradyzoites.  So bradyzoites are the slow  growing, asexual form.  And they're protected by a cyst  wall.  And you can see that in this  false colored electron  micrograph down here, you can  see all of these parasites and  around the edge there's this  wall, and that's indicated in  this arrow here as well.  And that pretty much sequesters  the parasites. 

 These cysts start off with maybe  a couple of parasites in them  and those parasites continue to  grow and this happens pretty  slowly, but those cysts can  accumulate hundreds of  parasites.  The cysts can be found  throughout the body.  So anywhere pretty much where  the tachyzoites disseminated to  when that immune response kicks  back up, that can transition to  bradyzoites and these cysts.  So you can have cysts all over,  but they're formed, primarily,  in the brain and major skeletal  muscles, although you can get  them in other places in like the  cardiac muscles and things like  that.  This is the chronic phase of  infection.  The tachyzoite stage is  considered the acute stage, and  the bradyzoite stage is the  chronic stage of infection.  And it's almost like a latent  infection.  Although, these parasites are  really slowly replicating and  releasing various proteins.  As far as we know, bradyzoites  are the reason that toxoplasma  infections are maintained for  life.  We don't have any way to clear  them. 

 Because they're covered with  this cyst wall, it's almost like  hiding from the immune response.  So our immune response doesn't  clear them, and as long as you  remain immunocompetent, these  cysts just stay there,  essentially.  And if you become  immunocompromised for whatever  reason, they can reactivate and  convert back to that fast  replicating form, the  tachyzoites, but generally they  just hang out in your body as a  cyst in your various muscles.  So these guys are fairly latent,  as I said, however they are  orally infectious so if you eat  meat contaminated with  bradyzoites you will get an  infection.  And they're particularly  infectious to the definitive  host.  A definitive host is a host  capable of supporting sexual  replication.  And it's called a definitive  host because essentially the  entire life cycle of the  parasite can occur in that  animal.  The asexual replication cycle  that I just told you about with  the tachyzoites and bradyzoites  can also occur but it can  progress to the sexual stages as  well.  For toxoplasma gondii, only  felids or animals of the cat  family, some of which are listed  here, are definitive hosts.  So obviously domestic cats are  the ones that are most relevant. 

 Most of us don't have common  interactions with lions or  jaguars, and if you do, your  life is much more exciting than  mine.  But any of these cats, when they  become infected with toxoplasma,  shed the infectious sexual form  of the parasite which is known  as an oocyst.  As I said, the oocysts are a  result of the sexual  replication, and they're shed in  cat feces.  And so this is the reason why  pregnant women are not supposed  to handle litter from the litter  box.  Cats can shed oocyst from seven  to 21 days after infection.  And a single cat can shed up to  500 million oocysts.  So they're shedding massive  amounts when I consider the  number of cats in the world, the  number of house cats and wild  cats, it's a pretty high  environmental burden.  These oocysts are incredibly  stable.  So if you just leave them on  your counter or in the litter  box they can last for up to two  weeks.  If they're buried in soil, like  cats general do, they can last  up to 18 months. 

 And these oocysts are incredibly  infectious for the intermediate  host.  They're less infectious for  other cats.  Cats are more susceptible to the  cysts that I was talking about,  but they're incredibly  infectious for an intermediate  host.  So when you consider the massive  number of oocysts that can be  shed even by a single cat and  the environmental stability of  them, you could see how even a  single cat could influence all  of the animals that it  encounters directly and  indirectly in its environment.  So I, hopefully, have convinced  you that they have, that  toxoplasma meets the first  requirement that it has a broad  host range and that it infects a  huge number of animals and this  is very prevalent.  So the next point is high  infection rates.  So I've told you that toxoplasma  has three infectious forms, the  two asexual forms, the  tachyzoites and the bradyzoites,  the fast replicating guys,  tachyzoites, and the slow  replicating insisted form, the  bradyzoites, and the sexual form  the oocyst.  So by having three infectious  forms, toxoplasma has really  maximized its opportunity for  transmission.  So it's really no surprise when  you consider the massive number  of people infected with  toxoplasma throughout the world.  It's estimated that up to a  third of the world's population  are infected with toxoplasma  gondii. 

 Although this prevalence varies  by country that you're looking  at and even within the country.  Throughout the world this ranges  from 11% to 85% of the  population being positive for  toxoplasma.  In the US, the numbers are  between 30% and 40% although  these numbers seem to be  decreasing as time goes on.  The number of people in a given  area that are infected with  toxoplasma gondii are influenced  by numerous factors.  First, the cultural practices of  that area.  So some places, for example,  France has an incredibly high  infectious rate.  Something like 85% to 90% of the  population is positive for  toxoplasma.  And this is likely related to  the fact that the French eat a  lot of undercooked meat which  increases the chances of getting  infected with those bradyzoite  cysts.  In some indigenous cultures, for  example in the Aborigines in  Australia, it's common  culturally to eat raw kangaroo  meat.  So, clearly, you're not cooking  those, you're not killing any of  those cysts, and in those  populations, the proportion of  individuals infected can  actually near 100%. 

 Another influencing factor is  the environment.  If you live in an environment  that is warm and moist, for  example in Latin America or in  Africa, you're much more likely  to be infected with toxoplasma  than if you live in a cool, dry  environment like Scandinavia.  And finally age.  So I told you that this  infection, once acquired, can't  be cleared.  It stays with you for life.  So clearly the older you get,  the more likely it is that you  are going to acquire an  infection.  So as the population gets older,  the prevalence rates increase.  So how is toxoplasma actually  spread?  The least common route actually  is just gestational infection.  This is fairly uncommon.  In the United States the risk of  this is only about one in every  thousand births. 

 And what happens is when a  pregnant woman becomes infected  for the first time, remember  when you become infected you get  that tachyzoite dissemination,  the rapid replication and the  movement throughout the whole  body, and that dissemination can  sometimes cross the placenta and  infect the fetus as well.  Sometimes this also occurs if  you get reactivation of a latent  infection during pregnancy.  But this usually only happens  when a pregnant woman becomes  severely immunocompromised.  By far the most common mode of  transmission is through the oral  route.  And this can happen in one of  two ways.  First, a potential host can eat  cyst-containing meat, perhaps  that's been undercooked or eaten  raw.  And this is actually the most  common perpetuation of the  asexual cycle, and it's shown  down here.  For example, a rat eating the  carcass of another animal that  was infected or vice versa.  And so you can get this  propagation asexually in that  way.  The other possibility is taking  in oocyst contaminated  substances. 

 So this could be something like  deer eating grass that's been  contaminated with cat feces or  drinking oocyst contaminated  water.  The relative contributions of  these two different types of  infections is unknown, but  obviously the fact that most  toxoplasma infections are caused  by an oral or an ingestion  really brings up an important  question and that is, how likely  is what we're putting in our  mouths to contain toxoplasma  gondii?  And this obviously has  epidemiological implications,  and so it's been pretty well  studied.  And it's been found that meat  actually breaks down into two  different categories.  Meat that's not likely to cause  toxoplasma infection and that  that's more likely to cause  toxoplasma infection.  So meat that is more likely to  cause toxoplasma infection  includes, surprisingly, beef.  So seroprevalence in cows is  actually pretty high, however,  for some reason that we don't  know yet, cows don't form very  many cysts in their meat.  So no toxoplasma infected beef  has ever been detected in a  commercial environment.  So this raises the question, are  they naturally resistant?  We don't really know.  But if you're eating beef,  you're probably pretty safe.  Chicken is also a pretty safe  meat. 

 And again it's not because  chickens can't be infected.  They are and it's fairly common.  However, the way that chicken is  treated before you purchase it  actually decreases the number of  cysts that are infectious.  So a lot of chicken is actually  injected with salt solutions,  and this decreases the  infectiousness of the cyst.  They also are often frozen and  then thawed and cooked at home,  and this freezing and thawing  and cooking really helps for  inactivate any potential cysts  that are there.  And horses, horse meat is not  very frequently consumed in the  United States but in other  countries it is.  And they seem to be in a similar  situation as cattle in which  they're seropositivity is pretty  high.  So a lot of horses have seen  toxoplasma, but they don't  maintain the cysts very well.  On the other end of the  spectrum, meat that's at a more  increased risk for transmitting  toxoplasma includes pork.  In the United States pork is the  most likely source of a  toxoplasma infection. 

 And cysts have been identified  in all commercially available  cuts of pork available.  Cysts are highly prevalent in  sheep, lamb and goats.  And actually there was a fairly  large outbreak associated with  goat milk, which doesn't happen  in a lot of animals but clearly  goats can excrete it in their  milk.  And finally, venison or  free-range wild meat is at an  increased risk.  And this makes sense once you  think about it.  So animals that are running  around are probably more likely  to come in contact with food  that's contaminated with oocysts  or to eat other wild animals  that contain cysts.  And actually black bears are one  of the most, have one of the  highest incidents of cysts in  their meat.  So they just have more  opportunity to become infected.  But there is an upside.  There is a way to prevent this  and that is to freeze your meat  solidly, thaw it and then cook  it thoroughly. 

 And the freezing and then  cooking inactivates most of  cysts.  So I've told you that it has a  very high infection rate.  Up to 33% of the world's  population and numerous animal  populations, very high  infection.  So the last one, benign  coexistence within host.  Toxoplasmosis or the group of  symptoms associated with the  toxoplasma infection, in most  people, most immunocompetent  people is generally  asymptomatic.  A subset of the population will  develop mild flu-like symptoms  which includes fever, malaise or  swollen lymph nodes.  But the majority of the people  will never know that they have  it until something happens to  trigger a reactivation.  In a small subset of healthy  individuals, you can get the  development of retinal carditis,  which is shown here.  And this is a toxo infection  essentially in your retina, and  you get lesions in your retina.  Symptomatic infections are much  more common in severely  immunocompromised people or in  children which were infected  during pregnancy. 

 Toxoplasma infection in the  immunocompromised can be a  result of a severe HIV infection  which has progressed to AIDS.  It can happen in people that are  clinically induced to be  immunosuppressed.  So this could include cancer  treatment or if you're being  immunosuppressed because you  received a transplant.  And in very rare circumstances  in people that have received  transfusions.  In these individuals in which  are severely immunocompromised,  you actually get reactivation of  those cysts.  So, again, the movement of that  slow growing stage to those  rapidly replicating and  disseminating stage.  And this leads to brain lesions,  which you can see in the picture  down here.  And this can result in speech  abnormalities or weakness on one  side of the body.  The most common symptom is  encephalitis, and this results  in headache, confusion and  fever.  And if it's not treated it can  actually lead to seizures or  coma. 

 And this used to be, actually, a  really severe problem in the HIV  population, particularly when  HIV was emerging.  But new drugs have, actually,  controlled that so it's fairly  well treated and well  recognized.  During gestationally acquired  toxoplasma infection, the risk  of infection actually increases  with the term of your pregnancy.  So if a woman becomes infected  with a toxoplasma within the  first trimester, the fetus is,  only about 10% to 15% of those  fetuses are likely to become  infected.  However, if the infection  originally occurs in the  pregnant woman while she's in  her third trimester, 60% to up  to 90% of those fetuses will be  infected.  As opposed to the risk of  infection, the degree of  severity of that infection  decreases with the age of the  fetus.  So a fetus that's in the first  trimester that becomes infected  it can be a very severe  infection.  It can result in spontaneous  abortion or stillbirth or  hydrocephalus, as shown here, or  retinal carditis, which I showed  you before.  In children infected in the  second trimester or beyond, the  symptoms are much more mild.  And you can get an ocular  infection, sometimes learning  disabilities or just a  generalized failure to thrive. 

 And often these infections are  not even noticed because  toxoplasma testing is not  mandatory in the US.  Luckily, we do have some  treatment options for  toxoplasma.  The current treatment of choice  is a combination treatment of  pyrimethamine and sulfadiazine,  and together these two drugs  block folic acid synthesis.  So essentially they inhibit  parasite replication by  preventing DNA or RNA synthesis.  A more mild drug, spiramycin, is  used to treat pregnant women.  But it's important to realize  that the current treatments only  work on that tachyzoite stage.  So that fast replicating stage  that arises real soon after  infection.  So you really have to catch this  quickly.  There are no known treatments  for cysts.  So once you get into that  chronic stage, you have it for  life. 

 There's no vaccine available to  date.  A vaccine for sheep has been  licensed in Europe, but no human  vaccines have been licensed yet.  So, as usual, our best bet is  prevention.  Interestingly for toxoplasma,  not all the symptoms are  physical.  Some behavioral changes have  been noticed and are kind of  interesting, I think.  A lot of research has been done  in both rodents and in humans.  So we'll start with some mice.  Mice infected can toxoplasma  have increased bouts of short  activity.  And this seems to be almost  senseless activity.  So they'll kind of spaz out and  not accomplish anything but be  moving around a lot. 

 Mice are very curious animals.  When you put them in a new  environment, generally they'll  explore the whole area, they'll  run into the center and just  look around, but in animals that  are infected with toxoplasma,  they don't explore the new  environments as much and they  have a decreased grooming time  which is related to their  exploration and comfort in new  environments.  In maze studies it's been shown  that mice infected with  toxoplasma have a decrease in  learning and memory.  In rats they also have this  decrease in activity.  And it's been documented that,  again, this, I'm sorry an  increase in activity.  The decrease in specific  movement and an increase in  nonspecific movement.  Rats, as opposed to mice, are  very afraid of new environments.  They're very cautious and if you  put them in a new environment it  takes them a while to start  exploring and then they stay  only along the edges.  They rarely move into the  center.  But mice that are infected with  toxoplasma go almost directly  into the center and have a  decreased fear in that it  doesn't take them long at all to  begin exploring once they're put  into new situations. 

 And this leads to an increased  ability, actually, to trap them.  Wild rats are very leery  of traps, and it's actually  pretty difficult to trap them.  But rats that have toxoplasma  infection are more likely to be  caught.  And this is actually what I  think is the most striking  effect, normal rats when they  smell cat urine will hit the  hills.  They do not want to be anywhere  that this potential predator is.  And that makes sense.  But mice that are infected with  toxoplasma are actually  attracted to the smell of cat  urine.  So it's very striking, this  effect, and it's very specific,  toxoplasma doesn't have any  effect on other fears, just the  cat urine attraction.  So it's pretty interesting.  But how does this actually  happen?  Well, I've told you that this  parasite lives in the brain so  it's perfectly poised to cause  different effects. 

 In rodents, the toxoplasma  actually lives in specifically  in the amygdala and the  hippocampus, which is right  here.  And when you examine mice or  rats that are infected with  toxo, you can see almost twice  as many cysts in those areas  compared to all the rest of the  brain.  So you can imagine that, I  didn't tell you this, but these  areas are important for learned  fears.  So you can imagine that if the  parasite is actually targeting  these areas via destruction, you   can get lesions in these areas  and through that way you can  diminish some of the fears that  they have.  An alternative way is secretion  of modulatory proteins.  So the cysts in the brain are  kind of latent but they're  actually secreting various  proteins.  If you just inject the parasite  into the brain, it has no  effect.  So it suggests that they're  doing something, these secreted  proteins.  And it's known that a couple of  these protein that is are  secreted interfere with the  neurotransmitters  norephinephrine and dopamine  which are important for  non-learned or intrinsic fears.  Why would it do this?  What possible benefit could it  have to the parasite?  Well, this brings up what people  in the community call the  manipulation hypothesis. 

 And the manipulation hypothesis  suggests that the parasite  actually alters the host's  behavior for its own benefits.  So in an intermediate host the  parasite can only undergo  asexual replication, and in  terms of the parasite, that's  kind of an immature stage to be  in.  From the parasite's point of  view it wants to undergo sexual  reproduction and be able to do  genetic exchange.  So, theoretically, if it can  manipulate the host to make it  more likely to be eaten by the  cat, that would be beneficial  because then the parasite could  undergo sexual replication.  And if you remember, all of  those changes that occur in  rodents actually increase the  likelihood of predation by cats.  So cats can't really see or at  least don't pay attention to  things that are stationary so  this increase in movement would  really draw attention to the  mice from the cats' point of  view.  This movement into the open  areas, particularly the  attraction to cat urine, all of  these make you much more likely  to be eaten by a cat if you're a  mouse.  So there's this idea that the  parasite is manipulating the  behavior so that it can get into  cats.  But what about in humans?  So various behavioral changes  have been noted in humans, as  well.  Some generalized changes such as  an increase in anxiety, a  decrease in reaction time and  concentration spans, and  actually these probably  translate into this: the  increase in motor accidents. 

 But they're, interestingly,  opposite gender specific  effects.  In men infected with toxoplasma  they become more jealous,  introspective, they have a  decrease in self-esteem and a  disregard for social rules so  they're more likely to rebel and  they have reduced motor  activities and reaction time.  And this is in contrast to woman  who become more corrigible, more  amicable, very outgoing, they  have an increase in self-esteem,  they become very socially  conscious, so they follow social  rules, and, seemingly, they seem  to have an increase in  intelligence as well.  There are also neurological  effects associated with  toxoplasma infection and these  can include schizophrenia,  depression and epilepsy.  These behavioral changes are  highly disputed in the field in  humans.  And this is mainly because it's  really difficult to establish a  cause and effect relationship.  So toxoplasma, people with  toxoplasma are more reckless.  Well, is that because toxoplasma  infection makes you reckless or  is it because you're a reckless  person so you're more likely to  eat uncooked meat and develop a  toxoplasma infection?  So it's hard, unless you  experimentally infect people,  which of course no one is going  to do, it's hard to establish  this cause and effect.  So there are a lot of studies  going both ways.  Also, it's disputed whether the  manipulation hypothesis holds up  in humans. 

 So you can make the argument  that evolutionarily when people  were hunters and gatherers if  we, for example, if you were a  male and you were less socially  inclined, you're more likely to  gather by yourself ask get eaten  by a jaguar or something.  Obviously that doesn't have a  whole lot of relevance these  days.  And so the other argument is  that toxoplasma, it seems pretty  clear that toxoplasma has  behavioral effects in other  animals, particularly in  rodents, and the argument is  that the parasite doesn't know  what intermediate host it's in.  And so it will exert these  behavioral effects in the hopes  that it will help with this  transmission, but if you're in  humans it's unlikely to do  anything but the parasite  doesn't care because it doesn't  realize it's in a human, it's  just trying to make you act  weird so it can be transmitted  to the definitive host.  So this last point, you're going  to have to make your own  decision about this, but the  infections are generally  asymptomatic even though there  are behavioral modifications  that people may say is not  benign.  But it seems to me that  toxoplasma meets all three  criteria.  And if you look at the whole  argument, it actually seems to  be one of the most successful  parasites on the face of the  earth.  And it's actually a pretty  interesting kind of bug.  And so we like to study it.  There are lots of reasons to  study it. 

 I was just going to go through a  couple of those.  The first one is probably the  most obvious one.  And that's the development of  new medications which is kind of  the underlying reason to study  most pathogens.  As I told you, current  medications only treat the  tachyzoite infections.  So it would be great if we could  figure out some sort of  medication that would lead to  clearance of the bradyzoites  because if we can clear the  cysts, we can eliminate the risk  of reactivation when people  become immunocompromised.  So we could remove that whole  list of potential dangers.  It also would decrease the  chances of fetuses becoming  infected when a pregnant woman  has a reactivation.  Our laboratory actually studies  differences in gene expression  in bradyzoites in the hopes of  finding some genetic indicators  of things to target for  medication or new medications  downstream.  Another reason is that studying  toxoplasma gives us insight into  genetically related pathogens.  So toxoplasma is related to a  variety of other pathogens. 

 The two listed here are the ones  that you're probably most likely  to have heard of.  Plasmodium falciparum is the  causative agent of malaria.  And there are 350 million to 500  million cases of malaria every  year, one million to three  million of which will lead to  death.  And there's an increase in  resistance to the current drugs  that are out there.  Cryptosporidium parvum, which is  shown right here, is a diarrheal  pathogen.  And this is mild in  immunocompetent people, but it's  actually very severe in  immunocompromised hosts and can  lead to death.  And it's very highly prevalent  so 20% to 60% of  immunocompromised individuals  have actually been infected with  it.  And there are a number of other  pathogens of medical and  veterinary importance that are  related to toxoplasma.  And so studying toxoplasma is  actually beneficial because it's  very experimentally manipulated.  It has strong genetics so we can  add things in, we can take  things out, it has a really  well-established animal model  and a relevant animal model. 

 We use mice and mice are  naturally occurring infected  hosts.  So we can make a lot of changes  and see what effect that has in  the host.  Toxoplasma has a really similar  life cycle to some of these  other pathogens, and so if we  can really under the toxoplasma  life cycle, maybe we can apply  that knowledge to other  pathogens.  And this could lead to the  development of common drug  targets.  And finally, vaccine  development, everybody wants it,  but you can use toxoplasma  gondii to actually over express  a protein from another related  pathogen, for example malaria  proteins in toxoplasma gondii  when they don't expression very  well in, say, E. coli.  You also can take an attenuated  form of T. gondii, for example  a parasite that can't form  cysts that only can undergo  that tachyzoite growth,  and you can express a  protein from another pathogen  and hope that the body mounts an  immune response to that other  protein as well.  And, hopefully, that will give  protection to the other  pathogen, too.  So it makes sense that studying  toxoplasma would give us insight  into related pathogens, but it  also can give us insight into  treatment for completely  unrelated pathogens like  influenza virus.  For example, recently a paper  has shown that some researchers  have made an influenza virus  that contains a surface protein  from toxoplasma, and this is  very immunostimulatory so they  use it to actually augment the  immune response to influenza.  So it's a way of increasing the  efficacy of influenza vaccines. 

 In our lab, actually, we've  shown that toxoplasma infection  protects against a lethal  infection with the highly  pathogenic avian influenza  viruses.  And I'll show you this data.  On the bottom here we have the  days post-infection.  And this is percent survival.  But mice that are infected with  influenza alone succumb to  infection by 12 days  post-infection.  If you received that influenza  infection with a toxoplasma  infection, it increases the  survival of the mice up to 80%.  And if you use a heat killed  toxoplasma, you lose that  protection.  So something about the parasite  is helping the mice live longer  and survive influenza  infections.  And we've actually seen similar  results when you prepare a  soluble protein extract of  toxoplasma infection.  And in mice we can actually  treat them later and still get  protection. 

 So it's exciting stuff and it  may lead to treatment of  influenza infections and perhaps  other unrelated pathogens,  as well.  And finally, and probably what I  think about most frequently, is  understanding the basic biology  of this parasite.  T. gondii still has a lot of  secrets but some of them that we  think about are things like what  makes up the parasites.  It's filled with these  organelles that are very unique.  We have no idea why they're  there or what they do.  We don't really have any idea  about what causes these asexual  forms to interconvert.  We know that there's immune  pressure that causes this  transition from the fast  replicating to the slow  replicating, but we don't know  what those are, and we don't  know the specific cues that  cause the slow replicating to go  back to the fast replicating.  And finally we don't know almost  anything about the sexual cycle.  I told you toxoplasma was  discovered almost a hundred  years ago, but the sexual cycle  wasn't discovered until almost  60 years later.  It's been really difficult to  study this, and it's almost  completely a black box. 

 We know, generally, the stages  that are involved but we don't  know how it goes through those  stages or anything that's going  on.  And so actually this is  something that we're working on  in our lab trying to develop a  model to be able to study those.  And there are lots, lots more  questions.  So hopefully I've given you guys  a bit of an insight into  toxoplasma.  It's a pretty complex organism,  but it's one of the most  successful parasites in the  world.  And it's very interesting.  It's fun to study.  We definitely learn something  new all the time, and it still  has a lot of secrets left to  unveil.  So that's pretty much the end of  my talk.  Thank you so much  for listening. 

 (applause)