Parasites: Leishmania

by Vincent Racaniello, PhD

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    00:01 Hello and welcome to Leishmania. This is one of a series of lectures where we'll look in depth at individual human parasites. After you hear this lecture, you will understand the lifecycle of leishmania and how it's transmitted to humans. You'll be familiar with the pathogenesis of the different forms of leishmaniasis and you'll understand how to prevent and treat leishmaniasis.

    00:33 We've been looking at a series of protozoan parasites and just to remind you, these are single celled eukaryotes of medical importance. We've looked at plasmodium, toxoplasma and now let's take a look at the leishmania. Here is a photograph of the blood form of leishmania, these are flagellated protozoan parasites, and leishmania come in a variety of species which are medically important. These species have different disease outcomes and have different global distributions. On the left, you have the distribution of a disease we call cutaneous leishmaniasis. This is a disease as you will see that mainly affects the skin and on the right is visceral leishmaniasis, where the parasite causes disease in your internal organs.

    01:33 Now you can see by just a glance at these two maps, that the distributions are overlapping but not identical. If we look at cutaneous first on the left, the darker countries have more cases, so you can see Central and South America have a number of cases, Africa, the north western part of the country and Egypt, Central Asia and that's cutaneous. Now on the right, if you look at visceral leishmaniasis, you see Central and South America as well, but now a different distribution on the eastern part of Africa and particularly high levels of cases in India. And these are reflection of in part that the animals that are infected and the vectors that transmit them. Now one of the species leishmania donovani causes visceral leishmaniasis. It's a very serious disease. There are about 300,000 cases a year and as you'll see on the map on the right, the lower right, many of them in South America, Eastern Africa and India. 300,000 cases per year and 20,000 deaths. That's leishmania donovani.

    02:49 Two strains, leishmania tropica and leishmania mexicana cause cutaneous leishmaniasis. This is again a lesion in the skin, a million cases in the past five years or so, that's the graph on the top and this is not a life-threatening disease, but the lesions can be disfiguring.

    03:11 If they occur on the face, you will have a lesion for the rest of your life and it will be seen of course. The fourth strain, leishmania brazilienesis causes muco-cutaneous leishmaniasis.

    03:28 These are lesions on the skin, but they also tend to travel to muco-cutaneous membranes, as we will see in a moment.

    03:36 Leishmania are obligate intracellular parasites, they need to get inside of cells in order to reproduce, although of course there are extracellular phases in which the parasites can move about the body. All of these leishmania infections are transmitted by the bite of a phlebotomous sandfly. Now you may know that the word phlebotomous means blood drawing and that's because these flies like to drink your blood and have it as a meal and in so doing, they transmit leishmaniasis. Leishmaniases are zoonotic infections, they are principally infections of animals of various kinds, the human becomes infected when the vector transmit the parasite from an animal to a human. Now some transmission does occur from human to human in areas where the parasite is endemic, but for the most part it's considered as a zoonotic infection.

    04:37 So here is the lifecycle of leishmania tropica and we see it has a mosquito cycle and a cycle in people. Now remember this parasite can be acquired largely from other animals, the horse, dog, animal, the mouse in the upper right there, but it can also be passed from human to human. And again the phlebotomous sandflies pick up the parasites, deliver them to humans and then they are passed around to other animals as well. Now on the lower right part of this slide, you can see a hand with a lesion on it, this is cutaneous leishmaniasis.

    05:15 Wherever the sandfly bites, that's where the lesion occurs, if it's on your face, you're left with a scarring lesion. So first here is a sandfly picking up the amastigote form of the leishmania, which it can do from many different mammals. On the top right, non-human animals and human animals as well. It takes a blood meal, it pulls up the parasites into its gut of course and there it will undergo a number of transformations and make its way back to the salivary gland so that it can be delivered through the saliva, to another host. The sandfly acquires the amastigote form, that's shown on the lower right, that form goes to the gut tract, it then transforms into flagellated promastigotes. These are freely swimming forms of the parasite, they replicate in the gut tract, make their way to the salivary gland, which you can see in the middle circle there and that's how they get delivered to a new host. Of course if they remained in the gut tract, they wouldn't get delivered to a new host because the contents of the gut are not injected when a biting animal, a biting fly bites a new host. So then, once the parasites have developed and moved to the salivary gland when the sandfly bites a new host, they can be injected into another animal. And as I said, very important observation, in endemic areas, that means areas where there are lots and lots of leishmania infections of humans, it is possible that the sandfly could bite an infected human, pick up leishmania parasites and deliver it to another human or perhaps even another animal that it's biting. This has to be an area of very high density infections, because as you can imagine, if there are just a few human infections, it is not likely that a sandfly bite is going to pick up the parasite from them, more likely picking it up from animals, which are more heavily infected. Once the sand fly injects the parasite, the flagellated form, into the skin, it leads to tissue destruction and the formation of a lesion at the site of the bite, which you can see on the hand shown here. And this is in part due to the fact that the flagellated forms are taken up by macrophages, they replicate in the macrophage, the macrophage is destroyed, it releases a variety of chemicals that then destroy the surrounding tissues. So this can be a lesion of an inch or so in diameter. On the hands it's of no consequence, but of course it often happens on the face, you can be bitten there, these are typically not treated and you have a scar for the rest of your life, unfortunately.

    08:06 So that's cutaneous leishmaniasis. Now leishmania braziliensis causes what's called muco-cutaneous leishmaniasis and the lifecycle is for the most part, very similar. A mosquito has picked up the amastigote form, the amastigote transforms into a flagellated form in the gut of the mosquito, it then moves to the salivary gland, the mosquito, sorry I am saying mosquito but I mean sandfly of course, the sandfly then bites another host, a lesion forms at the site of the bite through the same mechanisms that we've discussed. But for L. braziliensis, the infected macrophages, containing amastigotes, then leave the site of the initial bite and move to muco-cutaneous membranes, either in the oropharynx, or in the genital tract and those two are diagrammed at the bottom of the picture. There, additional tissue destruction occurs, forming the muco-cutaneous lesion and these can be quite horrific. Here's a photograph of a gentleman whose nose has been eroded away by this kind of replication and tissue destruction within macrophages. That's a muco-cutaneous lesion. This can occur in the mouth or in the genital areas, so you can imagine if you simply search for this condition online, you will find horrific photos of people who have amazingly degenerated muco-cutaneous lesions like this one.

    09:48 So that's leishmania braziliensis. Then we have visceral leishmaniasis, which is the more serious disease in terms of mortality. And this is called by leishmania donovani.

    10:02 And again the lifecycle is very similar. We have sandflies delivering flagellated forms to the tissues by a bite again, but these enter macrophages as before. You don't have a lesion forming at the bite site, but then these macrophages go to other tissues such as the liver and other internal tissues, they deliver the parasites to those organs where they replicate, induce cell death and damage the organs. That's why we call it visceral leishmaniasis. And once again the sandflies can pick up the flagellated forms, or the amistigote forms from the infected host, whether it’d be human or an animal and start the cycle all over again. So this is visceral leishmaniasis and again this is the one associated with substantial death. And the manifestation of visceral leishmaniasis, the disease is called Kala-azar, which means black fever, because the skin of the victims often turns a dark color at the height of infection. It has a 3 to 6 month incubation period, after the time that the sandfly delivers the parasite by a bite; it takes 3 to 6 months for the symptoms of Kala-azar to become evident. And after the black skin, or the black appearance of the skin that gives the disease its name, it is associated also with high fever and splenomegaly, swollen spleen, sometimes swollen liver and on this individual who has Kala-azar, you can see the spleen and liver have been outlined and you can see his belly is very distended as a consequence of this damage caused by replication of the parasite. Now this infection is also associated with anemia. You can also have congenital Kala-azar, if you are infected while pregnant; the parasites of course have the ability to go all over in the circulation. They can certainly enter the fetus and cause substantial damage there as well. So this is something you absolutely want to avoid, but in areas where the vector is present and the parasite is present, very difficult to avoid without good vector control.

    12:24 After this entire infection is over, there is an event called post Kala-azar dermal leishmaniasis.

    12:34 About 20% of the infections proceed to this point and these are associated with a most unusual presentation. Here we show a gentleman's face which is covered with these puffy swollen lesions and this can occur all over the body. It looks horrid if you look up the photographs online you can see, interestingly and amazingly, it all goes away after the parasite is gone.

    13:00 So this is some kind of dermal reaction that occurs well after the initial disease.

    13:06 So how do we diagnose Kala-azar or other leishmaniasis infections? One way that's very well documented is by polymerase chain reaction. We look for the DNA of the organism in samples from either a lesion or from blood, depending on the kind of disease and you can learn more about PCR in our earlier lectures on this topic. We can also examine histology material from biopsies, you can take biopsies of lesions for example and look in the microscope and see the typical forms of the parasite. There is also an antibody test, which is in ELISA-based test which can be done in the field. This is a very easy to carry out test, which involves a microscope slide that has been coated with a matrix and that matrix at one end contains antibodies that are looking for either proteins or proteins that can be used to detect antibodies.

    14:06 In this case we're asking, does the person have antibodies against leishmania? So what you do in practice is you take a little bit of blood, a drop of blood will do, and you drop it at one end of the slide. The blood then begins to move across the matrix on the slide and after a certain amount of incubation, 10 or 15 minutes, you can then read out the result as either negative or positive, or invalid. So embedded in this slide is a compound that will react with every blood sample, it is something known to be in all blood, infected or uninfected, so that gives you the line that tells you the assay worked and then the second slide there that's label positive, there's an additional line which would tell us in this case, that the sample contains antibodies to leishmania, because on that line on the side, we've embedded antigens against the parasite. So a very rapid inexpensive field applicable test for diagnosis.

    15:10 We can treat leishmania infections with a variety of compounds, one of them is sodium stibogluconate, shown here, and another is for amphotericin B. Unfortunately there is growing resistance to the use of some of these compounds, necessitating other approaches to treatment and one of those is cycloguanil pamoate. A number of vaccines are under development because leishmania, particularly the visceral form, is extensive and lethal. Many vaccines are being developed and eventually one of them or more will come to market. Under exploration are whole parasite vaccines, where we grow the parasite, they're inactivated, so they're no longer infectious, they can be injected. Individual proteins purified from the parasite or recombinant proteins made by recombinant DNA technology. Synthetic peptides, short amino acid sequences, 20 to 40 amino acids that are synthesized which can be injected to give rise to immunological protection and finally DNA vaccines, in which plasmids containing coding regions for various leishmania’s proteins can be injected into the host. Interestingly, another type of vaccine that's recently shown some promise in animal trials is a vaccine against sandfly salivary proteins. Apparently these are required for leishmania to be able to establish itself in the host, so if you can make antibodies against the fly proteins, this could be protective. So an interesting approach to dealing with this disease.

    16:50 How do we prevent leishmania infection? Well we can use insecticides to try and get rid of the sandfly, you could spray your entire home, you could just use bed nets and spray those as well and of course screens and curtains would help as well as that.

    17:08 So after listening to this lecture on the leishmanias, I hope that you will understand the lifecycle of leishmania and how it's transmitted to humans. I hope you'll be familiar with the pathogenesis of the different forms of leishmaniasis, and finally you should understand how to prevent and treat leishmaniasis.

    17:29 Thanks for listening and come back for more parasitology.

    About the Lecture

    The lecture Parasites: Leishmania by Vincent Racaniello, PhD is from the course Parasites. It contains the following chapters:

    • Parasites: Leishmania
    • Leishmaniasis
    • Leishmania Tropica
    • Leishmania brazilliensis
    • Leishmania donovani
    • Leishmaniasis - Diagnosis
    • Leishmaniasis - Treatment and Prevention
    • Leishmania: Learning Outcomes

    Author of lecture Parasites: Leishmania

     Vincent Racaniello, PhD

    Vincent Racaniello, PhD

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